Patent Application: US-5221098-A

Abstract:
a method of inhibiting parasitic activity is disclosed in which the biosynthesis , structure and / or function of the glycosyl phosphatidylinositol anchor of said parasite may be affected by incorporating into said gpi anchor selected analogs of myristic acid containing various heteroatoms , substituents and unsaturated bonds , including ester - containing analogs , ketocarbonyl - containing analogs , sulfur - containing analogs , double bond - and triple bond - containing analogs , aromatic moiety - containing analogs , nitrated analogs and halogenated analogs .

Description:
while the specification concludes with claims particularly pointing out and distinctly claiming the subject matter regarded as forming the present invention , it is believed that the invention will be better understood from the following detailed description taken in conjunction with the accompanying drawings in which briefly : fig1 is a bar graph which shows : assay of analog toxicity . the toxicity of 16 compounds , identified only by code number was assessed relative to 11 - oxatetradecanoic acid ( 0 - 11 ) and ethanol ( e ) controls . each bar shows the mean and standard deviation of quadruplicate assays . all compounds were tested at 10 μm . the 0 . 1 % ethanol in control e , corresponding to the final concentration of solvent present in other assays , had no effect on growth . brackets on the right of the graph indicate the efficacy group designations for this test . as described in methods herein below , 11 - oxatetradecanoic acid and ethanol controls are defined as the middle value of groups 1 and 3 , respectively . compound codes corresponded to the following structures : 21 , ch 3 --( ch 2 ) 3 -- co --( ch 2 ) 8 -- cooh ; 22 , ch 3 --( ch 2 ) 7 -- nh -- co --( ch 2 ) 3 -- cooh ; 23 , ch 3 --( ch 2 ) 5 -- cooh ; 24 , ethanol ; 25 , ch 3 --( ch 2 ) 4 -- co --( ch 2 ) 7 -- cooh ; 26 , ch 3 --( ch 2 ) 10 -- co -- ch 2 -- cooh ; 27 , ch 3 ( ch 2 ) 2 -- o --( ch 2 ) 9 cooh ( 11 - oxatetradecanoic acid ); 28 , ch 3 --( ch 2 ) 8 -- co --( ch 2 ) 3 -- cooh ; 29 , ch 3 --( ch 2 ) 6 -- nh -- co --( ch 2 ) 4 -- cooh ; 30 , ch 3 -- ch 2 -- co --( ch 2 ) 10 -- cooh ; 31 , ch 3 --( ch 2 ) 5 -- co --( ch 2 ) 6 -- cooh ; 32 , ch 3 --( ch 2 ) 9 -- co --( ch 2 ) 2 -- cooh ; 33 , ch 3 --( ch 2 ) 2 -- co --( ch 2 ) 9 -- cooh ; 34 , ch 3 --( ch 2 ) 8 -- nh -- co --( ch 2 ) 2 -- cooh ; 35 , ch 3 -- co --( ch 2 ) 11 -- cooh ; 36 , ch 3 --( ch 2 ) 7 -- co --( ch 2 ) 4 -- cooh . fig2 a and 2b show the chemical structures of the 20 myristate analogs most toxic to trypanosomes arranged into structural groups . most of the myristic acid analogs used in the method of the present invention are well - known compounds which have been previously described as useful antiviral agents . see , e . g ., bryant et al ., proc . natl . acad . sci . usa 86 , 8655 - 8659 ( 1989 ), and bryant et al ., ibid . 88 , 2055 - 2059 ( 1991 ). in their activity as antiparasitic agents in the present invention , these myristic analogs function in a different manner than as antiviral agents . in their antiviral activity , these compounds serve as substrates of myristoyl coa : protein n - myristoyltransferase , an enzyme which transfers myristate from myristoyl coa to the amino terminal glycine residue of eukaryotic cellular and viral protein . in their antiparasitic activity , these compounds are incorporated into the gpi anchor of the parasite . however , the antiparasitic activity may also be mediated , in part , by alteration of n - myristoylated proteins , or by some change in membrane structure caused by incorporation of the myristic acid analog into phospholipids . the syntheses of the myristic acid analogs used in the method of the present invention also are well - known . thus , the synthesis of sulfur - containing myristic acid analogs is described , e . g ., by heuckeroth et al ., j . biol . chem . 263 , 2127 - 2133 ( 1988 ), heuckeroth et al ., proc . natl . acad . sci . usa 85 , 8795 - 8799 ( 1988 ), and in u . s . pat . nos . 5 , 073 , 571 and 5 , 082 , 967 . double bond - and triple bond - containing myristic acid analogs are also described in said patents , in heuckeroth et al ., proc . natl . acad . sci . usa 85 , 8795 - 8799 ( 1988 ), and in rudnick et al ., proc . natl . acad . sci . usa 89 , 10507 - 10511 ( 1992 ). synthesis of azido - substituted myristic acid analogs is described in ep 480 , 901 . the preparation of many of these and other such myristic acid analogs containing oxygen , sulfur , double bond , triple bond and aromatic residues is described in kishore et al ., j . biol . chem . 266 , 8835 - 8855 ( 1991 ). synthesis of myristic acid analogs containing carbonyl groups , nitrogen heteroatoms and nitrogen heterocycles is described in devadas et al ., j . biol . chem . 267 , 7224 - 7239 ( 1992 ). the synthesis of still other such triple bond - and aromatic moiety - containing analogs of myristic acid is described by gokel et al ., israel j . chem . 32 , 127 - 133 ( 1992 ). examples 1 - 43 , below , illustrate the synthesis of 40 additional test compounds . in order to illustrate the invention in greater detail , a total of 247 different myristic acid analogs ( listed in table 2 , below ) were tested for toxicity to trypanosomes in culture in accordance with a state - of - the - art assay . for comparison the testing included five oxy - myristic acid analogs ( oxatetradecanoic acids ) described in u . s . pat . no . 5 , 151 , 445 , the disclosure of which is incorporated herein by reference . based on the test results , these 247 compounds were divided into three efficacy groups in which groups 2 and 3 consisted of the 60 active compounds whereas the 177 compounds of group 1 were inactive . of the active compounds , the 20 compounds in group 3 were the most active . although specific examples of the invention are thus illustrated herein , it will be understood that the invention is not limited to these specific examples or the details described therein . references to show the state - of - the - art are indicated in parentheses and appended at the end . materials -- fetal calf serum , hypoxanthine , mem &# 34 ; alpha &# 34 ; medium ( 320 - 2561 aj ), penicillin , pyruvate , streptomycin and thymidine were obtained from gibco / brl . other reagents , where not specified , were from sigma chemical co . synthesis of fatty acid analogs . the methods used for synthesizing 203 of the 247 fatty acids shown in table 1 are described in published reports ( rapaport and newman , 1947 ; kishore et al ., 1991 ; devadas et al ., 1992 ; gokel et al ., 1992 ; rudnick et al ., 1992 ; footnote 3 ). the methods used to synthesize 40 additional fatty acids included in the panel are described below . chemical analysis . melting points were measured on a laboratory devices mel - temp apparatus in open capillaries and are uncorrected . 1 h - nmr spectra were recorded on a hitachi perkin - elmer r - 600 high resolution nmr spectrometer and on a varian vxr 400 superconducting nmr . spectra were obtained in cdcl 3 and are reported in ppm ( δ ) downfield from internal me 4 si . ir spectra were recorded on a perkin - elmer model 298 or 599 infrared spectrophotometer . tlc analyses were performed on silica gel 60f - 254 plates ( thickness = 0 . 20 mm ; merck ). column chromatography was carried out with merck kieselgel 60 ( 70 - 230 mesh ). combustion analyses were conducted by atlantic microlab inc ., atlanta , ga . high resolution mass spectrometry was conducted at the southern california mass spectrometer facility , department of chemistry , university of california , riverside . the ci / nh 3 experiments did not typically show mh + ions so high resolution mass spectrometry was done on mnh 4 + ions . general procedure for wittig reaction . phosphonium bromide was treated with potassium t - butoxide in tetrahydrofuran ( thf ) under nitrogen with stirring for 30 min . the solution was cooled with ice . aldehyde in thf was added dropwise , and the mixture was stirred for 12 h . the mixture was poured into water ( 150 ml ), washed with et 2 o ( 50 ml ), acidified ( ph = 1 , 2n hcl ) and extracted ( hexanes , 4 × 50 ml ), dried over mgso 4 , and the solvent was removed in vacuo . chromatography ( silica gel , 1 : 1 hexanes - ethyl acetate ) and crystallization or kugelrohr distillation yielded the product . general procedure for hydrolysis reaction . a nitrile or ester containing compound , sodium hydroxide h 2 o ( 20 ml ), and etoh ( 20 ml ) were mixed and refluxed for 16 h . the mixture was cooled to room temperature , acidified ( ph = 1 , 2n hcl ), and extracted with ethyl acetate ( 4 × 50 ml ). the organic solution was washed with water ( 2 × 50 ml ), dried over mgso 4 and evaporated . the residue was crystallized or distilled to afford the product . general procedure for hydrogenation reaction an unsaturated compound , 5 % pd / c or pd / baso 4 and anhydrous etoh ( 50 ml ) were shaken under 15 psi h 2 for 1 . 0 - 4 . 0 h . the catalyst was filtered and washed with etoh ( 2 × 15 ml ). the solvent was evaporated in vacuo . the residue was crystallized or kugelrohr distilled to afford the product . this compound was synthesized from 7 - carboxyheptyltriphenylphosphonium bromide ( 9 . 71 g , 20 mmol ) and 2 - trans - hexenal ( 1 . 96 g , 20 mmol ) in 10 % hexamethylphosphoric triamide ( hmpa )- thf ( 100 ml ) by a wittig reaction . kugelrohr distillation yielded the product ( 1 . 97 g , 44 %) as a yellow oil ( bp 123 - 126 ° c ./ 0 . 01 torr ). ir : 3450 - 2500 , 1720 cm - 1 ; 1 h - nmr : 0 . 95 ( t , 3h ), 1 . 35 ( m , 8h ), 1 . 62 m , 2h ), 2 . 05 ( m , 4h ), 2 . 32 ( t , 2h ), 5 . 23 ( m , 1h ), 5 . 60 ( m , 1h ), 5 . 90 ( m , 1h ), 6 . 05 ( m , 1h ), 10 . 50 ( bs , 1h ). anal . calcd . for c 14 h 24 o 2 : c , 74 . 95 , h , 10 . 78 %; found : c , 75 . 01 , h , 10 . 80 %. this compound was synthesized from 5 - carboxypentyltriphenylphosphonium bromide ( 9 . 50 g , 20 mmol ) and 2 - trans - octenal ( 2 . 52 g , 20 mmol ) in 10 % hmpa - thf ( 100 ml ) by wittig reaction . kugelrohr distillation yielded the product ( 1 . 91 g , 43 %) as a pale yellow oil ( bp 122 - 125 ° c ./ 0 . 01 torr ). ir : 3500 - 2500 , 1730 cm - 1 ; 1 h - nmr : 0 . 95 ( t , 3h ), 1 . 40 ( m , 10h ), 2 . 30 ( m , 6h ), 6 . 00 ( m , 4h ), 11 . 30 ( bs , 1h ). anal . calcd . for c 14 h 24 o 2 : c , 74 . 95 , h , 10 . 78 %; found : c , 75 . 04 , h , 10 . 80 %. this compound was synthesized from 4 - carboxybutyltriphenylphosphonium bromide ( 8 . 87 g , 20 mmol ) and 2 - trans - nonenal ( 2 . 80 g , 20 mmol ) in 10 % hmpa - thf ( 100 ml ) by a wittig reaction . kugelrohr distillation afforded the product ( 1 . 96 g , 44 %) as a pale yellow oil ( bp 116 - 119 ° c ./ 0 . 01 torr ). ir : 3500 - 2500 , 1730 cm - 1 ; 1 h - nmr : 0 . 90 ( t , 3h ), 1 . 35 ( m , 10h ), 2 . 30 ( m , 6h ), 5 . 90 ( m , 4h ), 10 . 05 ( bs , 1h ). anal . calcd . for c 14 h 24 o 2 : c , 74 . 95 , h , 10 . 78 %; found : c , 74 . 87 , h , 10 . 79 %. phenol ( 1 . 88 g , 20 mmol ) was mixed with naoh ( 0 . 80 g , 20 mmol ) in etoh ( 50 ml ). 8 - bromooctanoic acid ( 2 . 23 g , 10 mmol ) was then added to the mixture and refluxed for 12 h . after cooling to room temperature , water ( 100 ml ) was added and the mixture was acidified with 2n hcl ( ph = 2 ). the solid was filtered and washed with water ( 2 × 50 ml ), and recrystallized from hexane - ethyl acetate ( 5 : 1 ) to give the product as white brick - like crystals ( 1 . 79 g , 76 %), mp 67 - 68 ° c . ; 1 h - nmr : 1 . 42 ( m , 6h ), 1 . 65 ( m , 2h ), 1 . 80 ( m , 2h ), 2 . 37 ( t , 2h ), 3 . 97 ( t , 2h ), 6 . 93 ( m , 3h ), 7 . 30 ( t , 2h ), 10 . 05 ( bs , 1h ). anal . calcd . for c 14 h 20 o 3 : c , 71 . 16 , h , 8 . 53 %; found : c , 71 . 09 , h , 8 . 54 %. this compound was synthesized from 6 - cyanohexyltriphenylphosphonium bromide ( 9 . 05 g , 20 mmol ) and p - anisaldehyde ( 2 . 72 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation afforded the products ( 3 . 26 g , 71 %) as a colorless liquid ( bp : 143 - 146 ° c ./ 0 . 05 torr ). ir : 2285 cm - 1 ; 1 h - nmr : 1 . 50 ( m , 6h ), 2 . 30 ( m , 4h ), 3 . 80 ( s , 3h ), 5 . 50 ( m , 1h ), 6 . 30 ( d , 1h ), 7 . 05 ( q , 4h ). this compound was synthesized from 8 -( p - methoxyphenyl )- 7 - octennitrile ( 3 . 34 g , 15 mmol ) by a hydrolysis reaction . crystallization ( hexanes - ethyl acetate ) yielded the product ( 3 . 29 g , 88 %) as white crystals ( mp 42 - 43 ° c .). ir : 3400 - 2500 , 1730 cm - 1 ; 1 h - nmr : 1 . 50 ( m , 6h ), 2 . 35 ( m , 4h ), 3 . 82 ( s , 3h ), 5 . 55 ( m , 1h ), 6 . 35 ( d , 1h ), 7 . 05 ( q , 4h ), 11 . 20 ( bs , 1h ). anal . calcd . for c 15 h 20 o 2 : c , 72 . 55 , h , 8 , 12 % found : c , 72 . 41 , h , 8 . 07 %, z : e = 67 : 33 . this compound was synthesized from 8 -( p - methoxyphenyl )- 7 - octenoic acid ( 1 . 24 g , 5 mmol ) and pd / baso 4 ( 125 mg ) by hydrogenation . crystallization ( petroleum ether ) afforded the product ( 1 . 20 g , 96 %) as white crystals ( mp 42 - 43 ° c .). ir : 3400 - 2500 , 1705 cm - 1 ; 1 h - nmr : 1 . 40 ( m , 10h ), 2 . 40 ( m , 4h ), 3 . 80 ( s , 3h ), 6 . 95 ( q , 4h ), 10 . 10 ( bs , 1h ). anal . calcd . for c 15 h 2 o 2 : c , 71 . 97 , h , 8 . 86 %; found : c , 72 . 07 , h , 8 . 88 %. this compound was synthesized from 5 - carboxypentyltriphenylphosphonium bromide ( 9 . 50 g , 20 mmol ) and p - ethoxybenzaldehyde ( 3 . 00 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . crystallization ( hexanes - ethyl acetate ) afforded the product ( 3 . 18 g , 64 %) as white crystals ( mp 62 - 63 ° c . ), ir : 3450 - 2500 , 1720 cm - 1 ; 1 h - nmr : 1 . 40 ( t , 3h ), 1 . 50 ( m , 2h ), 1 . 70 ( m , 2h ), 2 . 38 ( m , 4h ), 4 . 00 ( q , 2h ), 5 . 72 + 6 . 05 ( m , 1h ), 6 . 32 ( t , 1h ), 7 . 05 ( q , 4h ), 10 . 10 ( bs , 1h ). anal . calcd . for c 15 h 20 o 3 : c , 72 . 55 , h , 8 . 12 % found : c , 72 . 53 , h , 8 . 15 %. z : e = 45 : 55 . this compound was synthesized from 7 -( p - ethoxyphenyl )- 6 - heptenoic acid ( 1 . 24 g , 5 mmol ) and pd / c ( 125 mg ) by a hydrogenation reaction . crystallization ( petroleum ether ) afforded the product ( 1 . 21 g , 97 %) as white crystals ( mp 65 - 66 ° c .). ir : 3400 - 2500 , 1715 cm - 1 ; 1 h - nmr : 1 . 32 ( m , 7h ), 1 . 55 ( m , 5h ), 2 . 30 ( t , 2h ), 2 . 50 ( t , 2h ), 3 . 95 ( q , 2h ), 6 . 90 ( q , 2h ), 10 . 20 ( bs , 1h ). anal . calcd . for c 15 h 22 o 3 : c , 71 . 97 , h , 8 . 86 %; found : c , 71 . 91 , h , 8 . 87 %. this compound was synthesized from 4 - carboxybutyltriphenylphosphonium bromide ( 8 . 87 g , 20 mmol ) and p - propoxybenzaldehyde ( 3 . 28 g , 20 mmol , synthesized from p - hydroxybenzaldehyde and 1 - iodopropane ) in thf ( 100 ml ) by a wittig reaction . crystallization ( petroleum ether ) afforded the product ( 3 . 75 g , 76 %) as white crystals ( mp , 49 - 50 ° c .). ir : 3400 - 2500 , 1725 cm - 1 ; 1 h - nmr : 1 . 00 ( t , 3h ), 1 . 75 ( m , 4h ), 2 . 35 ( m , 4h ), 3 . 90 ( t , 2h ), 5 . 55 ( m , 1h ), 6 . 35 ( m , 1h ), 7 . 00 ( q , 4h ), 11 . 30 ( bs , 1h ). anal . calcd . for c 15 h 20 o 3 : c , 72 . 55 , h , 8 . 12 %; found : c , 72 . 45 , h , 8 . 13 %. z : e = 35 : 65 . this compound was synthesized from 6 -( p - propoxyphenyl )- 5 - hexenoic acid ( 1 . 49 g , 6 mmol ) and pd / baso 4 ( 150 mg ) by a hydrogenation reaction . crystallization ( petroleum ether ) yielded the product ( 1 . 38 g , 92 %) as white crystals ( mp 42 - 43 ° c . ), ir : 3400 - 2500 , 1715 cm - 1 ; 1 h - nmr : 1 . 00 ( t , 3h ), 1 . 55 ( m , 8h ), 2 . 40 ( m , 4h ), 3 . 90 ( t , 2h ), 6 . 95 ( q , 4h ), 7 . 90 ( bs , 1h ). anal . calcd . for c 15 h 22 o 3 : c , 71 . 97 , h , 8 . 86 %; found : c , 72 . 04 , h , 8 . 88 %. a . 7 - phenoxyheptyl bromide , phenol ( 3 . 10 g , 33 mmol ), 1 , 7 - dibromoheptane ( 7 . 74 g , 30 mmol ) and naoh ( 1 . 34 g , 33 mmol ) were refluxed in etoh ( 40 ml ) for 30 h . after cooling to room temperature , water ( 150 ml ) was added and the mixture was extracted with ethyl acetate ( 4 × 50 ml ). the organic phase was washed with water ( 50 ml ) and brine ( 50 ml ), and the mixture was dried over na 2 so 4 . after evaporation of solvent , the residue was purified by kugelrohr distillation to give 7 - phenoxyheptyl bromide ( 2 . 46 g , 30 %), bp 126 - 130 ° c ./ 0 . 10 torr , 1 h - nmr : 1 . 2 - 1 . 9 ( m , 10h ), 3 . 36 ( t , 2h ), 3 . 91 ( t , 2h ), 6 . 7 - 7 . 2 ( m , 5h ). b . ethyl 2 - ethoxycarbonyl - 9 - phenoxynonanoate . sodium ( 0 . 22 g , 9 . 6 mmol ) was dissolved in etoh ( 20 ml ). diethyl malonate ( 1 . 53 g , 9 . 6 mmol ) in etoh ( 5 ml ) and 7 - phenoxyheptyl bromide ( 2 . 36 g , 8 . 7 mmol ) in etoh ( 5 ml ) were subsequently added at room temperature . the reaction mixture was refluxed for 8 h . after evaporation of the solvent , the residue was taken up in ethyl acetate ( 150 ml ). the organic phase was washed with water ( 2 × 50 ml ), and brine ( 50 ml ), and dried over na 2 so 4 . the crude product was purified by kugelrohr distillation to give ethyl 2 - ethoxycarbonyl - 9 - phenoxynonanoate ( 1 . 92 g , 63 %), bp 150 - 154 ° c ./ 0 . 1 torr , 1 h - nmr : 1 . 24 ( t , 6h ), 1 . 1 - 1 . 8 ( in , 12h ), 3 . 30 ( t , 1h ), 3 . 91 ( t , 2h ), 4 . 18 ( q , 4h ), 6 . 7 - 7 . 2 ( m , 5h ). c . 9 - phenoxynonanoic acid . a solution of ethyl 2 - ethoxycarbonyl - 9 - phenoxynonanoate ( 1 . 84 g , 5 . 3 mmol ) in 20 % naoh ( 20 ml ) was refluxed for 10 h . the solution was acidified with hcl ( ph = 2 ) and extracted with ethyl acetate ( 3 × 50 ml ). the organic phase was - washed with water ( 2 × 30 ml ), and brine ( 30 ml ), and dried over na 2 so 4 . after removal of the solvent in vacuo , the residue was heated on an oil bath at 180 - 200 ° c . for 10 min . the crude product was distilled ( kugelrohr ) followed by crystallization ( hexane ) to give the product ( 1 . 14 g , 85 %), mp 66 . 5 - 67 . 5 ° c . ( lit . 3 68 - 69 ° c .). ir : 3450 - 2550 , 1720 cm - 1 ; 1 h - nmr : 1 . 26 - 1 . 39 ( m , 8h ), 1 . 61 ( q , 2h ), 1 . 75 ( q , 2h ), 2 . 34 ( t , 2h ), 3 . 93 ( t , 2h ), 6 . 83 - 6 . 96 ( m , 3h ), 7 . 28 ( t , 2h ), 10 . 8 ( bs , 1h ). a . 7 - phenylthioheptyl bromide was prepared from thiophenol ( 4 . 40 g , 40 mmol ) and 1 , 7 - dibromoheptane ( 10 . 32 g , 40 mmol ) as described above for 7 - phenoxyheptyl bromide . yield : 46 % bp ; 132 - 136 ° c ./ 0 . 05 torr ; 1h - nmr : 1 . 30 - 1 . 85 ( m , 10h ), 2 . 90 ( t , 2h ), 3 . 35 ( t , 2h ), 7 . 25 ( s , 5h )). b . ethyl 2 - ethoxycarbonyl - 9 - phenylthiononanoate was prepared from 7 - phenylthioheptyl bromide ( 4 . 31 g , 15 mmol ) and diethyl malonate ( 3 . 20 g , 20 mmol ) according to the procedure given above . yield : 68 %, bp : 174 - 178 ° c ./ 0 . 05 torr ; 1 h - nmr : 1 . 15 - 1 . 90 ( m , 18h ), 2 . 90 ( t , 2h ), 3 . 30 ( t , 1h ), 4 . 20 ( q , 4h ), 7 . 25 ( s , 5h ). c . 9 - phenylthiononanoic acid was obtained from ethyl 2 - ethoxycarbonyl - 9 - phenylthiononanoate ( 3 . 66 g , 10 mmol ) by basic hydrolysis as described above . yield : 82 %, mp 67 - 68 ° c . ; ir : 3450 - 2550 , 1695 cm - 1 ; 1 h - nmr : 1 . 20 - 1 . 80 ( m , 12h ), 2 . 35 ( t , 2h ), 2 . 85 ( t , 2h ), 7 . 20 ( s , 5h ), 10 . 50 ( bs , 1h ). anal . calcd . for c 15 h 22 o 2 s : c , 67 . 63 ; h , 8 . 32 ; s , 12 . 03 %. found : c , 67 . 54 ; h , 8 . 31 ; s , 12 . 09 %. a . 6 - benzyloxyhexyl bromide was prepared from benzyl alcohol ( 4 . 75 g , 44 mmol ) and 1 , 6 - dibromohexane ( 9 . 76 g , 40 mmol ) using the general procedure given above . yield : 36 %, bp 100 - 105 ° c ./ torr : 1 h - nmr : 1 . 2 - 1 . 9 ( m , 8h ), 3 . 37 ( t , 4h ), 4 . 46 ( s , 2h ), 7 . 28 ( m , 5h ). b . ethyl 2 - ethoxycarbonyl - 8 - benzyloxyoctanoate was prepared from 6 - benzyloxyhexyl bromide ( 3 . 52 g , 13 mmol ) and diethyl malonate ( 2 . 29 g , 14 mmol ) according to the general procedure given above . yield 60 %, bp 152 - 158 ° c ./ 0 . 15 torr . 1 h - nmr : 1 . 24 ( t , 6h ), 1 . 2 - 1 . 9 ( m , 10h ), 3 . 43 ( t , 2h ), 4 . 18 ( q , 4h ), 4 . 45 ( s , 2h ), 7 . 27 ( m , 5h ). c . 8 - benzyloxyoctanoic acid was prepared from ethyl 2 - ethoxycarbonyl - 8 - benzyloxyoctanoate ( 2 . 6 g , 7 . 4 mmol ) by basic hydrolysis as described above . yield : 83 %, bp 158 - 162 ° c ./ 0 . 15 torr ; ir : 3450 - 2550 , 1710 cm - 1 ; 1 h - nmr : 1 . 24 - 1 . 43 ( m , 6h ), 1 . 54 - 1 . 69 ( m , 4h ), 2 . 31 ( t , 2h ), 3 . 46 ( t , 2h ), 4 . 51 ( s , 2h ), 7 . 23 - 7 . 38 ( m , 5h ), 9 . 55 ( bs , 1h ). anal . calcd . for c 15 h 22 o 3 : c , 71 . 97 ; h , 8 . 86 %. found : c , 71 . 83 ; h , 8 . 90 %. a . ethyl 8 - benzylthiooctanoate . nah ( 0 . 63 g , 16 mmol ) was washed with hexane and then suspended in dry thf ( 60 ml ). benzylmercaptan ( 1 . 86 g , 15 mmol ) in thf ( 20 ml ) was added and the mixture stirred for 30 min at room temperature . ethyl 8 - iodooctanoate ( 4 . 47 g , 15 mmol ) in thf ( 20 ml ) was added and the mixture was refluxed for 12 h . after evaporation of the solvent , the residue was dissolved in ethyl acetate ( 150 ml ). the organic phase was washed with water ( 2 × 50 ml ), and brine ( 50 ml ) and dried over na 2 so 4 . the crude product was purified by column chromatography on silica gel with ethyl acetate : hexane ( 1 : 5 ) and subsequent kugelrohr distillation to give ethyl 8 - benzylthiooctanoate ( 3 . 7 g , 84 %), bp 134 - 138 ° c ./ 0 . 15 torr . 1 h - nmr : 1 . 21 ( t , 3h ), 1 . 2 - 1 . 8 ( m , 10h ), 2 . 27 ( t , 4h ), 3 . 68 ( s , 2h ), 4 . 09 ( q , 2h ), 7 . 24 ( m , 5h ). b . 8 - benzylthiooctanoic acid . a solution of ethyl 8 - benzylthiooctanoate ( 2 . 94 g , 10 mmol ) and 1m naoh ( 60 ml , 60 mmol ) in meoh ( 30 ml ) was heated at 70 ° c . for 6 h . the reaction mixture was acidified with hcl ( ph = 1 ) and extracted with ethyl acetate ( 150 ml ). the organic phase was washed with water ( 2 × 50 ml ), and brine ( 50 ml ), and dried over na 2 so 4 . the crude product was purified by crystallization from hexane to afford the product ( 2 . 45 g , 92 %), mp 37 - 37 . 5 ° c . ; ir : 3400 - 2500 , 1700 cm - 1 ; 1 h - nmr : 1 . 18 - 1 . 43 ( m , 6h ), 1 . 52 ( q , 2h ), 1 . 61 ( q , 2h ), 2 . 33 ( t , 2h ), 2 . 39 ( t , 2h ), 3 . 69 ( s , 2h ), 7 . 12 - 7 . 38 ( m , 5h ), 9 . 45 ( bs , 1h ). anal . calcd . for c 15 h 22 so 2 : c , 67 . 63 , h , 8 . 32 %; found : c , 67 . 74 , h , 8 . 35 %. this compound was synthesized from 6 - cyanohexyltriphenylphosphonium bromide ( 9 . 05 g , 20 mmol ) and p - propylbenzaldehyde ( 2 . 96 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation afforded the product ( 3 . 25 g , 67 %) as a colorless liquid ( bp 144 - 148 ° c ./ 0 . 05 torr ). ir 2290 cm - 1 ; 1 h - nmr : 0 . 95 ( t , 3h ), 1 . 55 ( m , 8h ), 2 . 40 ( m , 6h ), 5 . 60 ( in , 1h ), 6 . 40 ( d , 1h ), 7 . 10 ( s , 4h ). this compound was synthesized from 8 -( p - propylphenyl )- 7 - octenenitrile ( 2 . 41 g , 10 mmol ) by a hydrolysis reaction . kugelrohr distillation afforded the product ( 2 . 36 g , 90 %) as a colorless oil ( bp 148 - 152 ° c ./ 0 . 05 torr ). ir : 3400 - 2500 , 1720 cm - 1 ; 1 h - nmr : 0 . 95 ( t , 3h ), 1 . 45 ( m , 8h ), 2 . 45 ( m , 6h ), 5 . 65 ( m , 1h ), 6 . 40 ( d , 1h ), 7 . 15 ( s , 4h ), 11 . 30 ( bs , 1h ). anal . calcd . for c 17 h 24 o 2 : c , 78 . 42 , h , 9 . 29 %; found : c , 78 . 43 , h , 9 . 30 %. z : e = 88 : 12 . this compound was synthesized from 8 -( p - propylphenyl )- 7 - octenoic acid ( 1 . 30 g , 5 mmol ) and pd / baso 4 ( 130 mg ) by a hydrogenation reaction . crystallization ( petroleum ether ) afforded the product ( 1 . 25 g , 95 %) as white crystals ( mp 42 - 43 ° c .). ir : 3400 - 2500 , 1705 cm - 1 ; 1 h - nmr : 0 . 95 ( t , 3h ), 1 . 45 ( m , 12h ), 2 . 50 ( m , 6h ), 7 . 05 ( s , 4h ), 11 . 40 ( bs , 1h ). anal . calcd . for c 17 h 26 o 2 : c , 77 . 82 , h , 9 . 99 %; found : c , 77 . 75 , h , 10 . 04 %. this compound was synthesized from 5 - carboxypentyltriphenylphosphonium bromide ( 9 . 50 g , 20 mmol ) and p - butylbenzaldehyde ( 3 . 24 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation yielded the product ( 2 . 67 g , 51 %) as a colorless oil ( bp 154 - 157 ° c ./ 0 . 05 torr ). ir : 3400 - 2500 , 1720 cm - 1 , 1 h - nmr : 0 . 92 ( t , 3h ), 1 . 50 ( m , 8h ), 2 . 30 ( m , 4h ), 2 . 58 ( m , 2h ), 5 . 58 + 6 . 15 ( m , 1h ), 6 . 38 ( t , 1h ), 7 . 18 ( m , 4h ), 10 . 30 ( bs , 1h ). anal . calcd . for c 17 h 24 o 2 : c , 78 . 42 , h , 9 . 29 %; found : c , 78 . 38 , h . 9 . 29 %. z : e = 62 : 38 . this compound was synthesized from 7 -( p - butylphenyl )- 6 - heptenoic acid ( 1 . 30 g , 5 mmol ) by a hydrogenation reaction using pd / c ( 130 mg ). crystallization ( petroleum ether ) afforded the product ( 1 . 19 g , 97 %) as white crystals ( mp 32 - 33 ° c .). ir : 3400 - 2500 , 1718 cm - 1 ; 1 h - nmr : 0 . 92 ( t , 3h ), 1 . 35 ( m , 6h ), 1 . 60 ( m , 6h ), 2 . 32 ( t , 2h ), 2 . 55 ( m , 4h ), 7 . 02 ( s , 4h ), 9 . 70 ( bs , 1h ). anal . calcd . for c 17 h 26 o 2 : c , 77 . 82 , h , 9 . 99 %; found : c , 77 . 73 , h , 10 . 01 %. this compound was synthesized from p - pentylbenzaldehyde ( 3 . 52 g , 20 mmol , prepared from p - pentylbenzoyl chloride and lithium tri ( t - butoxy ) aluminum hydride ) and 4 - carboxybutyltriphenylphosphonium bromide ( 8 . 86 g , 2 , mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation ( bp 147 - 151 ° c ./ 0 . 05 torr ) afforded the product ( 2 . 49 g , 48 %). ir : 3400 - 2500 , 1725 cm - 1 ; 1 h - nmr : 0 . 90 ( t , 3h ), 1 . 28 ( m , 6h ), 1 . 82 ( m , 2h ), 1 . 37 ( m , 4h ), 2 . 57 ( t , 2h ), 5 . 55 + 6 . 10 ( m , 1h ), 6 . 38 ( m , 1h ), 7 . 10 ( m , 4h ), 10 . 50 ( bs , 1h ). anal . calcd . for c 17 h 24 o 2 : c , 78 . 42 , h , 9 . 29 %; found : c , 78 . 22 , h , 9 . 27 %. z : e = 35 : 65 . this compound was synthesized from 6 -( p - pentylphenyl )- 5 - hexenoic acid ( 1 . 30 g , 5 mmol ) by hydrogenation reaction using pd / c ( 130 mg ). crystallization ( petroleum ether ) afforded the product ( 1 . 13 g , 87 %) as white crystals ( mp 29 - 30 ° c . ), ir : 3400 - 2500 , 1730 cm - 1 ; 1 h - nmr : 0 . 89 ( t , 3h ), 1 . 32 ( m , 6h ), 1 . 60 ( m , 6h ), 2 . 35 ( t , 2h ), 2 . 58 ( m , 4h ), 7 . 07 ( s , 1h ), 10 . 30 ( bs , 1h ). anal . calcd . for c 17 h 26 o 2 : c , 77 . 82 , h , 9 . 99 %; found : c , 77 . 56 , h , 9 . 90 %. this compound was synthesized from p - propoxybenzaldehyde ( 3 . 26 g , 20 mmol , prepared from 1 - bromopropane and 4 - hydroxybenzaldehyde ) and 5 - carboxypentyltriphenylphosphonium bromide ( 9 . 50 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . crystallization ( petroleum ether ) afforded the product ( 3 . 15 g , 60 %) as white crystals ( mp : 52 - 53 ° c .). ir : 3450 - 2500 , 1730 cm - 1 ; 1 h - nmr : 1 . 00 ( t , 3h ), 1 . 48 ( m , 2h ), 1 . 67 ( m , 2h ), 1 . 82 ( m , 2h ), 2 . 35 ( m , 4h ), 3 . 92 ( t , 2h ), 5 . 72 + 6 . 05 ( m , 1h ), 6 . 35 ( d , 1h ), 7 . 05 ( q , 4h ), 10 . 40 ( bs , 1h ). anal . calcd . for c 16 h 22 o 3 : c , 73 . 25 , h , 8 . 45 %. found : c , 73 . 15 , h , 8 . 45 %. z : e = 30 : 70 . this compound was synthesized from 7 -( p - propoxyphenyl )- 6 - heptenoic acid ( 1 . 31 g , 5 mmol ) by hydrogenation reaction using pd / c ( 130 mg ). crystallization ( petroleum ether ) afforded the product ( 1 . 23 g , 93 %) as white crystals ( mp : 49 - 50 ° c .). ir : 3450 - 2550 , 1725 cm - 1 ; 1 h - nmr : 1 . 00 ( t , 3h ), 1 . 37 ( m , 4h ), 1 . 60 ( m , 4h ), 1 . 79 ( m , 2h ), 2 . 36 ( t , 2h ), 2 . 53 ( t , 2h ), 3 . 87 ( t , 2h ), 6 . 95 ( q , 4h ), 9 . 80 ( bs , 1h ). anal . calcd . for c 16 h 24 o 3 : c , 72 . 69 , h , 9 . 15 %; found : c , 72 . 79 , h , 9 . 16 %. this compound was synthesized from 4 - carboxybutyltriphenylphosphonium bromide ( 8 . 86 g , 20 mmol ) and p - butoxybenzaldehyde ( 3 . 56 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . crystallization ( petroleum ether ) afforded the product ( 3 . 82 g , 73 %) as white crystals ( mp : 56 - 57 ° c .). ir : 3350 - 2500 , 1700 cm - 1 1 h - nmr : 1 . 00 ( t , 3h ), 1 . 50 ( m , 2h ), 1 . 80 ( m , 4h ), 2 . 40 ( m , 4h ), 3 . 90 ( t , 2h ), 5 . 50 + 6 . 00 ( m , 1h ), 6 . 38 ( q , 1h ), 7 . 05 ( q , 4h ), 11 . 00 ( bs , 1h ). anal . calcd . for c 16 h 22 o 3 : c , 73 . 25 , h , 8 . 45 %; found : c , 73 . 32 , h , 8 . 46 %. z : e = 37 : 63 . this compound was synthesized from 6 -( p - butoxyphenyl )- 5 - hexenoic acid ( 2 . 62 g , 10 mmol ) by a hydrogenation reaction using pd / c ( 260 mg ). crystallization ( petroleum ether ) afforded the product ( 2 . 49 g , 94 %) as white crystals ( mp 39 - 40 ° c .). ir : 3400 - 2500 , 1705 cm - 1 ; 1 h - nmr : 0 . 96 ( t , 3h ), 1 . 35 ( m , 2h ), 1 . 50 ( m , 2h ), 1 . 62 ( m , 4h ), 1 . 75 ( m , 2h ), 2 . 35 ( t , 2h ), 2 . 52 ( t , 2h ), 3 . 92 ( t , 2h ), 6 . 95 ( q , 4h ), 10 . 30 ( bs , 1h ). anal . calcd . for c 16 h 24 o 3 : c , 72 . 69 , h , 9 . 15 %; found : c , 72 . 78 , h , 9 . 18 %. ethyl 8 -( 4 - ethyl ) phenoxyoctanoate . nah ( 0 . 25 g , 11 mmol ) was washed with hexane and then suspended in dry thf ( 50 ml ). 4 - ethylphenol ( 1 . 22 g , 10 mmol ) in thf ( 20 ml ) was added and stirred for 30 min at room temperature . ethyl 8 - iodooctanoate ( 2 . 98 g , 10 mmol ) in thf ( 20 ml ) was added and the mixture was refluxed for 12 h . after evaporation of the solvent , the residue was dissolved in ethyl acetate ( 150 ml ), and the organic phase was washed with water ( 2 × 50 ml ), and brine ( 50 ml ) and dried over na 2 so 4 . the crude product was purified by column chromatography on silica gel ( ethyl acetate : hexane = 1 : 5 ) and subsequent kugelrohr distillation to give the product ( 0 . 85 g , 24 %), bp 122 - 126 ° c ./ 0 . 1 torr . ir : 1740 cm - 1 ; 1 h - nmr : 1 . 19 ( t , 3h ), 1 . 25 ( t , 3h ), 1 . 30 - 1 . 80 ( m , 10h ), 2 . 28 ( t , 2h ), 2 . 57 ( q , 2h ), 3 . 90 ( t , 2h ), 4 . 12 ( q , 2h ), 6 . 86 ( d , 2h ), 7 . 08 ( d , 2h ). this compound was synthesized from ethyl 8 -( 4 - ethyl ) phenoxyoctanoate ( 1 . 76 g , 5 mmol ) by a hydrolysis reaction . crystallization from hexane gave white crystals ( 1 . 40 g , 87 %), mp 77 - 78 ° c . ; ir : 3450 - 2950 , 1720 cm - 1 ; 1 h - nmr : 1 . 17 ( t , 3h ), 1 . 29 - 1 . 49 ( m , 6h ), 1 . 63 ( q , 2h ), 1 . 74 ( q , 2h ), 2 . 31 ( t , 2h ), 2 . 56 ( q , 2h ), 3 . 88 ( t , 2h ), 6 . 77 ( d , 2h ), 7 . 06 ( d , 2h ), 10 . 2 ( bs , 1h ). anal . calcd . for c 16 h 24 o 3 : c , 72 . 69 , h . 9 . 15 %; found : c , 72 . 53 , h , 9 . 19 %. this compound was synthesized from 10 - carboxydecyltriphenylphosphonium bromide ( 10 . 55 g , 20 mmol ) and benzaldehyde ( 2 . 12 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation ( bp 152 - 155 ° c ./ 0 . 03 torr ) and crystallization afforded the product ( 2 . 43 g , 44 %) as white crystals ( mp 27 - 27 . 5 ° c .). ir : 3400 - 2500 , 1720 , 700 cm - 1 ; 1 h - nmr : 1 . 30 ( m , 10h ), 1 . 40 ( m , 2h ), 1 . 62 ( m , 2h ), 2 . 35 ( m , 4h ), 5 . 65 ( m , 1h ), 6 . 40 ( m , 1h ), 7 . 25 ( m , 5h ), 10 . 40 ( bs , 1h ). anal . calcd . for c 18 h 26 o 2 : c , 78 . 79 , h , 9 . 55 %; found : c , 78 . 66 , h , 9 . 60 %. z : e = 93 : 7 . this compound was synthesized from 12 - phenyl - 10 - dodecenoic acid ( 1 . 92 g , 7 mmol ) by a hydrogenation reaction using pd / c ( 190 mg ). crystallization ( petroleum ether ) afforded the product ( 1 . 88 g , 97 %) as white crystals ( mp 47 - 48 ° c .). ir : 3400 - 2500 , 1700 cm - 1 ; 1 h - nmr : 1 . 30 ( m , 14h ), 1 . 60 ( m , 4h ), 2 . 32 ( t , 2h ), 2 . 57 ( t , 2h ), 7 . 20 ( m , 5h ), 10 . 20 ( bs , 1h ). anal . calcd . for c 18 h 28 o 2 : c , 78 . 21 , h , 10 . 21 %; this compound was synthesized from 7 - carboxyheptyltriphenylphosphonium bromide ( 9 . 71 g , 20 mmol ) and 2 - furaldehyde ( 1 . 92 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation yielded the product ( 2 . 69 g , 61 %) as a pale yellow oil ( bp 136 - 139 ° c ./ 0 . 05 torr ). ir : 3500 - 2500 , 1730 , 710 cm - 1 ; 1 h - nmr : 1 . 40 ( m , 8h ), 2 . 35 ( m , 4h ), 5 . 55 ( m , 1h ), 6 . 30 ( m , 3h ), 7 . 35 ( s , 1h ), 11 . 40 ( bs , 1h ). anal . calcd . for c 13 h 18 o 3 : c , 70 . 25 , h , 8 . 16 %; found : c , 69 . 98 , h , 8 . 26 %. z : e = 79 : 21 . this compound was synthesized from 9 -( 2 - furyl )- 8 - nonenoic acid ( 0 . 89 g , 4 mmol ) by a hydrogenation reaction using pd / baso 4 ( 90 mg ). crystallization ( petroleum ether ) afforded the product ( 0 . 84 g , 93 %) as white crystals ( mp 31 - 32 ° c . ); ir : 3450 - 2500 , 1720 cm - 1 ; 1 h - nmr : 1 . 30 ( m , 8h ), 1 . 63 ( m , 4h ), 2 . 35 ( t , 2h ), 2 . 60 ( t , 2h ), 5 . 95 ( s , 1h ), 6 . 27 ( s , 1h ), 7 . 28 ( s , 1h ), 9 . 85 ( bs , 1h ). anal . calcd . for c 13 h 20 o 3 : c , 69 . 61 , h . 8 . 99 %; found : c , 69 . 42 , h . 9 . 04 %. this compound was synthesized from 5 - methylfurfural ( 2 . 20 g , 20 mmol ) and 7 - carboxyheptyltriphenylphosphonium bromide ( 9 . 71 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation afforded the product ( 2 . 35 g , 50 %) as a yellow oil ( bp 140 - 143 ° c ./ 0 . 05 torr ). ir : 3400 - 2500 , 1720 cm - 1 ; 1 h - nmr : 1 . 36 ( m , 4h ), 1 . 45 ( m , 2h ), 1 . 65 ( m , 2h ), 2 . 28 ( s , 3h ), 2 . 37 ( t , 2h ), 2 . 41 ( m , 2h ), 5 . 45 ( m , 1h ), 5 . 95 ( d , 1h ), 6 . 12 ( s , 1h ), 10 . 00 ( bs , 1h ). anal . calcd . for c 14 h 20 o 3 : c , 71 . 16 , h , 8 . 53 %; found : c , 70 . 85 , h , 8 . 63 %. z : e = 9 : 91 . this compound was synthesized from 9 -( 2 -( 5 - methyl ) furyl )- 8 - nonenoic acid ( 0 . 94 g , 4 mmol ) by a hydrogenation reaction using pd / baso 4 ( 94 mg ). crystallization ( petroleum ether ) afforded the product ( 0 . 87 g , 92 %) as white crystals ( mp 49 - 50 ° c .) ; ir : 3400 - 2500 , 1710 cm - 1 ; 1 h - nmr : 1 . 30 ( m , 8h ), 1 . 60 ( m , 4h ), 2 . 23 ( s , 3h ), 2 . 32 ( t , 2h ), 2 . 55 ( t , 2h ), 5 . 81 ( s , 2h ), 8 . 95 ( bs , 1h ). anal . calcd . for c 14 h 22 o 3 : c , 70 . 56 , h , 9 . 30 %; found : c , 70 . 39 , h , 9 . 33 %. this compound was synthesized from 2 - furaldehyde ( 1 . 92 g , 20 mmol ) and 9 - carboxynonyltriphenylphosphonium bromide ( 10 . 27 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . crystallization ( petroleum ether ) afforded the product ( 2 . 95 g , 59 %) as white crystals ( mp 45 - 46 ° c . ); ir : 3450 - 2500 cm - 1 ; 1 h - nmr : 1 . 33 ( m , 8h ), 1 . 46 ( m , 2h ), 1 . 65 ( m , 2h ), 2 . 34 ( t , 2h ), 2 . 45 ( m , 2h ), 5 . 55 ( m , 1h ), 6 . 18 ( d , 1h ), 6 . 25 ( d , 1h ), 6 . 38 ( d , 1h ), 7 . 38 ( s , 1h ), 9 . 80 ( bs , 1h ). anal . calcd . for c 15 h 22 o 3 : c , 71 . 97 , h , 8 . 86 %; found : c , 71 . 93 , h , 8 . 87 %. z : e = 43 : 57 . this compound was synthesized from 11 -( 2 - furyl )- 10 - undecenoic acid ( 1 . 25 g , 5 mmol ) by a hydrogenation reaction using pd / baso 4 ( 125 mg ). crystallization ( petroleum ether ) afforded the product ( 1 . 13 g , 90 %) as white crystals ( mp 40 - 41 ° c . ); ir : 3450 - 2500 , 1720 cm - 1 ; 1 h - nmr : 1 . 30 ( m , 12h ), 1 . 65 ( m , 4h ), 2 . 34 ( t , 2h ), 2 . 60 ( t , 2h ), 5 . 95 ( d , 1h ), 6 . 28 ( d , 1h ), 7 . 30 ( s , 1h ), 10 . 10 ( bs , 1h ). anal . calcd . for c 15 h 24 o 3 : c , 71 . 39 , h , 9 . 58 %; found : c , 71 . 21 , h , 9 . 63 %. this compound was synthesized from 10 - carboxydecyltriphenylphosphonium bromide ( 10 . 50 g , 20 mmol ) and furfural ( 1 . 92 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . crystallization afforded the product ( 2 . 38 g , 45 %) as pale yellow crystals ( mp 38 - 39 ° c . ); ir : 3450 - 2500 , 1715 , 695 cm - 1 ; 1 h - nmr : 1 . 35 ( m , 14h ), 2 . 35 ( t , 4h ), 5 . 60 ( m , 1h ), 6 . 30 ( m , 3h ), 7 . 35 ( s , 1h ), 9 . 40 ( bs , 1h ). anal . calcd . for c 16 h 24 o 3 : c , 72 . 69 , h , 9 . 15 ; found : c , 72 . 44 , h , 9 . 06 %. z : e = 43 : 57 . this compound was synthesized from 7 - carboxyheptyl - triphenylphosphonium bromide ( 9 . 71 g , 20 mmol ) and 2 - thiophenecarboxaldehyde ( 2 . 24 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . crystallization afforded the product ( 2 . 79 g , 59 %) as white crystals ( mp 45 - 46 ° c .). ir : 3400 - 2500 , 1720 , 710 cm - 1 ; 1 h - nmr : 1 . 45 ( m , 8h ), 2 . 35 ( m , 4h ), 5 . 55 ( m , 1h ), 6 . 50 ( d , 1h ), 7 . 00 ( m , 3h ), 11 . 00 ( bs , 1h ). anal . calcd . for c 13 h 18 so 2 : c , 65 . 51 , h , 7 . 61 %; found : c , 65 . 58 , h , 7 . 63 %. z : e = 75 : 25 . this compound was synthesized from 9 -( 2 - thienyl )- 8 - nonenoic acid ( 1 . 19 g , 5 mmol ) by a hydrogenation reaction using pd / c . ( 120 mg ). crystallization afforded the product ( 1 . 05 g , 88 %) as white crystals ( mp 32 - 33 ° c . ); ir : 3400 - 2500 , 1715 , 705 cm - 1 ; 1 h - nmr : 1 . 35 ( m , 12h ), 2 . 35 ( t , 2h ), 2 . 85 ( t , 2h ), 6 . 95 ( m , 3h ), 10 . 35 ( bs , 1h ). anal . calcd . for c 13 h 20 so 2 : c , 64 . 96 , h , 8 . 39 %; found : c , 64 . 81 , h , 8 . 43 %. this compound was synthesized from 7 - carboxyheptyl - phenylphosphonium bromide ( 7 . 28 g , 15 mmol ) and 2 -( 5 - methyl ) thiophenecarboxaldehyde ( 1 . 92 g , 15 mmol ) in thf ( 100 ml ) by a wittig reaction . kugelrohr distillation ( bp 155 - 159 ° c ./ 0 . 05 torr ) and crystallization ( petroleum ether ) afforded the product ( 2 . 43 g , 48 %) as pale yellow crystals ( mp 38 - 39 ° c .). ir : 3400 - 2500 , 1715 cm - 1 ; 1 h - nmr : 1 . 40 ( m , 6h ), 1 . 65 ( m , 2h ), 2 . 37 ( m , 4h ), 2 . 45 ( s , 3h ), 5 . 45 + 5 . 90 ( m , 1h ), 6 . 41 ( t , 1h ), 6 . 65 ( m , 1h ), 6 . 75 ( d , 1h ), 10 . 05 ( bs , 1h ). anal . calcd . for c 14 h 20 o 2 s : c , 66 . 63 , h , 7 . 99 %; found : c , 66 . 54 , h , 8 . 02 %. z : e = 72 : 28 . this compound was synthesized from 9 -( 2 -( 5 - methyl ) thienyl )- 8 - nonenoic acid ( 1 . 01 g , 4 mmol ) by a hydrogenation reaction using pd / c ( 200 mg ). crystallization ( petroleum ether ) afforded the product ( 0 . 91 g , 89 %) as white crystals ( mp 39 - 40 ° c .). ir : 3400 - 2500 , 1720 cm - 1 ; 1 h - nmr : 1 . 32 ( m , 8h ), 1 . 63 ( m , 4h ), 2 . 32 ( t , 2h ), 2 . 45 ( s , 3h ), 2 . 71 ( t , 2h ), 6 . 54 ( s , 2h ), 9 . 50 ( bs , 1h ). anal . calcd . for c 14 h 22 o 2 s : c , 66 . 10 , h , 8 . 72 %; found : c , 65 . 97 , h , 8 . 72 %. this compound was synthesized from 2 - thiophenecarboxaldehyde ( 2 . 24 g , 20 mmol ) and 9 - carboxynonyltriphenylphosphonium bromide ( 10 . 27 g , 20 mmol ) in thf ( 100 ml ) by a wittig reaction . crystallization ( hexanes - ethyl acetate ) afforded the product ( 2 . 45 g , 46 %) as white crystals ( mp 61 - 62 ° c . ); ir : 3450 - 2500 , 1715 cm - 1 ; 1 h - nmr : 1 . 31 ( m , 8h ), 1 . 45 ( m , 2h ), 1 . 65 ( m , 2h ), 2 . 34 ( t , 2h ), 2 . 38 ( t , 2h ), 5 . 55 ( m , 1h ), 6 . 50 ( d , 1h ), 6 . 95 ( m , 2h ), 7 . 23 ( d , 2h ), 10 . 05 ( bs , 1h ). anal . calcd . for c 15 h 22 o 2 s : c , 67 . 63 , h , 8 . 32 %; found : c , 67 . 60 , h , 8 . 34 %. z : e = 19 : 81 . this compound was synthesized from 11 -( 2 - thienyl )- 10 - undecenoic acid ( 800 mg , 3 mmol ) by a hydrogenation reaction using pd / c ( 80 mg ). crystallization ( petroleum ether ) afforded the product ( 0 . 73 g , 91 %) as white crystals ( mp 41 - 42 ° c . ): ir : 3450 - 2500 , 1715 cm - 1 ; 1 h - nmr : 1 . 30 ( m , 12h ), 1 . 63 ( m , 4h ), 2 . 32 ( t , 2h ), 2 . 80 ( t , 2h ), 6 . 78 ( d , 1h ), 6 . 90 ( t , 1h ), 7 . 10 ( d , 1h ), 9 . 80 ( bs , 1h ). anal . calcd . for c 15 h 24 o 2 s : c , 67 . 12 , h , 9 . 01 %; found : c , 67 . 55 , h , 8 . 89 %. the biological activity of a panel of fatty acid analogs that had been tested previously as substrates for purified e . coli - derived s . cerevisiae myristoylcoa : protein n - myristoyltransferase ( nmt ) were tested for toxicity against trypanosomes as potential candidates for anti - trypanosomal drugs . for purposes of comparison , several oxatetradecanoic acids described in u . s . pat . no . 5 , 151 , 445 as inhibitors of the growth and viability of bloodstream trypanosome parasites were included in the test panel . for convenience , this panel of fatty acid analogs was subdivided based on chemical differences in their secondary functional group . these functional groups vary with respect to their polarity , steric bulk , conformations , and to a limited degree , overall chain length . the 247 compounds thus tested are organized in table 2 , below , into 20 families . several of these functional groups should have complex effects on both conformation and stereoelectronic properties ( e . g . analogs with ester ) whereas others will predominantly affect only one of these properties ( e . g . conformation but not polarity in the case of olefins ; polarity but not conformation in the case of oxatetradecanoic acids ). in many of these families , the effects of the functional group have been assessed at every possible position from c3 through c13 in tetradecanoic acid ( e . g . see the thia - and oxotetradecanoic acids listed in table 2 ). to perform the large scale testing , a reproducible and rapid assay was employed . the method exploits the fact that growing trypanosomes secrete large amounts of pyruvic acid , an end product of glucose catabolism ( operdoes , 1987 ). the pyruvic acid causes a change in color of the phenol red indicator present in the culture medium , providing a quantitative measure of cell growth . a similar assay has been published previously ( zinsstag et al ., 1991 ). the detailed assay procedures used herein are as follows : trypanosomes were grown in the presence of analogs or positive and negative controls ( 11 - oxatetradecanoic acid and the ethanol solvent , respectively ). to avoid bias in data interpretation analog solutions were identified only by a code number . to evaluate reliability and reproducibility of the assay , several analogs were coded twice . all coded analogs were tested in quadruplicate on at least two separate occasions . after a standard growth period , the absorbance of the culture was determined at 550 nm and 405 nm and an efficacy value calculated from the ratio of these absorbances . results from a representative test are shown in fig1 . this set of coded compounds included samples of ethanol and 11 - oxatetradecanoic acid as both coded and uncoded samples ( compounds e and 24 and o11 and 27 respectively ). the excellent agreement between these samples and the controls attests to the reproducibility of this assay . quadruplicate samples were generally each within 5 % of the mean , and the ratio of the absorbance at 550 nm and 405 nm obtained for 11 - oxatetradecanoic acid averaged 1 . 12 with a standard error of 0 . 04 for over 100 determinations during a 6 month period . the analogs were grouped in terms of efficacy , defining 10 μm 11 - oxatetradecanoic acid as the center of group 3 and the ethanol controls as the center of group 1 ( fig1 ). the range of values were calculated defining each group independently for each test based on the 11 - oxatetradecanoic acid and ethanol values in that trial . this controlled for any differences in medium or cell growth . all compounds classified as group 3 were tested at - least twice . after screening and categorizing all analogs in this manner , the code was broken and the structures of the compounds were matched with their efficacy . note that 11 - oxa -, 13 - oxa -, and 6 - oxatetradecanoic acids fall in groups 3 , 2 , and 1 , respectively . these values correlate well with their effects on trypanosome growth assessed by cell counts using a hemocytometer ( doering et al ., 1991 ). fig2 shows the structures of the 20 most active compounds which collectively define group 3 . they are presented in decreasing order of potency in table 1 , above , and as structural groups in fig2 . nine of the compounds are either thiatetradecanoic or oxatetradecanoic acids . the ether functional group is also present in conjunction with an aromatic residue in three other compounds . an additional four analogs contain oxygen , either in the form of a ketocarbonyl or an ester group . the remaining structures include 13 - nitrotridecanoic acid and three unsaturated , fourteen carbon carboxylic acids . 9 - tetradecynoic acid was the most potent anti - trypanosomal agent identified among the 247 compounds screened . for toxicity assays , cloned t . brucei ( strain 427 ) of variant antigen type 221 ( obtained from g . a . m . cross , rockefeller university ) were harvested from cd - 1 mice at a parasitemia of 2 - 5 × 10 8 trypanosomes / ml . after centrifugation of the infected blood ( 430 x g ; 8 min ; 4 ° c . ), the upper portion of the buffy coat was retained , with care taken to avoid contamination with erythrocytes . this material , consisting predominantly of trypanosomes , was then resuspended in bbs containing 1 mg / ml fatty acid free bovine serum albumin . the suspension was centrifuged ( 3 , 000 x g ; 8 min ; 4 ° c . ), and the cell pellet resuspended in culture medium to a final density of 1 . 5 × 10 7 cells / ml . ( the composition of this culture medium was as described above except that 40 μm monothioglycerol was added ; duszenko et al ., 1985 ; doering et al ., 1990 ; hamm et al ., 1990 .) the doubling time of trypanosomes under these culture conditions is approximately 6 h at 37 ° c . this rapid assay , which can accommodate multiple samples , depends on measurement of the color change produced in the medium &# 39 ; s phenol red indicator dye due to acidification by growing trypanosomes . stocks of analogs ( 10 mm in absolute ethanol , identified only by a code number ) were diluted in culture medium to twice the concentration to be tested . aliquots of 100 μl were dispensed into 96 - well microtiter plates and warmed to 37 ° c . in a 5 % co 2 incubator before the addition of an equal volume of cell suspension ( 1 . 5 × 10 7 / ml , see above ). all assays were performed in quadruplicate in each plate . control wells included appropriately diluted ethanol ( which had no effect on cell growth ) and 10 μm 11 - oxatetradecanoic acid . the plate was incubated for 36 h at 37 ° c . and then stored at 4 ° c . for 12 h to allow equilibration of co 2 in the medium with that in air . the absorbance of each sample , at 550 nm and 405 nm ( values chosen based on the absorption spectra of fresh and acidified media ), was then read in a uv max kinetic microplate reader ( molecular devices ). to control for any variation in sample volume , the ratio of absorbance at 550 nm to absorbance at 405 nm for each well was calculated . this ratio was then averaged for each quadruplicate set and normalized to the average obtained in the set of control wells containing 10 μm 11 - oxatetradecanoic acid , yielding an &# 34 ; efficacy value &# 34 ;. table 2__________________________________________________________________________structure reference efficacy group . sup . 1__________________________________________________________________________saturated fatty acids . sup . 2 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 11 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 12 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 13 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 14 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 16 -- cooh 1 ch . sub . 3 --( ch . sub . 2 ). sub . 18 -- cooh 1 oxatetradecanoic acids ch . sub . 3 -- o --( ch . sub . 2 ). sub . 11 -- cooh kishore et al ., 1991 2 ch . sub . 3 -- ch . sub . 2 -- o --( ch . sub . 2 ). sub . 10 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- o --( ch . sub . 2 ). sub . 9 -- cooh kishore et al ., 1991 3 *. sup . 3 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- o --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 3 * ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- o --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 3b ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- o --( ch . sub . 2 ). sub . 5 -- cooh kishore et al ., 1991 3 **. sup . 4 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- o --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- o --( ch . sub . 2 ). sub . 3 -- cooh kishore et al ., 1991 3 * ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- o --( ch . sub . 2 ). sub . 2 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- o -- ch . sub . 2 -- cooh kishore et al ., 1991 1 thiatetradecanoic acids ch . sub . 3 -- s --( ch . sub . 2 ). sub . 11 -- cooh kishore et al ., 1991 3 * ch . sub . 3 -- ch . sub . 2 -- s --( ch . su b . 2 ). sub . 10 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- s --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- s --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 3b * ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- s --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- s --( ch . sub . 2 ). sub . 5 -- cooh kishore et al ., 1991 3 ** ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- s --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 2a ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- s --( ch . sub . 2 ). sub . 3 -- cooh kishore et al ., 1991 3 ** ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- s --( ch . sub . 2 ). sub . 2 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- s -- ch . sub . 2 -- cooh kishore et al ., 1991 1myristic acid analogs containing sulfur and / or oxygen substituentsch . sub . 3 -- ch . sub . 2 -- s --( ch . sub . 2 ). sub . 5 -- s --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- s --( ch . sub . 2 ). sub . 2 -- o --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 2 ch . sub . 3 -- ch . sub . 2 -- o --( ch . su b . 2 ). sub . 2 -- s --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- o --( ch . sub . 2 ). sub . 5 -- s --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- o --( ch . sub . 2 ). sub . 2 -- o --( ch . sub . 2 ). sub . 2 -- o --( ch . s ub . 2 ). sub . 5 -- cooh kishore et al ., 1991 1 oxotetradecanoic acids ch . sub . 3 -- co --( ch . sub . 2 ). sub . 11 -- cooh devadas et al ., 1992 2 ch . sub . 3 -- ch . sub . 2 -- co --( ch . s ub . 2 ). sub . 10 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- co --( ch . sub . 2 ). sub . 9 -- cooh devadas et al ., 1992 2a * ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- co --( ch . sub . 2 ). sub . 8 -- cooh devadas et al ., 1992 2b ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- co --( ch . sub . 2 ). sub . 7 -- cooh devadas et al ., 1992 2a * ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- co --( ch . sub . 2 ). sub . 6 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- co --( ch . sub . 2 ). sub . 5 -- cooh devadas et al ., 1992 3 ** ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- co --( ch . sub . 2 ). sub . 4 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- co --( ch . sub . 2 ). sub . 3 -- cooh devadas et al ., 1992 3b * ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- co --( ch . sub . 2 ). sub . 2 -- cooh devadas et al ., 1992 2 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- co -- ch . sub . 2 -- cooh devadas et al ., 1992 1 myristic acid analogs containing ester groups ch . sub . 3 -- o -- co --( ch . sub . 2 ). sub . 10 -- cooh devadas et al ., 1992 2 ch . sub . 3 -- ch . sub . 2 -- o -- co --( c h . sub . 2 ). sub . 9 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- o -- co --( ch . sub . 2 ). sub . 8 -- cooh devadas et al ., 1992 2 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- o -- co --( ch . sub . 2 ). sub . 7 -- cooh devadas et al ., 1992 2a ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- o -- co --( ch . sub . 2 ). sub . 6 -- cooh devadas et al ., 1992 1a ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- o -- co --( ch . sub . 2 ). sub . 5 -- cooh devadas et al ., 1992 2b ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- o -- co --( ch . sub . 2 ). sub . 4 -- cooh devadas et al ., 1992 2 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- o -- co --( ch . sub . 2 ). sub . 3 -- cooh devadas et al ., 1992 3 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- o -- co --( ch . sub . 2 ). sub . 2 -- cooh devadas et al ., 1992 3b * ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- o -- co -- ch . sub . 2 -- cooh devadas et al ., 1992 1 ch . sub . 3 -- ch . sub . 2 -- o -- co --( ch . sub . 2 ). sub . 10 -- cooh devadas et al ., 1992 1 myristic acid analogs containing amide groups ch . sub . 3 -- nh -- co --( ch . sub . 2 ). sub . 10 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- nh -- co --( ch . sub . 2 ). sub . 8 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- nh -- co --( ch . sub . 2 ). sub . 7 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- nh -- co --( ch . sub . 2 ). sub . 6 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- nh -- co --( ch . sub . 2 ). sub . 5 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- nh -- co --( ch . sub . 2 ). sub . 4 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- nh -- co --( ch . sub . 2 ). sub . 3 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- nh -- co --( ch . sub . 2 ). sub . 2 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- nh -- co -- ch . sub . 2 -- cooh devadas et al ., 1992 1myristic acid analogs containing acylamino amide groupsch . sub . 3 -- co -- nh --( ch . sub . 2 ). sub . 10 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- co -- nh --( ch . sub . 2 ). sub . 7 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- co -- nh --( ch . sub . 2 ). sub . 6 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- co -- nh --( ch . sub . 2 ). sub . 5 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- co -- nh --( ch . sub . 2 ). sub . 4 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- co -- nh --( ch . sub . 2 ). sub . 3 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- co -- nh --( ch . sub . 2 ). sub . 2 -- cooh devadas et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- co -- nh -- ch . sub . 2 -- cooh devadas et al ., 1992 1a nitroalkylcarboxylic acids o . sub . 2 n --( ch . sub . 2 ). sub . 9 -- cooh lu et al ., 1994 . sup . 5 1 o . sub . 2 n --( ch . sub . 2 ). sub . 10 -- cooh lu et al ., 1994 2a o . sub . 2 n --( ch . sub . 2 ). sub . 12 -- cooh lu et al ., 1994 3 halogenated analogs br --( ch . sub . 2 ). sub . 12 -- cooh lu et al ., 1994 2 br --( ch . sub . 2 ). sub . 13 -- cooh lu et al ., 1994 2 f . sub . 3 c --( ch . sub . 2 ). sub . 12 -- cooh lu et al ., 1994 1 f . sub . 3 c -- ch ═ ch --( ch . sub . 2 ). sub . 10 cooh lu et al ., 1994 1 tetradecenoic acids ch . sub . 2 = ch --( ch . sub . 2 ). sub . 11 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch ═ ch --( ch . sub . 2 ). sub . 10 -- cooh kishore et al ., 1991 z12 . sup . 6 1 ch . sub . 3 -- ch . sub . 2 -- ch ═ ch --( ch . sub . 2 ). sub . 9 -- cooh kishore et al ., 1991 z11 2b ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- ch ═ ch --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 z10 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 z8 1a ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- ch ═ ch --( ch . sub . 2 ). sub . 5 -- cooh kishore et al ., 1991 z7 2b ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- ch ═ ch --( ch . sub . 2 ). sub . 5 -- cooh kishore et al ., 1991 e7 . sup . 7 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 e6 2b ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 z6 1 isomer mixture : 15 % e6 , 85 % z6 kishore et al ., 1991 e : z6 1 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh kishore et al ., 1991 e5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh kishore et al ., 1991 z5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- ch ═ ch --( ch . sub . 2 ). sub . 2 -- cooh kishore et al ., 1991 z4 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- ch ═ ch --( ch . sub . 2 ). sub . 2 -- cooh kishore et al ., 1991 e4 1 ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- ch ═ ch -- ch . sub . 2 -- cooh kishore et al ., 1991 z3 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- ch ═ ch -- cooh kishore et al ., 1991 e2 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- ch ═ ch -- cooh kishore et al ., 1991 z2 1 ch . sub . 3 -- ch . sub . 2 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c8 : z5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c10 : z5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c12 : z5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- ch ═ ch --( ch . sub . 2 ). sub . 2 -- cooh rudnick et al ., 1992 c16 : z4 1 ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c16 : z5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh rudnick et al ., 1992 c16 : z6 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c17 : z5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 11 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c18 : z5 1 tetradecadienoic acids ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- ch ═ ch -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- ch ═ ch -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh see examples 2b ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- ch ═ ch -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh see examples 3 tetradecynoic acids hc . tbd . c --( ch . sub . 2 ). sub . 11 -- cooh kishore et al ., 1991 2b ch . sub . 3 -- c . tbd . c --( ch . sub . 2 ). sub . 10 -- cooh kishore et al ., 1991 1 ch . sub . 3 ch . sub . 2 -- c . tbd . c --( c h . sub . 2 ). sub . 9 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- c . tbd . c --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- c . tbd . c --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 3a ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- c . tbd . c --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 3 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- c . tbd . c --( ch . sub . 2 ). sub . 5 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- c . tbd . c --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- c . tbd . c --( ch . sub . 2 ). sub . 3 -- cooh kishore et al ., 1991 2 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- c . tbd . c --( ch . sub . 2 ). sub . 2 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- c . tbd . c -- ch . sub . 2 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- c . tbd . c -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- c . tbd . c --( ch . sub . 2 ). sub . 2 -- cooh rudnick et al ., 1992 c13 : y4 . sup . 8 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- c . tbd . c --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c13 : y5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- c . tbd . c --( ch . sub . 2 ). sub . 4 -- cooh rudnick et al ., 1992 c13 : y6 2b ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- c . tbd . c --( ch . sub . 2 ). sub . 2 -- cooh rudnick et al ., 1992 c15 : y4 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- c . tbd . c --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c15 : y5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- c . tbd . c --( ch . sub . 2 ). sub . 4 -- cooh rudnick et al ., 1992 c15 : y6 1 ch . sub . 3 --( ch . sub . 2 ). sub . 10 -- c . tbd . c --( ch . sub . 2 ). sub . 2 -- cooh rudnick et al ., 1992 c16 : y4 1 ch . sub . 3 --( ch . sub . 2 ). sub . 9 -- c . tbd . c --( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 c16 : y5 1 ch . sub . 3 --( ch . sub . 2 ). sub . 8 -- c . tbd . c --( ch . sub . 2 ). sub . 4 -- cooh rudnick et al ., 1992 c16 : y6 1 aromatic analogs 11 carbon equivalent length . sup . 9 c . sub . 6 h . sub . 5 --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 2b c . sub . 6 h . sub . 5 --( ch . sub . 2 ). su b . 2 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh kishore et al ., 1991 1 12 carbon equivalent length c . sub . 6 h . sub . 5 --( ch . sub . 2 ). sub . 8 -- cooh kishore et al . 1991 1 c . sub . 6 h . sub . 5 -- ch ═ ch --( c h . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 1a c . sub . 6 h . sub . 5 --( ch . sub . 2 ). sub . 2 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 1 c . sub . 6 h . sub . 5 -- o --( ch . sub . 2 ) . sub . 7 -- cooh see examples 1 13 carbon equivalent length c . sub . 6 h . sub . 5 --( ch . sub . 2 ). su b . 9 -- cooh kishore et al ., 1991 2b ch . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 2b ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). s ub . 5 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 4 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 3 -- cooh gokel , et al ., 1992 1a ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). s ub . 2 -- cooh gokel , et al ., 1992 1 c . sub . 6 h . sub . 5 -- ch . sub . 2 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 5 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). su b . 3 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). su b . 2 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- c . sub . 6 h . sub . 4 -- ch ═ ch -- ch . sub . 2 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- c . sub . 6 h . sub . 4 -- ch ═ ch --- - cooh gokel , et al ., 1992 1 ch . sub . 3 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 7 -- cooh see examples 1 ch . sub . 3 -- ch . sub . 2 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 6 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 5 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 4 -- cooh gokel , et al . 1992 3 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 3 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 2 -- cooh gokel , et al ., 1992 1 ch . sub . 3 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 5 -- cooh see examples 1 ch . sub . 3 -- ch . sub . 2 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ) . sub . 3 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 2 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch -- ch . sub . 2 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch -- cooh gokel , et al ., 1992 1 c . sub . 6 h . sub . 5 -- o --( ch . sub . 2 ) . sub . 8 -- cooh see examples 1 c . sub . 6 h . sub . 5 -- s --( ch . sub . 2 ) . sub . 8 -- cooh see examples 1 c . sub . 6 h . sub . 5 -- ch . sub . 2 -- o --( ch . sub . 2 ). sub . 7 -- cooh see examples 1 c . sub . 6 h . sub . 5 -- ch . sub . 2 -- s --( ch . sub . 2 ). sub . 7 -- cooh see examples 1 14 carbon equivalent length c . sub . 6 h . sub . 5 --( ch . sub . 2 ). sub . 10 -- cooh heuckeroth et al ., 1990 2b ch . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 9 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 1a ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 7 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 6 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 5 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 4 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 3 -- cooh gokel , et al ., 1992 1 c . sub . 6 h . sub . 5 --( ch . sub . 2 ). sub . 2 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh heuckeroth et al ., 1990 1 ch . sub . 3 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 1 ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). su b . 5 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). su b . 3 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 2 -- cooh gokel , et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- c . sub . 6 h . sub . 4 -- ch ═ ch -- ch . sub . 2 -- cooh gokel , et al ., 1992 1 ch . sub . 3 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 1a ch . sub . 3 -- ch . sub . 2 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 7 -- cooh kishore et al ., 1991 1a ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 6 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 5 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 4 -- cooh gokel et al ., 1992 3 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 3 -- cooh gokel et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- o -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 2 -- cooh gokel et al ., 1992 1 ch . sub . 3 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 5 -- cooh kishore et al ., 1991 1a ch . sub . 3 --( ch . sub . 2 ). sub . 2 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ) . sub . 4 -- cooh see examples 1 ch . sub . 3 --( ch . sub . 2 ). sub . 3 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 3 -- cooh see examples 2a ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ) . sub . 2 -- cooh gokel et al ., 1992 2 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch -- ch . sub . 2 -- cooh gokel et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- o -- c . sub . 6 h . sub . 4 -- ch ═ ch -- cooh gokel et al ., 1992 1 c . sub . 6 h . sub . 5 -- o --( ch . sub . 2 ) . sub . 9 -- cooh kishore et al ., 1991 1 c . sub . 6 h . sub . 5 -- s --( ch . sub . 2 ). sub . 9 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- c . sub . 6 h . sub . 4 -- s --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- s -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- s -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh kishore et al ., 1991 1 ch . sub . 3 -- ch . sub . 2 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 7 -- cooh see examples 1 15 carbon equivalent length c . sub . 6 h . sub . 5 --( ch . sub . 2 ). sub . 11 -- cooh rapoport and newman , 1947 1 c . sub . 6 h . sub . 5 -- ch ═ ch --( ch . sub . 2 ). sub . 9 -- cooh see examples 1 c . sub . 6 h . sub . 5 -- o --( ch . sub . 2 ) . sub . 10 -- cooh see examples 1 azido - aromatic analogs p - n . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 . sup . 5 1 p - n . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 7 -- cooh lu et al ., 1994 1b p - n . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1 m - n . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1 m - n . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 10 -- cooh lu et al ., 1994 1b p - n . sub . 3 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 5 -- cooh lu et al ., 1994 1b m - n . sub . 3 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 5 -- cooh lu et al ., 1994 1 p - n . sub . 3 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1b m - n . sub . 3 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 p - n . sub . 3 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 7 -- cooh lu et al ., 1994 1 m - n . sub . 3 -- c . sub . 6 h . sub . 4 -- o --( ch . sub . 2 ). sub . 7 -- cooh lu et al ., 1994 1 nitro - aromatic analogs o . sub . 2 n -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 o . sub . 2 n -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 5 -- cooh lu et al ., 1994 1a o . sub . 2 n -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 4 -- cooh lu et al ., 1994 1 h . sub . 2 n -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 h . sub . 2 n -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 7 -- cooh lu et al ., 1994 1 halo - aromatic analogs o - f -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1 m - f -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1 p - f -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1a p - cl -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1 p - br -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1a p - cf . sub . 3 -- c . sub . 6 h . sub . 4 --( ch . sub . 2 ). sub . 8 -- cooh lu et al ., 1994 1 o - f -- c . sub . 6 h . sub . 4 -- ch ═ c --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 m - f -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 p - f -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1a p - cl -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 p - br -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 p - cf . sub . 3 -- c . sub . 6 h . sub . 4 -- ch ═ ch --( ch . sub . 2 ). sub . 6 -- cooh lu et al ., 1994 1 hetero - aromatic analogs ch . sub . 3 --( ch . sub . 2 ). sub . 7 -- furyl -( ch . sub . 2 ). sub . 2 -- cooh rudnick et al ., 1992 1 ch . sub . 3 --( ch . sub . 2 ). sub . 6 -- furyl -( ch . sub . 2 ). sub . 3 -- cooh rudnick et al ., 1992 2 ch . sub . 3 --( ch . sub . 2 ). sub . 5 -- furyl -( ch . sub . 2 ). sub . 4 -- cooh rudnick et al ., 1992 3 ch . sub . 3 --( ch . sub . 2 ). sub . 4 -- furyl -( ch . sub . 2 ). sub . 5 -- cooh rudnick et al ., 1992 2b 2 - furyl -( ch . sub . 2 ). sub . 8 -- cooh see examples 1 [ 2 -( 5 - ch . sub . 3 - furyl )]-( ch . sub . 2 ). sub . 8 -- cooh see examples 1 2 - furyl -( ch . sub . 2 ). sub . 10 -- cooh see examples 2b 2 - furyl - ch ═ ch --( ch . sub . 2 ). s ub . 6 -- cooh see examples 1 [ 2 -( 5 - ch . sub . 3 - furyl )[- ch ═ ch --( ch . sub . 2 ). sub . 2 ). sub . 6 -- cooh see examples 1 2 - furyl - ch ═ ch --( ch . sub . 2 ). sub . 8 -- cooh see examples 1 2 - furyl - ch ═ ch --( ch . sub . 2 ). sub . 9 -- cooh see examples 1 2 - thienyl -( ch . sub . 2 ). sub . 8 -- cooh see examples 1a 2 - thienyl -( ch . sub . 2 ). sub . 9 -- cooh kishore et al ., 1991 1 [ 2 -( 5 - ch . sub . 3 - thienyl )]-( ch . sub . 2 ). sub . 8 -- cooh see examples 1 2 - thienyl -( ch . sub . 2 ). sub . 10 -- cooh see examples 2b 2 - thienyl - ch ═ ch --( ch . sub . 2 ) . sub . 6 -- cooh see examples 1 [ 2 -( 5 - ch . sub . 3 - thienyl )]- ch . db d . ch --( ch . sub . 2 ). sub . 6 -- cooh see examples 1 2 - thienyl - ch ═ ch --( ch . sub . 2 ). sub . 8 -- cooh see examples 1__________________________________________________________________________ . sup . 1 efficacy groups were assigned as described in methods and the text subgroup &# 34 ; a &# 34 ; indicates compounds near the upper boundary of an efficacy group ; subgroup &# 34 ; b &# 34 ; indicates compounds at the lower boundary . the 20 mos toxic compounds ( group 3 ) are highllghted in bold type . . sup . 2 purchased from nu chek prep , inc . ( elysian , mn ) . sup .. sup . 3 * indicates compounds that were categorized as group 2 when tested at 2 μm . . sup . 4 ** indicates compounds that remained in group 3 when tested at 2 μm . . sup . 5 t . lu , q . li , a . katoh , j . hernandez , k . duffin , e . jacksonmachelski , l . j . knoll , g . w . gokel , and j . i . gordon , j . biol . chem ., 269 , 5346 - 5357 ( 1994 ). . sup . 6 z , designates cis double bond geometry . sup . 7 e , designates trans double bond geometry . sup . 8 y , indicates triple bond . sup . 9 examination of cpk space filling atomic models indicates that the width of an aromatic ring is equivalent to three methylenes . the antiparasitic agents described herein can be used for administration to mammalian hosts infected with trypanosomes and the like by conventional means , preferably in formulations with pharmaceutically acceptable diluents and carriers . the amount of the active agent to be administered must be an effective amount , that is , an amount which is medically beneficial but does not present toxic effects which overweigh the advantages which accompany its use . it would be expected that the adult human dosage would normally range upward from about one milligram of the active compound . a suitable route of administration is orally in the form of capsules , tablets , syrups , elixirs and the like , although parenteral administration also can be used . appropriate formulations of the active compound in pharmaceutically acceptable diluents and carriers in therapeutic dosage form can be prepared by reference to general texts in the field such as , for example , remington &# 39 ; s pharmaceutical sciences , ed . arthur osol , 16th ed ., 1980 , mack publishing co ., easton , pa . various other examples will be apparent to the person skilled in the art after reading the present disclosure without departing from the spirit and scope of the invention . all such other examples are intended to be included within the scope of the appended claims . bryant , m . l ., heuckeroth , r . o ., kimata , j . t ., ratner , l ., and gordon , j . i . 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