bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and antifolate activity of 2,4‐diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine analogues of trimetrexate and piritrexim
Authors: Rosowsky Andre , Mota Clara E. , Queener Sherry F.
Published: March 2009

2,4‐Diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidines with di‐ and trimethoxyaralkyl substitution at the 6‐position were synthesized from theN6‐unsubstituted compound and appropriate aralkyl bromides inN,N‐dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4‐diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine from 2‐amino‐6‐benzyl‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidin‐4(3H)‐one was also developed, in whichN2was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4‐chlorophenylphosphorodichloridate and 1,2,4‐triazole, ammonolysis to replace the 4‐imidazolido group and remove theN2‐pivaloyl group, and catalytic hydrogenolysis to remove the 6‐benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase fromPneumocystis carinii, andToxoplasma gondii, and rat liver the most active of the compounds tested was 2,4‐diamino‐6‐(2′‐bromo‐3′,4′,5′‐trimethoxybenzyl)‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50% was 0.51 μMagainst theP. cariniienzyme, 0.09 μMagainst theT. gondii enzyme, and 0.35 μMagainst the rat enzyme. Thus, there was selectivity of binding toT. gondiienzyme, but notP. cariniienzyme, relative to rat enzyme. 2′,5′‐Dimethoxybenzyl analogues were less active than the corresponding 3′,4′,5′‐trimethoxybenzyl analogues, and compounds with a CH2CH2or CH2CH2CH2bridge were less active than those with a CH2bridge. 2,4‐Diamino‐6‐(2′‐bromo‐3′,4′,5′‐trimethoxybenzyl)‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for theP. cariniiandT. gondiienzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunisticP. cariniiandT. gondiiinfections in patients with AIDS and other disorders of the immune system.
A novel synthesis of 3′‐deoxy‐3′‐nitrothymidine via nucleophilic substitution with nitrite anion
Authors: Huang Jim J. , Ragouzeos Aris , Rideout Janet L.
Published: March 2009

Nucleophilic substitution at C3′ of 1‐(2‐deoxy‐5‐O‐trityl‐β‐D‐erythr‐pentofuranosyl)‐2‐methoxy‐5‐methyl‐4(1H)‐pyrimidinone (5) with methyl iodide/triphenylphosphine/diethyl azodicarboxylate gave the expected inverted iodide 6 and minor epimer 7. Treatment of 6 with lithium nitrite/phloroglucinol yielded the desired nitro derivative 8 and subsequent acidic deprotection afforded the title compound 1. This represents a novel method for the introduction of a nitro group into the furanosyl moiety of a nucleoside. The nmr spectroscopic techniques (COSY, NOESY, nOe, HMQC and HMBC) were used to determine the stereochemistry at C3′ of the nucleosides. Spectral analysis of H‐D exchange at the 3′‐position of 1 did not indicate the formation of its epimer 10.
Palladium(0)‐catalyzed allylation of 4(5)‐substituted imidazoles, 5(6)‐substituted benzimidazoles, benzotriazole and 5(6)‐methylbenzotriazole
Authors: Arnau N. , Arredondo Y. , Moreno‐Mañas M. , Pleixats R. , Villarroya M.
Published: March 2009

Pd(0)‐Catalyzed allylations of 4(5)‐nitroimidazole, 1, 2‐methyl‐4(5)‐nitroimidazole, 2, 4(5)‐bromo‐imidazole, 7, 4(5)‐methoxyimidazole, 10, 5(6)‐nitrobenzimidazole, 16a, 5(6)‐methylbenzimidazole, 16b, benzotriazole, 19, and 5(6)‐methylbenzotriazole, 22, were studied under several reaction conditions. Nitroimidazoles 1 and 2 were regioselectively allylated under thermodynamic control, leading to 1‐allyl‐4‐nitro derivatives.
Long‐range 1H‐15N correlation at natural abundance using gradient‐enhanced inverse‐detection
Authors: Crouch Ronald C. , Martin Gary E.
Published: March 2009

Inverse‐detected heteronuclear shift correlation efficiency has been significantly augmented by the incorporation of pulsed field gradients (PFG). Phase‐cycling requirements for t1‐noise suppression in gradient‐enhanced experiments are, for the most part, obviated, making it feasible to acquire data in one or a few transients/t1 increment. The benefits which acerue for 1H‐13C correlation (using GHMQC, GHMBC, and variants of GHMQC‐TOCSY) are well documented. Less obvious is the increased facility with which long‐range 1H‐15N correlation spectra can be acquired. An IDR‐(Inverted Direct Response)‐GHMQC‐TOCSY was used to establish unequivocal proton resonance assignments for the alkaloid ajmaline. Long‐range 1H‐15N heteronuclear couplings to the two nitrogen atoms of ajmaline were then probed using a gradient‐enhanced 1H‐15N heteronuclear shift correlation experiment derived from HMQC. Long‐range 1H‐15N couplings in ajmaline are assigned for the first time.
Synthesis of 4‐hydroxy‐6,9‐difluorobenz[g]isoquinoline‐5,10‐diones and conversions to 4‐hydroxy‐6,9‐bis[(aminoalkyl)amino]‐benz[g]isoquinoline‐5,10‐diones
Authors: Krapcho A. Paul , Maresch Martin J. , Gallagher Cynthia E. , Hacker Miles P. , Menta Ernesto , Oliva Ambrogio , Di Domenico Roberto , Da Re Giovanni , Spinelli Silvano
Published: March 2009

Synthetic procedures have been developed which lead to 4‐hydroxy‐6,9‐difluorobenz[g]isoquinoline‐5,10‐dione (4a) and its 3‐methyl analogue 4b. Attempts to displace the fluorides from 4a with N,N‐dimethylethylenediamine were unsuccessful. Analogue 4a on treatment with N‐(t‐butoxycarbonyl)ethylene diamine led to 15, formed from addition of the nucleophilic amine to C‐3. On the other hand, analogue 4b, on treatment with N,N‐dimethylethylenediamine led to the anticipated difluoride displacement product 3c. The protection of the hydroxy group of 4a by benzylation with phenyldiazomethane led to 4c which on treatment with N‐(t‐butoxycarbonyl)ethylene diamine or N,N‐dimethylethylenediamine led to the corresponding 6,9‐bis‐substituted analogues 18a and 18b, respectively. Reductive debenzylations of 18a and 18b by hydrogenation over Pearlman's catalyst also effected partial reductions of the quinone. However, air oxidation of the over reduced products led to 3a and 3b, respectively. Treatment of 3a with hydrogen chloride gas led to the hydrochloride salt of 3d. Addition of O‐p‐Methoxybenzyl‐N,N'‐diisopropylurea to 4a led to the p‐methoxybenzyl analogue 4d. Treatment of 4d with N,N‐dimethylethylene diamine or N‐(t‐butoxycarbonyl)ethylene diamine led to displacements of the fluorides to yield 18c and 18d, respectively. Deprotection of 18c to 3b was accomplished using methanesulfonic acid. Treatment of 18d with trifluoroacetic acid followed by addition of maleic acid led to dimaleate salt of 3d.
Ring transformations of heterocyclic compounds. XIII. Bis(2,4,6‐triarylphenyl) substituted bispyridinium salts from methyl derivatives by double pyrylium and thiopyrylium ring transformations
Authors: Zimmermann Thomas , Schmidt Klaus
Published: March 2009

The synthesis of hitherto unknown 4,4′‐bis(2,4,6‐triarylphenyl) substituted bispyridinium diperchlorates 3, in which the N‐atoms are linked by a carbon chain, a heteroatom containing a carbon chain or a bis(methylene) substituted aromatic/heteroaromatic ring, from 4,4′‐dimethylbispyridinium derivatives 2 by a double 2,6‐[C5+C] ring transformation of 2,4,6‐triarylpyrylium and 2,4,6‐triarylthiopyrylium salts 1/4 is reported. Spectroscopic data of the bispyridinium diperchlorates 3 and their mode of formation are discussed.
Tetrazole compounds. 11. electron impact mass spectrometry of 1‐aryl‐5‐(l‐acyl‐2‐dialkylaminovinyl)‐1H‐tetrazoles
Authors: Fischer Gerhard W. , Herrmann Michael , Möder Monika
Published: March 2009

The mass spectrometric behaviour of 1‐aryl‐5‐(1‐acyl‐2‐dialkylaminovinyl)‐1H‐tetrazoles was studied, especially using 1‐phenyl‐5‐(1‐benzoyl‐2‐dimethylaminovinyl)‐1H‐tetrazole 1 and its D‐and 15N‐labeled derivatives. All tetrazoles investigated showed a clearly observable molecular ion and underwent as the main fragmentation the elimination of nitrogen followed by a number of various subsequent processes. Besides, primary fragments such as [M − N3•]+ and [M — ArN3]+• were also observed.
Synthesis and alkylation of 3,4‐dihydro‐1H‐1,3‐4‐benzotriazepine‐2,5‐diones and related systems
Authors: Karp Gary M.
Published: March 2009

A synthesis of the 1,3,4‐benzotriazepine‐2,5‐dione 2a and its 2‐thio analog 11 is described. The key step was the mild and efficient cyclization of the o‐(aminobenzoyl)hydrazine 10, obtained from the reaction of a protected hydrazine derivative with the o‐nitrobenzoyl chloride 3. Alkylation of 2a takes place exclusively at N‐3 while alkylation of 11 takes place on sulfur. Cyclization of the o‐(aminobenzoyl)hydrazine 14 gave the 2,4(1H,3H)‐quinazolinedione 15 as the sole product.
Inhibition of folylpolyglutamate synthetase by substrate analogues with an ornithine side chain
Authors: Rosowsky Andre , Forsch Ronald A. , Moran Richard G.
Published: March 2009

Nα‐[4‐[[(4‐Aminopteridin‐6‐yl)methyl]amino]benzoyl]‐L‐ornithine (dAPA‐Orn) was synthesized, and its ability to inhibit folylpolyglutamate synthetase from mouse liver was compared with that of the corresponding 2,4‐diamino analogue APA‐Orn. Also compared were the inhibitory activities of the deaza analogues 5‐deazaAPA‐Orn, 8‐deazaAPA‐Orn, and 5,8‐dideazaAPA‐Orn, as well as those ofNα‐pteroyl‐L‐ornithine (PteOrn) and its deaza analogues 5‐deazaPteOrn and 5,8‐dideazaPteOrn. The inhibition constant Kiof dAPA‐Orn was 7‐fold greater than that of APA‐Orn, indicating that the 2‐amino group plays a role in binding to the active site. The binding affinity of the 2,4‐diamino compounds increased in the order 5‐deazaAPA < APA‐Orn <5,8‐dideazaAPA‐Orn < 8‐deazaAPA‐Orn, and that of the 2‐amino‐4(3H)‐oxo compounds increased in the order 5‐deazaPteOrn < PteOrn < 5,8‐dideazaPteOrn. The most potent inhibitor of both groups was 8‐deazaAPA‐Orn, with a Kiof 0.018 μM, coresponding to an 8‐fold and 15‐fold increase in affinity relative to APA‐Orn and 5‐deazaAPA‐Orn, respectively. The results suggest (a) that the binding of Orn‐containing folylpolyglutamate synthetase inhibitors is affected to a greater degree by replacement of N8by a carbon atom than it is by the corresponding change at N5, (b) that the effect of carbon for nitrogen replacement is greater in the 2,4‐diamino derivatives than in the 2‐amino‐4(3H)‐oxo compounds, and (c) that the 2,4‐diamines are the better inhibitors. Comparison of the Kivalues of the Orn‐containing inhibitors with the Kmvalues of the corresponding glutamate‐containing substrates revealed that Km/Kiratio can vary as much as 100‐fold depending on the nature of the heterocyclic moiety, suggesting that caution should be exercised in using Kmvalues of known substrates to predict Kivalues of putative inhibitors.
Synthesis of a series of diaminobenzo[f]‐ and diaminobenzo[h]pyrimido[4,5‐b]quinolines as 5‐deaza tetracyclic nonclassical antifolates
Authors: Donkor Isaac O. , Devraj Rajesh , Queener Sherry F. , Barrows Louis R. , Gangjee Aleem
Published: March 2009

A series of diaminobenzo[f]‐ and diaminobenzo[h]pyrimido[4,5‐b]quinolines 1–11 were designed as 5‐deaza tetracyclic nonclassical, lipophilic antifolates. The compounds were designed as conformationally semi‐rigid and rigid analogs of 2,4‐diamino‐6‐phenyl‐12 and 2,4‐diamino‐7‐phenylpyrido[2,3‐d]pyrimidines 13 and 14. The target compounds were synthesized by cyclocondensation of chlorovinyl aldehydes obtained from appropriately substituted 1‐ or 2‐tetralone, with 2,4,6‐friaminopyrimidine. Compounds 1–11 were evaluated as inhibitors of P. carinii and T. gondii dihydrofolate reductases. These pathogens cause fatal opportunistic infections in AIDS patients. In addition, the selectivity of these agents was evaluated using rat liver dihydrofolate reductase as the mammalian source. In general the benzo[f]pyrimido[4,5‐b]quinolines 1–5 were more potent than the corresponding benzo[h]pyrimido[4,5‐b]quinoline analogues 6–11 against P. carinii and rat liver dihydrofolate reductase and were equipotent against T. gondii dihydrofolate reductase. Compounds 6–11 were moderately selective towards T. gondii dihydrofolate reductase with IC50S in the 10−7 M range. In contrast analogues 1–5 lacked selectivity against P. carinii or T. gondii dihydrofolate reductase and were, in general, potent inhibitors of rat liver dihydrofolate reductase with IC50S in the 10−8 M range. Analogues 1 and 4 were evaluated against a series of tumor cell lines in vitro and were found to have moderate antitumor activity (IC50 10−6 M). The structure activity/selectivity relationships suggest that benzo[f]pyrimido analogues 1–5 with the phenyl ring substitution in the “upper” portion of the tetracyclic ring are better accommodated within the rat liver (mammalian) dihydrofolate reductase and P. carinii dihydrofolate reductase active sites compared to the benzo[h]pyrimido analogues 6–11 which have the phenyl ring substitution in the “lower” portion of the tetracyclic ring. In contrast T. gondii dihydrofolate reductase does not discriminate between the isomers and binds to both series of compounds with similar affinities.
Synthesis of novel near‐infrared cyanine dyes for metal ion determination
Authors: Górecki Tadeusz , Patonay Gabor , Strekowski Lucjan , Chin Robert , Salazar Noe
Published: March 2009

Four heptamethine cyanine dyes10, 19–21containing anortho‐hydroxy‐carboxy functionality for metal ion complexation and absorbing at λ max (methanol) 761±1 nm have been synthesized.
Preparation of tetrazoles from organic nitriles and sodium azide in micellar media
Authors: Jursic Branko S. , Leblanc Blaise W.
Published: March 2009

An effective method for the preparation of 5‐substituted tetrazoles from the corresponding nitriles in micellar media is described. It was demonstrated that almost quantitative yields of tetrazoles can be obtained if the amount of water‐surfactant is optimized. The advantages of the methods presented over many others currently used are the simplicity, facility of isolation of tetrazole products and elimination of using relatively expensive solvents and reagents.
Applications of benzotriazole methodology in heterocycle ring synthesis and substituent introduction and modification
Authors: Katritzky Alan R. , Henderson Scott A. , Yang Baozhen
Published: March 2009

Applications of benzotriazole methodology for the preparation of heterocyclic compounds are reviewed. The characteristic advantages of benzotriazole as a synthetic auxiliary are first briefly considered. This is followed by a summary of its use in ring synthesis in which the construction of small; five‐membered; six‐membered; and larger heterocyclic rings using benzotriazole methodology are each examined separately. Finally, consideration of the use of benzotriazole in the ring annulation ‐ particularly benzannulation ‐ of heterocycles. Subsequent sections deal with the introduction of substituents into aromatic heterocycles; the ring substitution of saturated heterocycles; and benzotriazole assisted modification of heterocyclic substituents.

The present review supplements a recent comprehensive review of benzotriazole chemistry [1] which covers the literature through 1996.
Synthesis of certain 5‐substituted thieno[2,3‐b]thiophene‐2‐sulfonamides and thieno[2,3‐b]thiophene‐2‐sulfonamide 6,6‐dioxides
Authors: Chen Hwang‐Hsing , May Jesse A. , Lynch Vincent M.
Published: March 2009

A series of the title compounds were prepared for evaluation as inhibitors of carbonic anhydrase II. Oxidation of 5‐substituted thieno[2,3‐b]thiophene‐2‐sulfonamides provided the first examples of thiophene[2,3‐b]thiophene‐2‐sulfonarnide 6,6‐dioxides. These cyclic vinyl sulfones readily underwent addi tion to give predominately that 4,5‐cisaddition product.
Synthesis of 1‐ and 3‐arylcarbonyl derivatives of 5‐fluorouracil
Authors: Caram Lolita , Doeleman Mech , Roberts William J. , Prankerd Richard J. , Perrin John H. , Underberg William J. , Sloan Kenneth B.
Published: March 2009

4′‐Substituted 1‐arylcarbonyl‐5‐fluorouracil derivatives were synthesized from the reaction of the potassium salt of 5‐fluorouracil with one equivalent of aryl acid chloride in acetonitrile. 4′‐Substituted 3‐arylcar‐bonyl‐5‐fluorouracil derivatives were synthesized from the reaction of 5‐fluorouracil with 3 equivalents of the aryl acid chloride in pyridine and the subsequent hydrolysis of the 1,3‐diarylcarbonyl‐5‐fluorouracil derivatives in situ with a small amount of water. If a large amount of water were used in the second step, the 1,3‐diarylcarbonyl‐5‐fluorouracil precipitated before it hydrolyzed. The melting behaviors of both the 1‐arylcarbonyl‐5‐fluorouracil and 3‐arylcarbonyl‐5‐fluorouracil series suggested that thermal decomposition or rearrangement occurred on heating. The position of the C6‐H absorption in the 1H nmr spectra of 1‐arylcarbonyl‐5‐fluorouracils was 0.14 to 0.23 ppm farther downfield than that of the corresponding 3‐arylcarbonyl‐5‐fluorouracils while that of the 1,3‐diarylcarbonyl‐5‐fluorouracils was even farther downfield. The Rf values of 1‐arylcarbonyl‐5‐fluorouracils were significantly greater (0.23 to 0.41) than those of the corresponding 3‐arylcarbonyl‐5‐fluorouracils, while that of 1,3‐diarylcarbonyl‐5‐fluorouracil was slightly greater than that of 1‐arylcarbonyl‐5‐fluorouracils.
PolycyclicN‐Heterocyclic compounds.50. Synthesis and pharmacological evaluation of 2,3,6,7‐Tetrahydrothieno[2,3‐H]‐imidazo[2,1‐f][1,6]naphthyridines,3,4,7,8‐Tetrahydro‐2H‐thieno‐[2,3‐h]pyrimido[2,1‐f][1,6]naphthyridines and their precursor
Authors: Sasaki Kenji , Rouf Abu Shara S. , Hirota Takashi , Nakaya Naoki
Published: March 2009

Some novel 5‐hydroxyalkylamino‐1,2‐dihydrothieno[2,3‐h][1,6]naphthyridines were prepared by the reaction of 5‐chloro‐1,2‐dihydrothieno[2,3‐h][1,6]naphthyridine derivatives with some aminoalcohols in the presence of base. These derivatives were cyclized to the corresponding imidazo or pyrimido derivatives. The bronchodilatory activity of these compounds was evaluated on the basis of their relaxation activity to tracheal contraction induced by carbamylcholine chloride as a primaryin vitroassays. Effect of some naphthyridines on carbamylcholine chloride‐induced contractions of trachea in the presence or absence of milrinone or 4‐(3‐butoxy‐4‐methoxyphenyl)imidazolidin‐2‐one, which is inhibitor of phosphodiesterase III or IV, were also evaluated.
4‐Chloro‐3′‐methylsulfinyl‐5(6 or 8)‐nitro‐3,4′‐diquinolinyl sulfides
Authors: Maślankiewicz Maria J.
Published: March 2009

Reaction of 4‐chloro‐3′‐methylthio‐3,4′‐diquinolinyl sulfides 3, 9b, 9c with a nitrating mixture proceeds via the 3′‐methylthio group monooxidation and yields 3′‐methylsulfinyl diquinolinyl sulfides 4, 5b, 5c, respectively. Further treatment of 4 with a nitrating mixture followed as C5‐ and C8‐nitration and gives mixture of 5a and 5c. Treatment of 3′‐methylsulfinyl quinolines 6 and 7 with hydrochloric acid/potassium iodide system causes reduction of the sulfoxide group in 6 and 7 to the sulfide group yielding 8, in case of 4‐methoxyquinolines 6, hydrolysis of the 4‐methoxyquinoline moiety to the 4‐quinolinone moiety takes place simultaneously. The proton and carbon chemical shifts of 4 and 5a were completely assigned following COSY, HETCOR and INEPT or COLOC studies.
Quinolone analogues 1. A convenient synthesis of 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylic acids
Authors: Kurasawa Yoshihisa , Tsuruoka Akiko , Rikiishi Nanae , Fujiwara Noriko , Okamoto Yoshihisa , Kim Ho Sik
Published: March 2009

The reaction of the alkylhydrazinoquinoxaline N‐oxides 2a‐d with dimethyl acetylenedicarboxylate gave the dimethyl 1‐alkyl‐1,5‐dihydropyridazino[3,4‐b]qumoxaline‐3,4‐dicarboxylates 3a‐d, whose reaction with nitrous acid effected the C4‐oxidation to afford the dimethyl 1‐alkyl‐4‐hydroxy‐1,4‐dihydropyridazino‐[3,4‐b]quinoxaline‐3,4‐dicarboxylates 4a‐d, respectively. The reaction of compounds 4a‐d with 1,8‐diazabicyclo[5.4.0]‐7‐undecene in ethanol provided the ethyl 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxa‐line‐3‐carboxylates 5a‐d, while the reaction of compounds 4a‐d with potassium hydroxide furnished the 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylic acids 6a‐d, respectively. Compounds 6c,d were also obtained by the reaction of compounds 5c,d with potassium hydroxide, respectively.
A simple method for knoevenagel condensation of α,β‐conjugated and aromatic aldehydes with barbituric acid
Authors: Jursic Branko S.
Published: March 2009

Several aromatic and α,β‐conjugated aromatic aldehydes were condensed with barbituric acid in methanol solution in the absence of acid or base as a catalyst, affording 5‐ylidenebarbituric acid derivatives in almost quantitative yields.
Synthesis and spectral properties of 2‐[(o‐ and p‐substituted)aminophenyl] ‐3H‐5‐[(o‐ and p‐substituted)phenyl]‐7‐chloro‐1,4‐benzodiazepines
Authors: Cortés Eduardo Cortés , Franco Raúl Salazar , Mellado Olivia García
Published: March 2009

A series of twelve new 2‐[(o‐ and p‐substituted)aminophenyl]‐3H‐5‐[(o‐ and p‐substituted)phenyl]‐7‐chloro‐1,4‐benzodiazepines, which have possible pharmacological properties has been obtained. The synthesis was carried out following six steps. The structure of all products was corroborated by ir, 1H nmr, 13C nmr and ms. In addition for the compound 2‐(o‐chloroaminophenyl)‐3H‐5‐(o‐fluorophenyl)‐7‐chloro‐1,4‐benzodiazepine 7, its structure was confirmed by X‐ray diffraction.
Studies with functionally substituted N‐alkylazoles: The reactivity of 1‐(3,5‐dimethylpyrazol‐1‐yl)‐acetone towards electrophilic reagents
Authors: Mohamed Mona Hassan , Elnagdi Mohamed Hilmy , Abdel‐Khalik Mervat Mohammed
Published: March 2009

The reaction of 1‐(3,5‐dimethylpyrazol‐1‐yl)acetone 4 with aromatic diazonium salts afforded the corresponding arylhydrazones 5a,b that were converted into pyridazines 6a,b and 8 via condensation with active methylene nitriles and dimethylformamide dimethylacetal, respectively. Condensation of 4 with phenylhydrazine afforded the phenylhydrazone 10, which could be converted into the indolylpyrazole 11 on treatment with ethanolic hydrochloric acid. Compound 4 also reacted with nitrous acid, benzyl‐idenemalononitrile to yield a variety of substituted new pyrazoles.
A facile synthesis of fluorine‐containing heterocycles ‐ use of 1,1,1‐trifluoro‐2‐alkanones as a convenient synthetic intermediate
Authors: Kamitori Yasuhiro
Published: March 2009

1,1,1‐Trifluoro‐2,3‐alkanediones 2 easily obtainable from various aldehyde dialkylhydrazones were reacted with several diamines to afford trifluoromethylquinoxalines 3 and trifluoromethylpyrazines 4 in good yields. With the use of aldehydes and aqueous ammonia instead of diamines, diketones 2 were successfully converted to the corresponding 4‐trifluoromethylimidazoles 5 in satisfactory yields.
Synthesis of pyridazinone‐substituted 1,3,4‐thiadiazoles, ‐1,3,4‐oxadiazoles and ‐1,2,4‐triazoles
Authors: Zou Xiajuan , Jin Guiyu
Published: March 2009

Several 1‐(1‐aryl‐1,4‐dihydro‐3‐carboxy‐6‐methylpyridazin‐4‐one)‐4‐aryl thio‐semicarbazides and their corresponding oxadiazole, thiadiazole and triazole derivatives were prepared and characterized by their spectral data. The preliminary biological tests showed that some new compounds exhibit good anti‐fungal activity.
Synthesis of novel flavonoid derivatives as potential HIV‐ Integrase inhibitors
Authors: Mateeva Nelly N. , Kode Rao N. , Redda Kinfe K.
Published: March 2009

Eighteen novel flavonoid derivatives ‐ substituted chalcones and flavones were synthesized and characterized by using NMR, IR, UV/Vis spectroscopy and elemental analysis. The target compounds were achieved by using a sequence of simple and effective reactions starting from phloroglucinol. The initial hydroxyl groups were protected by methylation and in the final flavones the 5‐OH group was selectively demethylated by means of AlBr3. 5‐methoxy flavones exhibit a strong fluorescence, which was quenched after the removal of the methyl group.
A study concerning the synthesis, basicity and hydrolysis of 4‐amino‐2‐(N,N‐diethylamino)quinazoline derivatives
Authors: Zieliński Wojciech , Kudelko Agnieszka
Published: March 2009

A group of 2‐(N,N‐diethylamino)‐4‐aminoquinazoline derivatives have been synthesized in the reaction of N1,N1‐diethyl‐N2‐arylchlorocarboxyamidines with cyanamide in the presence of T1Cl4 as a catalyst. Such quinazolines decompose into the corresponding quinazolones in dilute aqueous HC1 solutions at higher temperature. Hydrolysis rates of 2‐(N,N‐diethylamino)‐4‐aminoquinazoline and 2‐(N,N‐diethylamino)‐4‐(N,N‐dimethylamino)‐quinazoline have been determined to observe the influence of substituents at the 4‐amino group upon the hydrolysis. pKa values have been also determined for these compounds and analyzed in conjunction with the Hammett σ constants.
Novel synthesis of N‐{6‐aryl‐4‐[(E)‐2‐furylmethylene]‐1,2,3,4‐tetrahydro‐3‐oxopyridazin‐1 ‐ylcarbonyl}‐p‐toluenesulfonamides and N‐{5‐[(E)‐1‐aroylmethyl‐2‐(2‐furyl) vinyl]‐1,3,4‐oxadiazol‐2‐yl} ‐p‐toluenesulfonamides
Authors: Hamad Abdel‐Sattar S. , Hashem Ahmed I.
Published: March 2009

Novel N‐{6‐aryl‐4‐[(E)‐2‐furylmethylene]‐1,2,3,4‐tetrahydro‐3‐oxopyridazin‐1 ‐ylcarbonyl}‐p‐toluene‐sulfonamides 4a‐d were prepared by the reaction of (E)‐2‐aroylmethyl‐3‐(2‐furyl) acrylohydrazides 2a‐d with tosylisocyanate. This has been shown to occur by initial formation of (E)‐2‐aroylmethyl‐3‐(2‐furyl)‐N'‐(tosylaminocarbonyl) acrylohydrazides 3a‐d followed by acid catalyzed cyclization to afford N‐{5‐[(E)‐1‐aroylmethyl‐2‐(2‐furyl)vinyl]‐1,3,4‐oxadiazol‐2‐yl}‐p‐toluenesulfonamides 5a‐d.
Diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles by a tandem reduction‐reductive amination reaction
Authors: Bunce Richard A. , Herron Derrick M. , Lewis Jason R. , Kotturi Sharadsrikar V. , Holt Elizabeth M.
Published: March 2009

A two‐step diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles has been developed from cyclic β‐ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2‐oxo‐cycloalkanecarboxylates with 2‐nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxyl‐amine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated in high yield as single diastereomers having the trans‐fused ring junction. The observed selectivity is rationalized in terms of a steric effect imposed by the ester group in the final reductive amination step which directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference for the cis‐fused heterocycle.
Preparation of unsubstituted dipyridine‐dibarbituric acid ylide through dimerization of pyridin‐2‐ylmethylenepyrimidinetrione as a reactive intermediate
Authors: Jursic Branko S.
Published: March 2009

Preparation of 5,5′‐(pyridin‐2‐ylmethylene)dipyrimidinetrione from barbituric acid and 2‐pyridinecarbox‐aldehyde in any polar solvent is a straightforward synthetic procedure, while preparation of the dipyridine‐dibarbituric acid ylide from the same starting materials is sensitive to the reaction media, pH, and temperature. For both products, the formation of the reactive intermediate 2‐pyridin‐2‐ylmethylenepyrimidinetrione is certain and this intermediate is a cross road for the reaction to be directed in one way or other. The experimental evidence for the formation of this important intermediate, as well as synthetic procedures for the preparation of both condensation products are presented.
Synthesis of trans‐disubstituted cyclam ligands appended with two 6‐hydroxymethylpyridin‐2‐ylmethyl sidearms: Crystal structures of the 1,8‐dimethyl‐4,ll‐di(6‐hydroxymethylpyridin‐2‐ylmethyl)cylam ligand and its Co(II) and Ni(II) complexes
Authors: Xue Guoping , Bradshaw Jerald S. , Dalley N. Kent , Savage Paul B. , Izatt Reed M.
Published: March 2009

Two new trans‐disubstituted cyclam ligands; 1,8‐di(6‐hydroxymethylpyridin‐2‐ylmethyl)‐1,4,8,11‐tetra‐azacyclotetradecane (5) and 1,8‐dimethyl‐4, 11‐di(6‐hydroxymethylpyridin‐2‐ylmethyl)‐1,4,8,11 ‐tetraaza‐cyclotetradecane (6); have been synthesized and characterized. The crystal structures of ligand 6 and its Ni(II) and Co(II) complexes have been determined. Crystal data are given for 6, space group, P21/c, a = 11.095 (6) Å, b = 9.467 (5) Å, c = 13.283 (8) Å; β = 106.95 (5)°, Z = 2, R = 0.0715; for [Ni 6](C104)2, space group P21/c, a = 9.4848 (14) Å, b = 33.941(6) Å, c = 9.793(2) A, β = 95.264(14)°, Z = 4, R = 0.0567; for [Co 6](C104)2, space group, P21/c, a = 9.440 (6) Å, b = 33.848 (13) Å, c = 9.820 (3) Å, β = 95.16(3)°, Z = 4, R = 0.0718. In both complexes, the metal atoms are six‐coordinate with only one of the pendants interacting with the central metal atom and the other pendant remaining uncoordinated.
Synthesis of carbazole, acridine, phenazine, 4H‐benzo[def]carbazole and their derivatives by thermal cyclization reaction of aromatic amines
Authors: Horaguchi Takaaki , Oyanagi Takako , Creencia Evelyn Cuevas , Tanemura Kiyoshi , Suzuki Tsuneo
Published: March 2009

A variety of nitrogen‐containing heterocycles were synthesized by passing vapors of aromatic amines over calcium oxide at 450–650 °C under nitrogen carrier gas. Reaction of 2‐aminobiphenyl 3a at 560 °C gave carbazole 4 in 80% yield. Reaction of 2, 2′‐diaminobiphenyl 3b afforded a mixture of carbazole 4 and 4‐aminocarbozole 6b. In the case of 2‐amino‐2′‐nitrobiphenyl 3c, benzo[c]cinnoline 7 was obtained along with carbazole 4. Reaction of 2‐amino‐2′‐methoxybiphenyl 3d gave four products of carbazole 4,4‐hydroxycarbazole 6e, phenanthridine 8 and dibenzofuran 9. Reaction of 2‐aminodiphenylmethane 5a afforded acridine 10. In the case of 2‐aminobenzophenone 5b, acridone 11 was obtained as a major product. Reaction of 2‐aminobenzhydrol 5c gave acridine 10. When 2‐aminodiphenylamine 5d was reacted, phenazine 12 was obtained in good yield. In contrast, reaction of 2‐aminodiphenyl ether 5e produced only 2‐hydroxydiphenylamine 13. Reaction of 4‐aminophenanthrene 14 produced 4H‐benzo[def]carbazole 15 in 61% yield.
First synthesis of novel pentaheterocyclic ring system of 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole
Authors: Elwan Nehal M.
Published: March 2009

Reaction of 1‐amino‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (1) with dimethylformamide‐dimethylacetal (DMF‐DMA) gave 1‐[N,N‐(dimethylaminomethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (2). Compounds (1) reacted with triethylorthoformate yielding 1‐[N‐(ethoxymethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (3). 3‐Amino‐4‐imino‐5‐aryl‐6‐cyanopyrimido[5′,4′:5,6]pyrido[1,2‐α] benzimidazole (4) was synthesized via condensation of either (2) or (3) with hydrazine hydrate. Reactions of (4) with acetic anhydride, ethyl chloroformate or aryl isothiocyanate yielded the respective derivative of the new ring system namely 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole (5–7).
Ruthenium‐catalyzed formal alkyl group transfer: Synthesis of quinolines from nitroarenes and alkylammonium halides
Authors: Cho Chan Sik , Lee Na Young , Kim Tae‐Jeong , Shim Sang Chul
Published: March 2009

Nitroarenes are reductively cyclized with an array of tetraalkylammonium halides and trialkylarnmonium chlorides in the presence of a catalytic amount of a ruthenium catalyst along with tin(II) chloride dihydrate at 180° to afford the corresponding quinolines in moderate to good yields. The addition of tin(II) chloride dihydrate is necessary for the effective formation of quinolines and toluene is the solvent of choice. A reaction pathway involving initial reduction of nitroarenes to anilines and conversion of alkylammonium halides to alkylamines, alkyl group transfer from alkylamines to anilines to form an imine, dimerization of imine, and heteroannulation is proposed for this catalytic process.
Stereoselective synthesis of conformationally constrained tropane analogues: 6‐Chloro‐2,5‐diazatetracyclo[8.5.0.02,13.04,9]pentadeca‐4,6,8‐triene‐11‐one and 6‐chloro‐2,7‐diazatetracyclo‐[8.5.0.02,13.04,9]pentadeca‐4,6,8‐triene‐11‐one
Authors: Cheng Jie , Xu Liang , Stevens Edwin D. , Trudell Mark L. , Izenwasser Sari , Wade Dean
Published: March 2009

Two conformationally constrained tropane derivatives were prepared as rigid nicotinic acetylcholine receptor ligands. A palladium catalyzed intramolecular α‐arylation reaction was employed to generate the tricyclic compounds in good yields fromN‐(bromo‐chloropyridylmethyl)‐8‐azabicyclo[3.2.1]octan‐3‐ones.
Synthesis and structures of new chiral diamide‐ester macrocycles
Authors: Gao Ming Zhang , Reibenspies Joseph H. , Zingaro Ralph A. , Wang Bo , Xu Zun Le
Published: March 2009

A series of new hetero‐macrocyclic diamide‐ester compounds (4a — 4z, 6a — 6b) were synthesized using 4‐(dimethylamino)pyridine as catalyst and characterization by infrared spectra, nuclear magnetic resonance spectra, mass spectra and elemental analyses. The structures of 4e and meso 4b were determined by X‐ray crystallography. The association constants of the compounds with various metal ions were determined by UV‐visible spectroscopic titration, and showed a selective recognition for certain metal ions.
A versatile CARS microscope for biological imaging
Authors: Downes Andrew , Mouras Rabah , Elfick Alistair
Published: March 2009

We have constructed a novel, versatile Coherent anti‐Stokes Raman scattering (CARS) microscope for biological imaging. The system employs a Nd:YVO4 laser as Stokes (6 ps, 1064 nm), and a tunable optical parametric oscillators (OPOs) (5 ps, 700–1000 nm) as pump excitation, resulting in an observable range of ∼600–4000 cm−1. A second OPO can be used as a replacement pump for low wavenumber excitation (down to ∼100 cm−1). Pump and Stokes excitations are focused onto a single‐mode fibre for ease of alignment, which is connected to the input of a confocal inverted optical microscope. The epi‐detected CARS signal is filtered using a spectrometer, and the photons counted with an avalanche photodiode. This detection is preferable to using bandpass filters and photomultipliers, as it allows all wavenumbers to be imaged and ensures rejection of unwanted fluorescent and scattered light. Our microscope comprises a heater stage and perfusion cell for imaging live cells, and allows complementary biological imaging techniques (differential interference contrast (DIC), second harmonic generation, sum frequency generation, one‐ and two‐photon fluorescence, fluorescence lifetime imaging). In addition, our system features an atomic force microscope (AFM) which enables CARS imaging at 10‐nm resolution. The details and advantages of the modular imaging system are described more fully, and the latest results are presented. Copyright © 2009 John Wiley & Sons, Ltd.
Assessment of hydrolysis of cheese whey and use of hydrolysate for bioproduction of carotenoids by Sporidiobolus salmonicolor CBS 2636
Authors: Valduga Eunice , Tatsch Piehtra , Vanzo Larissa Tonial , Rauber Fernanda , Di Luccio Marco , Treichel Helen
Published: March 2009

BACKGROUND: The increasing industrial demand for carotenoids has led to growing interest in their bioproduction. The need to reduce production costs has encouraged the use of low‐cost agroindustrial substrates. In this context, this work studied the pretreatment of Mozzarella cheese whey and the use of the pretreated whey as fermentation medium for the bioproduction of carotenoids by Sporidiobolus salmonicolor CBS 2636.

RESULTS: Bioproduction was carried out in an orbital shaker using a 10 mL L−1 inoculum, incubation at 25 °C and a stirring rate of 180 rpm for 120 h in a non‐illuminated environment. The carotenoids were recovered using liquid N2 combined with dimethyl sulfoxide for cell rupture and an acetone/methanol mixture (7:3 v/v) for extraction. The maximum concentration of total carotenoids obtained was 590.4 µg L−1 in a medium with 900 g L−1 cheese whey hydrolysate and 4 g L−1 K2HPO4 at 180 rpm, 25 °C and pH 4.

CONCLUSION: The use of enzyme‐hydrolysed cheese whey was more effective in carotenoid bioproduction by S. salmonicolor CBS 2636 than the use of acid‐hydrolysed cheese whey. The concentration of total carotenoids obtained with the enzymatic hydrolysate was six times higher than that obtained with the acid hydrolysate. Copyright © 2009 Society of Chemical Industry
Crops with target‐site herbicide resistance for Orobanche and Striga control
Authors: Gressel Jonathan
Published: March 2009

It is necessary to control root parasitic weeds before or as they attach to the crop. This can only be easily achieved chemically with herbicides that are systemic, or with herbicides that are active in soil. Long‐term control can only be attained if the crops do not metabolise the herbicide, i.e. have target‐site resistance. Such target‐site resistances have allowed foliar applications of herbicides inhibiting enol‐pyruvylshikimate phosphate synthase (EPSPS) (glyphosate), acetolactate synthase (ALS) (e.g. chlorsulfuron, imazapyr) and dihydropteroate synthase (asulam) for Orobanche control in experimental conditions with various crops. Large‐scale use of imazapyr as a seed dressing of imidazolinone‐resistant maize has been commercialised for Striga control. Crops with two target‐site resistances will be more resilient to the evolution of resistance in the parasite, if well managed. Copyright © 2009 Society of Chemical Industry
Assessing stakeholder evaluation concerns: An application to the Central Arizona water resources system
Authors: Robin Keller L. , Kirkwood Craig W. , Jones Nancy S.
Published: March 2009

We present an approach for efficiently assessing stakeholder evaluation concerns in the first stage of problem structuring for decisions involving complex systems. We used a Web survey to assess the appropriateness of a set of evaluation concerns for evaluating Central Arizona water resources system policies and to gather information on stakeholder priorities. The resulting set of concerns brings a “decision focus” to the modeling efforts of the NSF‐funded Decision Center for a Desert City at Arizona State University. This problem structuring approach, the set of evaluation concerns, and the analysis of variations among stakeholder group priorities can serve as a starting point for other similar policy settings. © 2009 Wiley Periodicals, Inc. Syst Eng
Nanotechnology for bone materials
Authors: Tran Nhiem , Webster Thomas J.
Published: March 2009

It has been established that for orthopedic‐related research, nanomaterials (materials defined as those with constituent dimensions less than 100 nm in at least one direction) have superior properties compared to conventional counterparts. This review summarizes studies that have demonstrated enhancedin vitroandin vivoosteoblast (bone‐forming cells) functions (such as adhesion, proliferation, synthesis of bone‐related proteins, and deposition of calcium‐containing mineral) on nanostructured metals, ceramics, polymers, and composites thereof compared to currently used implants. These results strongly imply that nanomaterials may improve osseointegration, which is crucial for long‐term implant efficacy. This review also focuses on novel drug‐carrying magnetic nanoparticles designed to treat various bone diseases (such as osteoporosis). Although further investigation of thein vivoresponses and toxicity of these novel nanomaterials pertinent for orthopedic applications are needed, nanotechnology clearly has already demonstrated the ability to produce better bone implants and therefore should be further investigated. Copyright © 2009 John Wiley & Sons, Inc.

This article is categorized under:

Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement
Over‐expression of the Anti‐apoptotic Protein Bcl‐2 Affects Membrane Lipid Composition in HL‐60 Cells
Authors: Cantrel Catherine , Zachowski Alain , Geny Blandine
Published: March 2009

We studied modifications induced at the membrane lipid level by over‐expression of the anti‐apoptotic protein Bcl‐2. When total cell phospholipids were analyzed, the transformation led to a moderate decrease in poly‐unsaturated fatty acids, compensated by an increase in mono‐unsaturated species. At the mitochondrial membrane level, the changes were more important and occurred in saturated and dimethyl acetal fatty acids, which became more abundant, while unsaturated fatty acid content diminished. This indicates a decline in oxidation‐sensitive fatty acids (unsaturated species) together with a gain in oxidation‐insensitive saturated fatty acids and in plasmalogen (as detected by dimethyl acetal fatty acids) considered as oxygen species scavengers. Theses changes, combined with the protective role of Bcl‐2 against oxidation due to its effect on the redox potential, should protect cells from apoptosis starting in mitochondria.
Hearing and vestibular loss in Streptococcus suis infection from swine and traditional raw pork exposure in northern Thailand
Authors: Navacharoen N , Chantharochavong V , Hanprasertpong C , Kangsanarak J , Lekagul S
Published: March 2009

Objectives:

To describe a series of 40 culture-proven, Streptococcus suis infected patients, focusing on route of entry and on hearing and vestibular dysfunction.

Methods:

Retrospective study of patient records in a tertiary care hospital in northern Thailand, 2003–2007.

Results:

The majority (75 per cent) of cases were men with heavy drinking habits. A past history of the consumption of raw pork and/or pig's blood was found in 62.5 per cent of cases, whereas contact with swine products was found in 25 per cent. Thirty patients presented with sepsis, 19 with meningitis and 10 with infective endocarditis. The overall mortality rate was 20 per cent. After a mean follow up of 17 months, 73 per cent of the surviving meningitis cases had persistent sensorineural hearing loss and 50 per cent demonstrated vestibular impairment. In one patient, roentgenographic studies of the temporal bone were compatible with labyrinthitis ossificans.

Conclusions:

Permanent hearing loss and vestibular impairment occur frequently in persons surviving meningitis caused by Streptococcus suis.
The Emperor Jahangir and the Pursuit of Pleasure
Authors: BALABANLILAR LISA
Published: March 2009

The Mughal emperors of India were remarkably mobile kings, inspiring modern historians to describe their imperial court culture as ‘peripatetic’. While the Mughals were not immune to the impulse to construct massive urban architect, no Mughal city, no matter how splendid, innovative, accessible or enlightened, remained the imperial centre for long. Through generations of Mughal rule in India, the political relevance of Mughal imperial cities continued to be very limited; it was physical mobility which remained at the centre of Mughal imperial court life and, for much of the Mughal period, the imperial court was encapsulated in the physical presence of the king.
Psychosis and Human Rights: Conflicts in Mental Health Policy and Practice
Authors: Spandler Helen , Calton Tim
Published: March 2009

This paper examines conflicts in polices in England and Wales pertaining to the demand for alternative, non-medical crisis support for those experiencing ‘psychosis’. We examine the limitations of current treatment, policy and legislative frameworks in supporting these demands. In particular, we focus on the limitations of prevailing conceptualisations of ‘human rights’, ‘social inclusion’ and ‘recovery’. These concepts, we argue, are embedded within a broader treatment framework which renders medication as mandatory and all other treatment modalities as inherently subsidiary, and a broader policy framework which is complicit with bio-medical orthodoxies of ‘mental illness’ and prioritises treatment compliance and compulsion. Therefore, in order to advance a ‘human rights’ approach to mental health policy, we argue that reigning orthodoxies inherent within policy and practice must be explicitly challenged to open up spaces for the availability of alternatives.
The ratio of NR2A/B NMDA receptor subunits determines the qualities of ocular dominance plasticity in visual cortex
Authors: Cho Kathleen K. A. , Khibnik Lena , Philpot Benjamin D. , Bear Mark F.
Published: March 2009

Bidirectional synaptic plasticity during development ensures that appropriate synapses in the brain are strengthened and maintained while inappropriate connections are weakened and eliminated. This plasticity is well illustrated in mouse visual cortex, where monocular deprivation during early postnatal development leads to a rapid depression of inputs from the deprived eye and a delayed strengthening of inputs from the non-deprived eye. The mechanisms that control these bidirectional synaptic modifications remain controversial. Here we demonstrate, both in vitro and in vivo, that genetic deletion or reduction of the NR2A NMDA receptor subunit impairs activity-dependent weakening of synapses and enhances the strengthening of synapses. Although brief monocular deprivation in juvenile WT mice normally causes a profound depression of the deprived-eye response without a change in the non-deprived eye response, NR2A-knockout mice fail to exhibit deprivation-induced depression and instead exhibit precocious potentiation of the non-deprived eye inputs. These data support the hypothesis that a reduction in the NR2A/B ratio during monocular deprivation is permissive for the compensatory potentiation of non-deprived inputs.
Sumoylation of ABI5 by the
Arabidopsis
SUMO E3 ligase SIZ1 negatively regulates abscisic acid signaling
Authors: Miura Kenji , Lee Jiyoung , Jin Jing Bo , Yoo Chan Yul , Miura Tomoko , Hasegawa Paul M.
Published: March 2009

SUMO (small ubiquitin-related modifier) conjugation (i.e., sumoylation) to protein substrates is a reversible posttranslational modification that regulates signaling by modulating transcription factor activity. This paper presents evidence that the SUMO E3 ligase SIZ1 negatively regulates abscisic acid (ABA) signaling, which is dependent on the bZIP transcripton factor ABI5. Loss-of-function T-DNA insertion
siz1–2
and
siz1–3
mutations caused ABA hypersensitivity for seed germination arrest and seedling primary root growth inhibition. Furthermore, expression of genes that are ABA-responsive through ABI5-dependent signaling (e.g.,
RD29A
,
Rd29B
,
AtEm6
,
RAB18
,
ADH1
) was hyperinduced by the hormone in
siz1
seedlings.
abi5–4
suppressed ABA hypersensitivity caused by
siz1
(
siz1–2 abi5–4
), demonstrating an epistatic genetic interaction between
SIZ1
and
ABI5
. A K391R substitution in ABI5 [ABI5(K391R)] blocked SIZ1-mediated sumoylation of the transcription factor in vitro and in
Arabidopsis
protoplasts, indicating that ABI5 is sumoylated through SIZ1 and that K391 is the principal site for SUMO conjugation. In
abi5–4
plants,
ABI5(K391R
) expression caused greater ABA hypersensitivity (gene expression, seed germination arrest and primary root growth inhibition) compared with
ABI5
expression. Together, these results establish that SIZ1-dependent sumoylation of ABI5 attenuates ABA signaling. The double mutant
siz1–2 afp-1
exhibited even greater ABA sensitivity than the single mutant
siz1
, suggesting that SIZ1 represses ABI5 signaling function independent of AFP1.