MEMBRANE-PERMEANT PHOSPHOINOSITIDES

Abstract: Membrane-permeant phosphoinositides, including phosphatidylinositol phosphate esters, are described. A membrane-permeant phosphoinositide includes groups that neutralize the charges of the phosphate moieties of the phosphoinositide. A cell can be treated with the membrane-permeant phosphoinositide, which is then absorbed into the cell. The neutralizing groups can be removed intracellularly to afford the charged phosphoinositide.

Description: Membrane-Permeant Phosphoinositides Statement as to Federally Sponsored Research This invention was made with Government support under Grant (or Contract) No. NS27177, awarded by the National Institutes of Health. The Government has certain rights in this invention. Background of the Invention A family of phosphoinositide 3 -OH kinases (PI3K) biosynthesize D-3 phosphorylated inositol lipids. See, for example, Toker, A. and Cantley, L.C., Nature 387:673-676 (1997) . These enzymes phosphorylate phosphatidylinositol, phosphatidylinositol-4 -phosphate and phosphatidylinositol- 4, 5-bisphosphate on the D-3 position of the inositol ring to generate phosphatidylinositol-3-phosphate (PI(3)P), phosphatidylinositol-3,4-bisphosphate (PI(3,4)P 2 ) and phosphatidylinositol-3,4, 5-trisphosphate (PIP 3 ) , respectively. Some forms of PI3K, such as that of yeast Vps34p and its homologues, produce exclusively PI (3) P. In mammalian cells, PI(3)P is usually constitutively present. PI(3,4)P 2 and PIP 3 are normally undetectable in unstimulated cells, but their concentrations can become transiently elevated within seconds to minutes following stimulation with various growth factors or cytokines. This behavior can be indicative of signaling roles for both PI(3,4)P 2 and PIP 3 . Various PI3Ks can be activated through both tyrosine kinase and G-protein dependent pathways. Multiple putative downstream targets have been identified including Ca 2+ -independent protein kinase C (PKC) isoforms δ , e , ζ , and η , and proteins with pleckstrin homology domains such as Akt/PKB, as well as other proteins such as synaptotagamin . Summary of the Invention In general, the invention features membrane-permeant phosphoinositides, including phosphatidylinositol phosphate esters. A membrane-permeant phosphoinositide includes groups that neutralize the charges of the phosphate moieties of the phosphatidylinositol. A cell can be treated with the membrane-permeant phosphoinositide, which is then absorbed into the cell. The neutralizing groups can be removed intracellularly to afford the charged phosphoinositide. In one aspect, the invention features a membrane- permeant phosphoinositide. The membrane-permeant phosphoinositide can be a compound of formula: or 2 - In the compound, R 1 is H, -CH 2 0C(0)CH 3 , -CH 2 OC (O) CH 2 CH 3 , -CH 2 OC(0) (CH 2 ) 2 CH 3 , or a caging group, R 2 is H, -CH 2 0C(0)CH 3 , -CH 2 OC(0)CH 2 CH 3 , -CH 2 OC(0) (CH 2 ) 2 CH 3 , or -P(O) (OR 11 ) (X 2 R 12 ) , or a caging group, R 3 is H, -CH 2 OC(0)CH 3 , -CH 2 OC (0) CH 2 CH 3 , -CH 2 OC(0) (CH 2 ) 2 CH 3 , -P(O) (OR 13 ) (X 3 R 14 ) , or a caging group, R 4 is H, -CH 2 0C(0)CH 3 , -CH 2 OC(0)CH 2 CH 3 , -CH 2 OC(0) (CH 2 ) 2 CH 3 , -P(O) (OR 15 ) (X 4 R 16 ) , or a caging group, R 5 is H, -CH 2 OC(0)CH 3 , -CH 2 OC(0)CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3/ or a caging group, each of X 1 , X 2 , X 3 , and X 4 , is, independently, S or 0, each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, H, -CH 2 0C (O) CH 3 , -CH 2 0C (0) CH 2 CH 3 , or -CH 2 OC(0) (CH 2 ) 2 CH 3 , each of R 7 and R 8 is, independently, a saturated or unsaturated C 4 -C 22 group; Z is 0, CH 2 , or NH, and at least one of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R )16 is -CH 2 0C(0)CH 3 , -CH 2 OC(0)CH 2 CH 3 , or -CH 2 0C(0) (CH 2 ) 2 CH 3 . At least one of R 2 , R 3 , and R 4 can be a phosphorus- containing group. For example, R 2 can be -P(0) (OR 11 ) (X 2 R 12 ) , R 3 can be -P(O) (OR 13 ) (X 3 R 14 ) , or R 4 can be -P(O) (OR 15 ) (X 4 R 16 ) . In preferred embodiments, at least two of R 2 , R 3 , and R 4 are phosphorus-containing groups. R 2 can be -P(0) (OR 11 ) (X 2 R 12 ) and R 3 can be -P(O) (OR 13 ) (X 3 R 14 ) , R 2 can be -P(O) (OR 11 ) (XR 12 ) and R 4 can be -P(O) (OR 15 ) (X 4 R 16 ) , or R 3 can be -P(O) (OR 13 ) (X 3 R 14 ) and R 4 can be -P(O) (OR 15 ) (X 4 R 16 ) . In other preferred embodiments, R 2 , R 3 , and R 4 are phosphorus- containing groups. In other embodiments, R 2 is - (O) (OR 11 ) (X 2 R 12 ) , R 3 is -P(0) (OR 13 ) (X 3 R 14 ) , and R 4 is -P(O) (OR 15 ) (X 4 R 16 ) . In preferred embodiments, Z is 0, each of X 1 , X 2 , X 3 , and X 4 is 0, or each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is -CH 2 OC(0)CH 3 . Each of R 7 and R 8 can be a saturated or unsaturated C 4 -C 22 acyl, a C 4 -C 22 alkyl, a C 4 -C 22 alkenyl, or a C 4 -C 22 polyene. For example, each of R 7 and R 8 can be derived from a fatty acid. A saturated or unsaturated C 4 -C 22 - acyl is a carbonyl-terminated alkyl, alkenyl, or polyene containing a total of 4-22 carbon atoms. The acyl, alkyl, alkenyl, or polyene can be branched or linear and can include cyclic groups. The acyl, alkyl, alkenyl, or polyene can be substituted with one or more hydroxy, amino, or halogen groups. The alkyl group is saturated and the alkenyl and polyene groups are unsaturated. The double bond of the alkenyl and the polyene can be positioned anywhere along the C 4 _c 22 chain. The polyene group contains two or more double bonds (e.g., two to six double bonds) which can be conjugated or non-conjugated. Each of the double bonds of the polyene or alkenyl groups, independently, can be in a cis or trans configuration. 4 - In preferred embodiments, each of R 7 and R 8 is, independently, -C(O) (CH 2 ) m CH 3 where m is an integer between 4-20, inclusive, -C (O) - (CH 2 ) 7 CH=CH (CH 2 ) 7 CH 3 , -C(0) - (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 , -C(0)- (CH 2 ) 7 CH=CHCH 2 CH=CH (CH 2 ) 4 CH 3 , or -C(O) - (CH 2 ) 2 (CH 2 CH=CH) 4 (CH 2 ) 4 CH 3 . Each double bond can be in a cis or trans configuration. In preferred embodiments, the compound is included in a pharmaceutical composition. A caging group is a group that can be removed from the compound by exposing the compound to light, for example, UV-photolyzable groups that can be removed by a flash of UV. Caging groups are described, for example, in Adams, S.R. and Tsien, R.Y. Annual .Rev. Physiology 55 : 755-784 (1993), incorporated herein by reference. The caging group can be 2-nitrobenzyl, 1- (2-nitrophenyl) ethyl, 4 , 5-dimethoxy-2- nitrobenzyl, 6-nitropiperonyl, 4-hydroxyphenacyl, 7- hydroxycoumarin-4-ylmethyl, or a derivative thereof. In another aspect, the invention features a method of delivering a phosphoinositide to a cell. The method includes contacting a cell with a membrane-permeant phosphoinositide, transporting the membrane-permeant phosphoinositide into the cell, and converting the membrane- permeant phosphoinositide to a phosphoinositide within the cell. In another aspect, the invention features a method for identifying a biological process within a cell triggered by intracellular phosphoinositide. The method includes contacting a cell with a membrane-permeant phosphoinositide, transporting the membrane-permeant phosphoinositide into the cell, converting the membrane-permeant phosphoinositide to a phosphoinositide within the cell, and measuring an effect of the phosphoinositide on a biological process. The phosphoinositide can directly affect the biological process, - 5 - or a metabolite of the phosphoinositide can effect the biological process. Transporting a membrane-permeant phosphoinositide into the cell can include active transport, passive transport, or diffusion. The membrane-permeant phosphoinositides can be delivered exogenously to its site of action inside intact cells. PIP 3 has at least four negative charges at physiological pH. Therefore, PIP 3 is extremely unlikely to diffuse into cells by itself and effective administration of PIP 3 itself to intact cells is problematic. A membrane- permeant phosphoinositide is a neutral molecule that can cross the plasma membrane by passive diffusion. Thus, an example of a membrane-permeant phosphoinositide can be PIP 3 having the phosphate groups derivatized with acetoxymethyl (AM) groups. The resulting acetoxymethyl phosphate esters can be readily hydrolyzed by intracellular esterases, thereby regenerating PIP 3 inside the cells. Other features or advantages of the present invention will be apparent from the following detailed description and from the claims. Brief Description of the Drawing FIG. 1 is a schematic drawing depicting transport of PIP 3 /AM into cells and its conversion to PIP 3 . FIG. 2 is a graph depicting the effects of insulin, wortmannin, and PIP 3 /AM on hexose uptake in adipocytes. The adipocytes were incubated in the presence (+) or absence (-) of the agents listed below each bar. FIG. 3 is a graph depicting the effects of EGF and PIP 3 /AM on chloride secretion from T 84 monolayers . FIG. 4 is a graph depicting the effects of PIP 3 /AM on 86 Rb + efflux from preloaded T 84 colonic epithelia. - 6 - Description of the Preferred Embodiments In general, the invention features membrane-permeant phosphoinositides that can be converted intracellularly to a corresponding phosphoinositide. The membrane-permeant phosphoinositide is a neutral molecule that can cross the plasma membrane by passive diffusion. For example, a membrane-permeant phosphoinositide can be PIP 3 having the phosphate groups derivatized with acetoxymethyl (AM) groups. The resulting acetoxymethyl phosphate esters can be readily hydrolyzed by intracellular esterases, thereby regenerating PIP 3 inside the cells. To form a membrane-permeant phosphoinositide, all the phosphate negative charges of PIP 3 were esterified. It is also possible to prepare a membrane-permeant PIP 3 derivative in which the 2- and 6-hydroxyls are protected. The 2- and 6-hydroxyls can be protected with hydrolyzable groups such as AM groups. Alternatively, they can be protected to form UV-photolyzable caging groups such as 3,4- dimethoxy-2-nitrobenzyl, 2-nitrobenzyl, 1- (2- nitrophenyl) ethyl, 6-nitropiperonyl 4-hydroxyphenacyl, or 7- hydroxycoumarin-4-ylmethyl ethers. For example, the 3,4- dimethoxy-2-nitrobenzyl group of a corresponding ether can be instantaneously removed with a flash of UV, making it an suitable group for unleashing the immediate actions of this fast-acting, rapidly metabolized messenger. The acyl chain can be derived from a fatty acid. The chain length can be selected to provide compounds that are more soluble or tractable. For example, Reddy, K. K. , et al . J. Org. Chem. 60:3385-3390 (1995), have shown that di-C 8 -PIP 3 was more soluble and tractable than PIP 3 's having chain lengths of C 18 or C 20 . Because the diacylglycerol group can be added intact at a late stage of the synthesis, this part of the molecule can be varied relatively easily. - 7 - A generalized synthesis of membrane-permeant phosphoinositides is shown in Schemes I-IV. In the schemes: TMS-OTf is trimethylsilyl trifluoromethanesulfonate; TBDPS is ϋert-butyldiphenylsilyl; Bz is benzoyl; py is pyridine; BOM is benzyloxymethyl; TBAF is tetrabutylammonium fluoride; THF is tetrahydrofuran; DMIPS is dimethylisopropylsilyl ; λ Pr is isopropyl; R is 2-cyanoethyl; Ak is a C 3 -C 21 alkyl, alkenyl, or polyene; and R' is a protecting group such as, for example, acetoxymethyl. The synthesis of membrane-permeant esters of PIP 3 (Scheme I) can start with enantiomerically pure D-l-O- (tert- butyldiphenylsilyl) -3,4, 5-O-tribenzoyl-myo- inositol (4' ) which can be prepared from myo-inositol in 4 steps via 1' , 2', and 3' with 30% yield, for example, by the method described in Bruzik, K. S. and Tsai, M. D. J. Am. Chem. Soc . 114:6361-6374 (1992). 4' can be prepared with high enantiomeric purity and good yield. The hydroxyls of diol 4' can be protected with benzyloxymethyl (BOM) groups to afford 5', which can be easily removed by hydrogenolysis at the end of the synthesis without affecting the other groups on the product. In 5', the myo-inositol 1-hydroxyl was still protected as a tert-butyldiphenylsilyl (TBDPS) ether, whose bulk can be important in the regioselective synthesis of 4' . The TBDPS group in 5' can be removed with tetrabutylammonium fluoride to afford 6' , which can be silylated with DMIPS (dimethylisopropylsilyl) to give 7' . The benzoate groups on 7' can be removed with KCN in methanol to give triol 8' , which can be phosphorylated on the 3, 4, and 5 positions with phosphite esters protected as jβ-cyanoethyl esters and oxidized to give 9' . The DMIPS protecting group can be cleaved by 2.5% HF to give 10'. The 1-hydroxyl of 10' can be linked to a sn- 1 , 2-diacylglycerol via a phosphite ester and oxidized to afford 11' . - 8 - Diacylglycerols are available, for example, from Avanti Polar Lipids, Inc. The 3-cyanoethyl groups on the phosphates can be removed with anhydrous triethylamine to give 12'. The phosphates of 12' can be esterified with R' - X, where X is a leaving group such as bromide, iodide, or trifluoromethanesulfonate, (e.g., bromomethyl acetate) to give 13' to mask all seven potential negative charges, for example, as acetoxymethyl (AM) esters. The final product 14' (PIP 3 /MP) can be obtained by hydrogenolysis of the BOM groups to free the 2, 6-hydroxyls . Alternatively, the BOM groups can be removed prior to esterification, resulting in R' groups on the 2- and 6-hydroxyls. myo-inositol OH HO * . ^ _ * OH OMe OH OMe HO' Y OH OH OH OH OH ,OH OTBDPS BzCl. py BOM-C1 HS' 3' BF 3 -Et 2 0 HO •' Y ' " OH OH OBOM OBOM OBOM OTBDPS OH ODMIPS TBAF/THF DMIPS-C1 OBOM __„, imidazole„ BzO OBOM BzO OBOM OBz OBz OBOM ^ODMIPS (RO) 2 PO, ODMIPS KCN/MeOH, i Pr : NP(OR) 2 .tetrazole 'BuOOH OBOM [R = -CH 2 CH 2 CN| (RO) 2 POV OBOM OH 0 2 P(OR) 2 OBOM 1— OCOAk (RO) 2 P0 3 OH OR I — OCOAk 2.5% HF in CH,CN 'Pr,N-P— O- tetrazole 'BuOOH (RCMJPOJ' OBOM 0 : P(OR), I — OCOAk OBOM OR (RO) 2 PO 2 ^ 0 - w 11' o (RO) 2 P0 2 - Ύ * OBOM 0 2 P(OR) 2 -OCOAk I — OCOAk OBOM OR* I — OCOAk OH OR' -OCOAk P— O — ' O H 2 /Pd R'O ' \\-o OBOM o OH R'O ' O p ,OR' θ ' - O ' PIP 3 /MP Scheme I - 10 - Other derivatives can be prepared by similar methods. For example, thiophosphate analogs can be prepared by oxidizing the phosphite esters with sulfur. In particular, membrane-permeant phosphtidylinositol-4 , 5- diphosphates (PI (4 , 5) P 2 /MP) , phosphtidylinositol-3 , 4- diphosphates (PI (3 , 4) P 2 /MP) , and caged phosphtidylinositol - 4, 5 -diphosphates (caged PI (4 , 5) P 2 /MP) can be prepared, as shown in Scheme II-IV, respectively. Different protecting groups can be used to produce the different membrane- permeant phosphoinositides. In Schemes II and III, compounds 20' and 30' can be prepared by the methods described in Bruzik, K. S. and Tsai, M. D. J. Am . Chem. Soc . 114:6361-6374 (1992). Generally, the other synthetic steps shown in Schemes II and III are similar to those described for Scheme I. 11 - OTBDPS I.TIPDS-CK 2. F3C00H OH \ °- s π OBOM A BOM -° k OTBDPS OBOM OBOM O' OBOM BOM-0 4 OTBDPS BOM-O /s^ 1 OH Et 3 NH"F_ ^ 1. BzCl/pyridine ^^ ^ ^^ 2. Bu 4 M F HO ' OBOM BzO OBOM OBz OBOM OBOM BO ODMIPS 1. DMIPS-C1 M" °V/ ODM1PS BOiy,'0 V \ 1 i Pr 2 NP(OR) 2 ,tetrazole 'BuOOH 2. KCNVMeOH OBOM [R = -CH 2 CH 2 CM (RO) 2 PO,' OBOM OH 0 2 P(OR) 2 OBOM -OCOAk BO MM-O* OR -OCOAk I 3 CN tetrazoie 'BuOOH 2.5% HF in CH 'Pr,.N — P— O- (RO) 2 PO,- V OBOM 0 2 P(OR) 2 —OCOAk ■ OCOAk OBOM OR — OCOAk -OCOAk Et,N R'-Br (RO) 2 P0 2 ' X' jX " OBOM ° — 0 3 PO ' ^ "' OBOM 0 2 P(OR) 2 OP0 3 " -OCOAk — OCOAk OBOM OR' —OCOAk OH OR' — OCOAk BOM-O O— P— O— *0 H,Pd (RO) 2 P0 2 OBOM 0 2 P(OR') 2 R' R' sO ' f N 0 ' V O. " R O1H PI(4,5)P 2 /MP 0 P "O ' Scheme II - 12 - OTBDPS • 0H TMS-OTf/DMSO H0 - HO " OH HO ' " OH OH OH OH BOM-CI DIEA OBOM -Si-O* ^OTBDPS HO, OTBDPS BzO* / Et 3 NH F 1. BzCl/pyridine O \ 2. Bu^ F .Si HO' Y " OBOM r v-O ' OBOM BzO ' " OBOM OBOM OBOM OBOM OBOM OBOM HO v Λ ^ODMIPS (RO) 2 P0 2 ^ ^^ ^ODMIPS l. DMIPS-CI 'Pr 2 NP(OR) 2 ,tetrazole 'BuOOH 2. KCN/MeOH HO ' Υ 'OBOM [R = -CH,CH 2 CN| (RO) 2 PO OBOM O OBBOOM OBOM OBOM ■ OCOAk (RO) 2 P0 2 i k OH OR I — OCOAk I 2.5% HF in CH -,CN 'Pr,N — P— O tetrazoie 'BuOOH (RO) 2 P0 2 ' OBOM OBOM 1 — OCOAk -OCOAk OBOM OR — OCOAk OBOM O " -OCOAk (RO) 2 PO, k o- -o- Et,N ^O j PO^ .O-P-O R'-Br (RO) 2 PO ,-γ z 0 3 PO' ^r^ ' OBOM O - OBOM BOM OBOM -OCOAk OCOAk OBOM OR" -OCOAk i\ ^O— P— O RO. „'P OH — OCOAk (RO) ,P0 2 K / W K f I 1 ,/Pd R (RO) 2 PO, ' ' ^Y . 1 OBO ^M OBOM RO ' V O OH PI(3,4)P 2 /MP Scheme III - 13 - HO myo-inositol °l d1,d2, d3 / -OH 0 ~- -7~~~-t-- 0 C a m p ODMNB ODMNB NC O O ) e1. e2, e3 O^ ^-^O s ? , / "" -OCOAk ODMNB P-o ' O OCOAk NC f1,f2, f3 OCOAk ODMNB OCOAk E SiO OSiEt 3 gi.g2 2 0 3 PO- HO OH '0 3 PO^y-^O ° " ^ '-OCOAk (RO) 2 P0 2 -7^i^ πR . ODMNB P-o ' (RO) 2 Pθ2 ^ -— ^-O κ _^ ^ OCOAk O OCOAk ODMNB P-o O OCOAk caged PI(4,5) 2 P/MP Scheme IV 14 The synthesis of one group of caged compounds is shown in Scheme IV. In Scheme IV, step a can be carried out using 2-methoxypropene in acidic DMF; and steps bl and b2 can be carried out using Bu 2 SnO, and toluene azeotropy followed by exposure to 4 , 5-dimethoxy-2-nitrobenzyl (DMNB) bromide and CsF in DMF. Step c can be carried out by exposure to S- (-) -camphanic (Camp) acid chloride, Et 3 N, and 4-dimethylaminopyridine followed by silica gel chromatography and crystallization to separate the diastereomeric camphanates . Steps dl, d2, and d3 can be carried out by exposure of the intermediate to K 2 C0 3 /MeOH, followed by (i-Pr) 2 NP (OCH 2 CH 2 CN) OCH 2 CH (OCOAk) CH 2 OCOAk and tetrazole, which is then followed by exposure to t-BuOOH. Steps el, e2 , and e3 can be carried out by exposure to BF 3 /Et 2 0 and HSCH 2 CH 2 OH followed by (i-Pr) 2 NP (OCH 2 CH 2 CN) 2 and tetrazole, and then t-BuOOH. Steps fl, f2, and f3 can be carried by exposure to BF 3 /Et 2 0 and HSCH 2 CH 2 OH followed by CF 3 CON(Me)SiEt 3 and then Et 3 N. Steps gl and g2 can be carried out by exposure to CH 3 COOCH 2 Br and then Bu 4 N + HF 2 " . The membrane-permeant phosphoinositides can be applied to intact cells in vi tro or in vivo . A cell can be contacted with a membrane-permeant phosphoinositide by exposing the cell to a solution including the membrane- permeant phosphoinositide. The membrane-permeant phosphoinositide can then diffuse or be transported into the cell. Once absorbed into a cell, a membrane-permeant phosphoinositide can be converted into the charged phosphoinositide . When caging groups are present , photolysis can remove the groups to generate the phosphoinositide. Once converted into a phosphoinositide, biological processes that can be triggered by phosphoinositide can be observed. The biological process can be enhanced or - 15 - inhibited by the phosphoinositide. The effect of the phosphoinositide, or metabolite thereof, on the biological process can be measured by, for example, an assay designed to monitor that process. For example, the membrane-permeant phosphoinositides can be a reliable means to introduce the phosphoinositides into intact cells. Once introduced, the physiological roles of the phosphoinositides can be observed. In particular, the specificity of pharmacological inhibitors of kinases can be tested. In specific examples, a membrane-permeant phosphoinositide can deliver phosphatidylinositol-3 , 4, 5- trisphosphate across cell membranes of adipocytes and T 84 colon carcinoma cells. The effects of the phosphoinositide can be measured, for example, by monitoring hexose uptake, chloride secretion, or potassium ion efflux. Other biological processes that can also be monitored. Esters of phospholipids can help reveal which interconversions occur inside cells and which lipids are the proximal agonists for many downstream targets. In addition, thiophosphate derivatives can be employed in other situations because the thiophosphate groups are generally not metabolizable. A pharmaceutical composition can include an effective amount of the membrane-permeant inositol phosphate. As used herein, an effective amount of the membrane-permeant inositol phosphate is the amount of the compound which, upon administration to cells or a patient, causes a desired result in the cells or patient. For example, administration of an effective amount of the membrane-permeant inositol phosphate can stimulate glucose uptake in cells, or chloride efflux from cells. The effective amount to be administered is typically based on the number of cells being treated, the body surface area, patient weight, or the patient condition. The - 16 - interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich, E. J., et al . , Cancer Chemother. Rep., 50(4) :219 (1966). Body surface area may be approximately determined from patient height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, pages 537-538 (1970) . Effective doses can vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments . The pharmaceutical formulation may be administered via the parenteral route, including subcutaneously, intraperitoneally, intramuscularly, and intravenously. Examples of parenteral dosage forms include aqueous solutions of the active agent, in a isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carrier. The membrane-permeant inositol phosphate can be formulated into dosage forms for other routes of administration utilizing well-known methods. The pharmaceutical composition can be formulated, for example, in dosage forms for oral administration in a capsule, a gel seal or a tablet. Capsules may comprise any well-known pharmaceutically acceptable material such as gelatin or cellulose derivatives. Tablets may be formulated in accordance with the conventional procedure by compressing mixtures of the membrane-permeant inositol phosphate and a solid carrier, and a lubricant. An example of a solid carriers includes starch. The membrane-permeant inositol phosphate can also be administered in a form of a hard shell tablet or capsule containing, for example, lactose or - 17 - mannitol as a binder and a conventional filler and a tableting agent. The carrier in the pharmaceutical composition must be "acceptable" in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely representative, and not limitive, of the remainder of the disclosure. All publications cited in this disclosure are incorporated by reference. Example 1 The synthesis of acetoxymethyl esters of PIP 3 (PIP 3 /AM) is summarized in Scheme V. The synthesis started with enantiomerically pure D-l-O- (tert-butyldiphenylsilyl) - 3,4, 5-0-tribenzoyl-iijyo-inositol (4). 4 was prepared from myo-inositol in 4 steps with 30% yield according to the method described in Bruzik, K. S. and Tsai, M. D. J. Am. Chem. Soc. 114:6361-6374 (1992) . The NMR spectra, mass spectrum, and optical rotation of 4 were all consistent with literature report. The two hydroxyl groups of 4 were then protected with benzyloxymethyl (BOM) ether groups by reaction with benzyloxymethylchloride (BOM-Cl) to afford 5. The BOM groups can be easily removed by hydrogenolysis at the end of the synthesis without affecting the other groups on the product. - 18 r £2. -o OH OMe TMS-OTf/DMSO H0 OH OH OH OH .OH HO*. ^ ^ ^OTBDPS BzO_v r^ ^OTBDPS HS' BzCI. py *γ * BOM-CI 3 3 4 BF,-Et,0 HO ' Y " OH BzO Υ OH OH OBz OBOM OBOM OBOM Bzθ ^ OTBDPS OH BzO*. TBAF/THF DMIPS-C1 BzO ' y OBOM ^r . ^ .. imidazole„ „. BzO OBOM BzO OBOM OBz OBz OBOM HO^ ^ODMIPS (RO) 2 P0 2v J^ .O ODD?MIPS KCN/MeOH . ite- j 8 I i Pr 2 NP(OR) 2 ,tetrazole 'BuOOH ^^ HO ' OBOM |R = -CH 2 CH,CN] (RO) 2 PO OBOM OH 0 2 P(OR) 2 OBOM OCOAk (RO) 2 P0 2J- OR 1— OCOAk I 2.5% HF in CH-.CN 'Pr,N — P— O- tetrazole 'BuOOH (RO) 2 PO,' OBOM (a) Ak = - (CH : ) 6 CH 3 0 2 P(OR) 2 (b) Ak -(CH 2 )ιoCH 3 1 — OCOAk -OCOAk OBOM OR OCOAk OBOM O -OCOAk (RO) 2 PO, O-P— O- w Et,N R'-Br (RO) 2 P0 2 OBOM 0 2 P(OR) 2 [R' = CH 3 COOCH 2 -| -OCOAk OBOM OR' -OCOAk -OCOAk O — ' RO. p ' OH OR " -OCOAk (RO) 2 P0 2 O— P— O H 2 /Pd R'O "θk. O — ' (RO) 2 PO; 0 2 P(OR') 2 RO * O O. OR' p,p /AM O' OR' Scheme V - 19 - The tert-butyldiphenylsilyl (TBDPS) group protecting the myo-inositol 1-hydroxyl was removed by treatment of 5 with tetrabutylammonium fluoride (TBAF) to afford 6. The myo-inositol 1-hydroxyl was protected by treating 6 with dimethylisopropylsilyl (DMIPS) chloride to afford 7. The benzoyl groups on 7 were removed by treating 7 with KCN in methanol to give triol 8. 8 was then phosphorylated on the 3, 4, and 5 positions and oxidized to 9 by treating 8 with phosphite esters protected with cyanoethoxy groups, followed by oxidation with terϋ-butyl peroxide. The DMIPS group protecting the 1-hydroxyl of 9 was cleaved by treatment with 2.5% HF to give 10 without affecting the other protecting groups. The 1-hydroxyl of 10 was linked to sn-1,2- dioctanoylglycerol or the analogous dilauroylglycerol to 11a or lib, respectively by treatment of 10 with 2- cyanoethyl (1,2-diacyl) glyceryl diisopropylchlorophosphoramidite and subsequent oxidation with tert-butyl peroxide. The cyanoethoxy protection groups on the phosphates was removed with anhydrous triethylamine to 12a or 12b without affecting the diacylglycerol esters. 12a or 12b was esterified with bromomethyl acetate to afford 13a or 13b, thereby masking all seven potential negative charges with acetoxymethyl (AM) groups . The PIP 3 /AM compounds 14a and 14b were obtained by hydrogenolysis of the BOM groups to free the 2, 6-hydroxyls . For biological comparison, the corresponding di-C 8 -PIP 3 lacking the AM groups was prepared by hydrogenolysis of 12a. All chemicals from commercial sources were used without further purification. Myo-inositol (Aldrich) was dried at 80°C under high vacuum overnight before use. sn- 1,2-Dioctanoylglycerol and sn-1, 2-dilauroylglycerol were purchased from Avanti Polar Lipids, Inc. Reagents were dried by mixing with activated molecular sieves at least one - 20 - day before use. 1 H NMR spectra were obtained on Varian 200 MHz or Bruker 300 MHz instruments. 13 C NMR spectra were obtained at 50 MHz. Mass spectra were recorded on a electrospray mass spectrometer (Hewlett Packard 59987A) . Column chromatography was performed on silica gel (230-400 mesh from EM Science) . Synthesis of Compound 5: 4 (730 mg, 1 mmol) in dry CH 2 C1 2 was treated with 3 mli of diisopropylethylamine (DIEA, 17 mmol) and 1 m benzyloxymethyl chloride (BOM-Cl, Fluka, 60% purity, 4 mmol) and heated at 60°C for 30 hours. The reaction mixture was allowed to cool and solvent was removed under vacuum. The brown material was redissolved in CH 2 C1 2 and purified by silica gel chromatography, eluting with 6:4 (v/v) CH 2 Cl 2 :hexane. 950 mg colorless oily 5 was obtained, 98% yield. X H NMR (CDC1 3 , ppm) δ 7.72-7.82 (m, 6H) , 7.13-7.48 (m, 29H) , 6.31 (t, 1H) , 5.59 (t, 1H) , 5.03 (dd, 1H) , 4.92 (s, 4H) , 4.80 (d, 1H) , 4.68 (s, 4H) , 4.52 (dd, 1H) , 4.24 (dd, 1H) , 1.11 (s, 9H) ; 13 C NMR (CDC1 3 , ppm) δ 166.2, 159.6, 138.2, 136.4, 133.3, 130.6, 130.4, 130.1, 128.9, 128.7, 128.6, 128.3, 128.2, 127.9, 127.8, 127.7, 97.2, 96.3, 91.8, 74.8, 73.0, 72.0, 71.4, 70.3, 70.1, 27.8, 19.6. Mass spectrum calculated for C^H^C^Si = 971.2, found 972.2 (positive ion, M +H + ) . Synthesis of Compound 6: 5 (3.5 g, 3.61 mmol) was dissolved in THF and 1.2 g tetrabutylammonium fluoride (TBAF, 4.6 mmol, 1.27 equiv) was added slowly. After stirring for 20 minutes at room temperature, the reaction was completed and solvent was removed. Silica gel column chromatography eluting with 98:2 v/v CHC1 3 :CH 3 0H furnished 2.48 g of 6, 94% yield. X H NMR - 21 - (CDCI 3 , ppm) δ 7.65-7.88 (m, 6H) , 7.01-7.48 (m, 19H) , 6.08 (t, IH) , 5.53 (t, IH) , 5.22 (dd, IH) , 4.92 (d, IH) , 4.82 (d, IH) , 4.34-4.72 ( , 10H) , 4.08 (t, IH) ; 13 C NMR (CDCl 3 , ppm) δ 166.0, 165.8, 165.7, 137.3, 137.1, 133.4, 133.2, 133.1, 129.8, 129.7, 128.5, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 96.2, 80.6, 72.5, 72.0, 71.3, 70.5, 70.3, 70.0. Mass spectrum calculated C^H^O^ = 732.8, found 733.7 (positive ion, M+H + ) . Synthesis of Compound 7: 6 (732 mg, 1 mmol) was dissolved in dry dimethylformamide (DMF) with 170 mg imidazole (2.5 mmol). 250 μl dimethylisopropylsilyl chloride (DMIPS-C1, 1.6 mmol) was added and the reaction mixture stirred under argon at room temperature for 4 hours . DMF was removed under vacuum and the product purified on a silica gel column with CHC1 3 as eluant. 7 was obtained as 800 mg colorless oil, 96% yield. H NMR (CDC1 3 , ppm) δ 7.80-7.98 (m, 6H) , 7.25-7.48 (m, 19H) , 6.24 (t, IH) , 5.68 (t, IH) , 5.28 (dd, IH) , 5.10 (dd, 2H) , 4.91 (s, IH) , 4.84 (d, IH) , 4.79 (d, IH) , 4.66 (s, 2H) , 4.57 (s, 2H) , 4.31 (s, 2H) , 4.12 (dd, IH) , 0.96-0.98 (m, 7H) , 0.16 (d, 6H) ; 13 C NMR (CDC1 3 , ppm) δ 166,2, 138.2, 134.0, 133.6, 130.3, 130.1, 128.9, 128.8, 128.7, 128.6, 127.9, 127.8, 96.4, 96.0, 74.3, 72.8, 72.5, 71.3, 70.2, 69.8, 18.4, 16.5, -2.2. Mass spectrum: CaHsjO^Si calculated 833.0, found 834.0 (positive ion, M+H + ) . Synthesis of Compound 8: 7 (290 mg, 0.35 mmol) was dissolved in dry methanol . KCN (100 mg, 1.53 mmol, dried over KOH under vacuum) was added and the reaction mixture was stirred at room temperature for 9 hours. After removing solvent, the reaction mixture was redissolved in CHC1 3 and purified on a - 22 - silica gel column, eluting with 95:5 (v/v) CHCl 3 :MeOH. 200 mg 8 was obtained, 89% yield. X H NMR -(CDC1 3 , ppm) δ 7.34- 7.37 (m, 10H) , 5.01 (d, IH) , 4.93 (d, IH) , 4.85 (d, IH) , 4.83 (s, 2H) , 4.78 (m, 6H) , 4.63 (d, IH) , 4.57 (d, IH) , 4.09 (d, IH) , 3.3-3.7 (m, 3H) , 0.96 (s, 3H) , 0.93 (s, 3H) , 0.85 (m, IH) , 0.06 (s, 6H) ; 13 C NMR (CDCl 3 , ppm) δ 129.1, 128.5, 97.3, 97.2, 85.0, 82.8, 74.3, 74.2, 72.6, 71.5, 70.8, 17.5, 15.3, -2.4. Mass spectrum: C 27 H 40 O 8 Si calculated 520.7, found 521.8 (M+H * ) . Synthesis of Compound 9: 2-Cyanoethyl diisopropylchlorophosphoramidite (0.5 g, 2.1 mmol) in dry CH 2 C1 2 was mixed with 0.4 mL DIEA (1.1 eq) and 160 μL (2.34 mmol) 2-cyanoethanol . After stirring for 30 minutes at room temperature, solvent was removed and dry ethyl ether added to precipitate diisopropylethylammonium chloride. The ether extract containing bis (2-cyanoethyl) diisopropylphosphoramidite was mixed with 110 mg of triol 8 (0.17 mmol), then the ether was removed under vacuum. The mixture was redissolved in dry CH 2 C1 2 and 160 mg lH-tetrazole (1.1 equiv) added. After stirring overnight at room temperature under argon, 1 mL of 5 M tert-butyl hydroperoxide in hexane was added at 0°C and stirred 10 minutes at that temperature and then for 2 hours at room temperature. The product was purified on a silica gel column, eluting with 95:5 v/v CHCl 3 :CH 3 OH. 220 mg 9 was obtained, 97% yield. X H NMR (CDCl 3 , ppm) δ 7.32-7.42 (m, 10H) , 4.55-5.22 (m, 10H) , 4.18-4.50 (m, 15H) , 4.08 (t, IH) , 2.82 (t, 12H) . Mass spectrum: C 45 H 61 N 6 0 17 P 3 Si calculated 1079, found 1102 (M+Na + ) . - 23 Synthesis of Compound 10: 9 (100 mg) was added to 5 mL acetonitrile containing 2.5% aqueous HF and stirred at room temperature for 2 hours. After removing solvent, the product was purified on a silica gel column eluted with 95:5 v/v CHCl 3 :CH 3 OH. 85 mg 10 was obtained, 94% yield. l K NMR (CDC1 3 , ppm) δ 7.30-7.40 (m, 10H) , 5.05 (dd, 2H) , 4.86 (s, 2H) , 4.84 (d, 2H) , 4.82 (s, 2H) , 4.78 (t, IH) , 4.64 (s, 2H) , 4.63 (d, 2H) , 4.22-4.48 (m, 13H) , 3.89 (t, IH) , 2.78-2.80 (m, 12H) ; 13 C (CDC1 3 , ppm) δ 138.2, 137.4, 129.1, 129.0, 128.5, 117.8, 117.6, 117.0, 97.8, 97.5, 82.2, 67.9, 67.6, 67.3, 63.2, 63.1, 20.2, 20.0. Mass spectrum: C 40 H 49 N 6 O 17 P 3 calculated 978.4, found 979.4 (M+H * ) . Synthesis of Compound 11a: sn-1, 2-Dioctanoylglycerol (80 mg, 0.23 mmol) in CH 2 C1 2 was mixed with 45 μL DIEA and 55 μL 2-cyanoethyl diisopropylchlorophosphoramidite. After stirring for 8 hours at room temperature, solvent was removed and dry ether was added. The crude ether extract of 2-cyanoethyl (1,2- dioctanoyDglyceryl diisopropylchlorophosphoramidite was mixed with 100 mg 5 (0.1 mmol) and 100 mg tetrazole (1.4 mmol) and kept at room temperature overnight. 150 μL 5 M tert-butylhydroperoxide was then added. Two hours later, solvent was removed and product was purified on a silica gel column eluted with 98:2 v/v CHCl 3 :CH 3 OH. 120 mg 11a was obtained, 82% yield. X H NMR (CDCl 3 , ppm) δ 7.32-7.42 (m, 10H) , 5.42 (q, IH) , 5.05 (dd, 4H) , 4.82 (d, IH) , 4.65-4.80 (m, 7H) , 4.20-4.50 (m, 15H) , 3.91 (t, IH) , 2.70-2.95 (m, 14H) , 2.35-2.48 (m, 4H) , 1.50-1.72 (m, 8H) , 1.18-1.38 (m, 16H) , 0.80-0.96 (m, 6H) ; 13 C (CDCl 3 , ppm) δ 173.8, 173.6, 138.2, 137.6, 128.9, 128.5, 128.2, 117.7, 117.5, 117.2, 24 - 97.6, 97.4, 71.1, 68.7, 66.7, 63.5, 63.2, 62.1, 34.2, 32.0, 29.4, 29.3, 25.2, 22.9, 20.1, 20.0, 19.9, 14.3. Mass spectrum: C 62 H 87 N 7 0 24 P 4 calculated 1438, found 1461 (M+Na * ) . Synthesis of Compound 13a: 11a (50 mg, 35 μmol) in CH 2 C1 2 was stirred overnight with 50 μL Et 3 N at room temperature, then solvent was removed under vacuum. The crude product (12a) was used directly for the next step by dissolving in 1 mL dry acetonitrile and adding 100 μL bromomethyl acetate (1.02 mmol) and 200 μL DIEA (1.15 mmol) . The reaction mixture was stirred overnight at room temperature. Solvent was removed and the residue was extracted with dry ethyl ether. The ether supernatant was evaporated and the resulting yellow oil chromatographed on a silica gel column with 98:2 v/v CHC1 3 :CH 3 0H. 30 mg 13a was obtained, 55% yield. X H NMR (CDC1 3 , ppm) δ 7.28-7.42 (m, 10H) , 5.52-5.82 (m, 14H) , 5.18 (q, IH) , 4.62-4.98 (m, 5H) , 4.04-4.42 (m, 8H) , 2.04-2.38 (m, 25H) , 1.46-1.72 (m, 8H) , 1.20-1.42 (m, 16H) , 0.82-0.98 (m, 6H) . Mass spectrum: C 62 H 93 0 38 P 4 calculated 1571, found 1594 (M+Na + ) . Synthesis of Compound 14a: 15 mg 13a in THF was hydrogenated with 5 mg palladium black for 4 hours at room temperature and atmospheric pressure. After filtering off the catalyst and removing solvent, 4 mg 14a (di-C 8 -PIP 3 /AM) was obtained, 96% yield. ^ NMR (CDC1 3 ppm) δ 5.52-5.80 (m, 14H) , 5.18 (q, IH) , 4.64-4.98 (m, 5H) , 2.06-2.38 (m, 25H) , 1.44-1.74 (m, 8H) , 1.20-1.42 (m, 16H) , 0.84-0.94 (m, 6H) . Mass spectrum: C 46 H 79 0 36 P 4 calculated 1330, found 1353 (M+Na + ) . 25 - Synthesis of Compound lib: lib was prepared in the same manner as 11a, 79% yield. X U NMR (CDC1 3 , ppm) δ 7.31-7.42 (m, 10H) , 5.41 (q, IH) , 5.06 (dd, 4H) , 4.80 (d, IH) , 4.64-4.82 (m, 7H) , 4.20- 4.48 (m, 15H) , 3.92 (t, IH) , 2.68-2.95 (m, 14H) , 2.34-2.46 (m, 4H) , 1.52-1.72 (m, 12H) , 1.17-1.40 (m, 28H) , 0.81-0.95 (m, 6H) ; 13 C NMR (CDCl 3 , ppm) δ 174.1, 173.8, 138.3, 137.5, 128.8, 128.5, 128.3, 117.8, 117.4, 117.2, 97.5, 97.3, 71.2, 68.8, 66.8, 63.4, 63.2, 62.1, 34.1, 31.9, 29.6, 29.4, 25.3, 22.9, 20.2, 20.1, 20.0, 19.9, 19.8, 14.3. Mass spectrum: C 70 H 103 N 7 O 24 P 4 calculated 1550, found 1573 (M+Na + ) . Synthesis of Compound 13b: 12b and 13b were prepared in the same manner as 12a and 13a. 12b was used directly for synthesis of 13b without purification. 52 mg of 13b was obtained in 48% yield. 1 H NMR (CDClj, ppm) 67.26-7.41 ( , 10H) , 5.52-5.83 (m, 14H) , 5.17 (q, IH) , 4.63-5.00 (m, 5H) , 4.05-4.45 (m, 8H) , 2.05- 2.40 (m, 25H) , 1.44-1.74 (m, 12H) , 1.19-1.44 (m, 28H) , 0.82- 0.98 (m, 6H) . Mass spectrum: C 70 H 109 O 38 P 4 calculated 1683, found 1706 (M+Na + ) . Synthesis of Compound 14b: 14b was prepared in the same manner as 14a. 40 mg 14b (di-C 12 -PIP 3 /AM) was obtained in 95% yield. X H NMR (CDC1 3 , ppm) δ 5.51-5.79 (m, 14H) , 5.16 (q, IH) , 4.65-4.96 (m, 5H) , 2.02-2.41 (m, 25H) , 1.45-1.74 (m, 12H) , 1.17-1.46 (m, 28H) , 0.83-0.92 (m, 6H) . Mass spectrum: C 54 H 93 0 36 P 4 calculated 1442, found 1465 (M+Na + ) . - 26 Example 2 Glucose Transport Insulin stimulated uptake of glucose into muscle and fat tissue plays a central role in the maintenance of whole body glucose homeostasis. See, Kahn, C. R. Diabetes 45:1644-1654 (1996). The signal transduction pathway utilized by insulin to promote glucose transport involves autophosphorylation of the insulin receptor with ensuing activation of its intrinsic receptor tyrosine kinase activity and phosphorylation of insulin receptor substrates such as IRS-1, IRS-2 and IRS-3. See, for example, Cheatham, B. and Kahn, C. R. Endocrine Reviews 6:117-142 (1995); and Yenush, L. and White, M. F. BioEssays 19:491-500 (1997). PI 3 -kinase interacts with tyrosine-phosphorylated IRS proteins through an SH2 domain on its regulatory p85 subunit, thereby activating its catalytic pllO subunit. See, for example, Myers, M. G.,Jr., et al . Proc . Natl . Acad. Sci . USA 89:10350-10354 (1992); and Shoelson, S. E., et al . EMBO J. 12:795-802 (1993). The inhibitors wort annin and LY294002 have been used in experiments to show that PI 3 -kinase is essential for insulin regulation of glucose transport. See, for example, Okada, T. , et al . J. Biol . Chem. 269:3568-3573 (1994); and Cheatham, B., et al . Mol . Biol . Cell 14, 4902-4911 (1994) , respectively. The impact of PI 3 -kinase stimulation on glucose transport is mediated either directly by the D-3- phosphorylated inositol phospholipid products of the enzyme, or by activation of intermediate molecules. Because of the known pharmacology of 3T3-L1 adipocytes and the importance of insulin-stimulated glucose transport in these cells, they were used to test the effects of the membrane-permeant PIP 3 esters on the glucose uptake in adipocytes. In particular, 27 the ability of the membrane-permeant PIP 3 esters to bypass wortmannin blockade was examined. Adipocvte Cell Culture: All cell culture solutions and supplements were obtained from Gibco/BRL (Burlington, ON, Canada) . 3T3-L1 cells were obtained from the University of Bath, England and were grown in monolayer culture in 12-well plates, bathed in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (v/v) calf serum and 1% (v/v) antibiotic solution (10,000 U/mL penicillin and 10 mg/mL streptomycin) in an atmosphere of 5% C0 2 at 37°C. The medium was replenished every 48 hours. Prior to experimental manipulation, the cells were depleted of serum for 3 hours. Determination of 2-deoxyglucose uptake in 3T3-L1 adipocytes: 3T3-L1 adipocyte monolayers were rinsed with 140 mM NaCl, 2.4 mM MgS0 4 , 5 mM KCl, 1 mM CaCl 2 and 20 mM Na-HEPES, at pH 7.4. Glucose uptake was measured in 0.25 mL incubation volumes using 10 μM 2- [ 3 H] deoxyglucose (1 μCi/mL; New England Nuclear) for 5 minutes. 2-Deoxyglucose uptake is generally linear during this exposure time period. The radioactive solution was aspirated, and the cells were rinsed three times with ice-cold isotonic saline solution. Cells were disrupted with 1.0 mL of 0.05 N NaOH, and the radioactivity of a 0.75 mL aliquot of the cell lysate was quantitated by liquid scintillation counting using an LKB 1217 beta counter. Protein concentration of the lysate was determined using the Bradford method. See, Bradford, M.M. Anal. Biochem. 72:247-254 (1976). Nonspecific uptake was determined in the presence of 10 μM cytochalasin B (Sigma) and was subtracted from total uptake. - 28 - Effects on glucose uptake into 3T3-L1 adipocytes: Glucose uptake into adipocytes was markedly stimulated by a maximally effective dose of insulin. Referring to FIG. 2, the graphs summarize the effects of insulin, wortmannin, and PIP 3 /AM on hexose uptake in adipocytes. The adipocytes were incubated in the presence (+) or absence (-) of the agents (insulin, wortmannin, or PIP 3 /AM) listed below each bar. Insulin (100 nM) was added to the adipocytes 30 minutes before measurement of deoxyglucose uptake. PIP 3 /AM (14a or 14b) (150 μM) and wortmannin (100 nM) were added for a 15 min pre-incubation before insulin treatment. The left and right panels of FIG. 2 indicate experiments using di-C 8 -PIP 3 /AM (14a) and di-C 12 - PIP 3 /AM (14b) , respectively. Referring to FIG. 2, the increase in glucose uptake was inhibited by the PI3K inhibitor wortmannin. Notably, the wortmannin inhibition was largely circumvented by treatment of the cells with the membrane-permeant phosphoinositide PIP 3 /AM. Di-C 8 PIP 3 /AM (14a) restored a greater percentage (87%) of the insulin stimulation chan di- C 12 PIP 3 /AM (14b) , which restored 56% of the insulin stimulation. Neither PIP 3 /AM had a significant effect on glucose uptake in the absence of insulin. The membrane permeable inositol phosphates alone did not stimulate basal glucose transport. A bifurcation of the insulin induced signal can occur in which one signal involves generation of PIP 3 , while the other is independent of this product. Full stimulation of glucose transport would require activation of both signals. For example, the transport can depend on two enzymes whose activity was recently shown to depend on prior PI3K activation: the protein kinase c-Akt (also known as PKB) and protein kinase C-f. - 29 - The membrane-permeant inositol phosphate esters can be useful to study the PI3K product and insulin action. Example 3 Chloride Flux Regulation of chloride flux plays a key role in a number of biological systems, including in the control of salt and fluid secretion across mucous membranes. Epithelial transport can be modelled using the T 84 colon carcinoma cell line which forms monolayers that actively transport chloride in response to a variety of agonists. For example, chloride secretion in T 84 cells can be triggered through cyclic AMP and calcium-dependent signaling mechanisms. See, for example, Weymer, A., et al . J. din . Invest . 76, 1828-1836 (1985); and Dharmsathaphorn, K. et al . Am. J. Physiol . 256, C1224-C1230 (1989) . As in many other systems, these pathways interact synergistically in T 84 . See, for example, Cartwright, C. A., et al . J. Clin . Invest . 76, 1837-1842 (1985); MacVinish, L. J. , et al . Br. J. Pharmacol . 108, 462-468 (1993); and Vajanaphanich, M., et al . J. Clin . Invest . 96, 386-393 (1995). Two receptor activated pathways have been recently identified which limit chloride secretion through the calcium-dependent pathway, but not through the cyclic AMP- dependent pathway. In one pathway, prolonged stimulation of the muscarinic M 3 receptor on T 84 cells leads to accumulation of intracellular inositol-3,4,5, 6-tetraphosphate, which, in turn, inhibits transepithelial chloride efflux by restricting flow through apically located chloride channels. See, for example, Vajanaphanich, M. , eϋ al . Nature 371:711- 714 (1994) . Another pathway, which is stimulated by EGF and inhibited by wortmannin, also restricted transepithelial chloride transport by limiting basolateral efflux through - 30 - potassium ion channels. Moreover, the effects of EGF and carbachol are additive, further indicating that the two inhibitory pathways are independent. EGF probably partly works through stimulation of PI3K, because EGF treatment elevates PIP 3 , and the effect of EGF can be ablated by the PI3K inhibitor wortmannin. See, for example, Uribe, J. M. , et al . J. Biol . Chem. 271, 26588-26595 (1996); Barrett, K. E., et al . Am. J. Physiol . (1998); and Eckmann, L., et al . Proc . Natl . Acad . Sci . USA 94, 14456-14460 (1997). The previous experiments did not address whether the wortmannin block is specific and whether EGF might also have other biochemical effects that are also necessary for its inhibition of carbachol-stimulated chloride flux. We tested whether either PIP 3 /AM or PIP 3 could mimic the effect of EGF on chloride transport in the T 84 colon carcinoma cell . T fl4 colon carcinoma cell culture : T 84 cells (passages 15-45) were grown and maintained in DMEM/F12 media (JRH Biosciences, Lexena, KS) supplemented with 5% newborn calf serum, 2 mM glutamine and 50 U/mL each of penicillin/streptomycin (Core Cell Culture Facility, University of California, San Diego) as previously described in Dharmsathaphorn, K., et al. Am. J " . Physiol . 264 :G204-G208 (1984) . Cells used in experiments were plated on Costar snap-well inserts and maintained in culture for 6-10 days to allow for formation of tight junctions prior to the experiment . Short circuit current measurements : Snap-well inserts containing confluent T 84 monolayers were incubated for 0.5 hr at 37°C with 0.1 mL PIP 3 derivatives (200 μM) or vehicle applied to the apical side. The monolayers were then mounted into modified Ussing - 31 - chambers (Physiologic Instruments, San Diego, CA) , whose basolateral side was bathed with Ringers solution warmed to 37°C and gassed continuously with 95% 0 2 /5% C0 2 at a rate of 30-35 mL/min. The spontaneous potential difference across the monolayer was short-circuited with a voltage clamp (Model VCC MC6, Physiologic Instruments, San Diego, CA) Short circuit current (I sc ) and conductances were recorded at 4 second intervals using Acquire and Analyse Software 1.1. (Physiologic Instruments, San Diego, CA) . Increased I sc in T 84 reflects transepithelial chloride secretion. See, Dharmsathaphorn, K. , et al . Am. J. Physiol . 256 :C1224-C1230 (1989) . Rubidium ion efflux measurements: Rubidium ion flux measurements were obtained by a modification of a method previously published by Venglarik, et al . Am. J. Physiol . 259 :C358-C364 (1990). Cell monolayers grown on Costar snap-well inserts (Cambridge, MA) were rinsed in Hank's balanced Salt Solution containing sodium ion (137.6 mM) , chloride (146.3 mM) , potassium ion (5.8 mM) , H 2 P0 4 _ (0.44 mM) , HP0 4 2- (0.34 mM) , calcium ion (1 mM) , magnesium ion (1 mM) , HEPES (pH 7.2) (15 mM) , and D- glucose (10 mM) . The cells were loaded for 30 minutes with 5 μCi/0.25 mL of 86 Rb at 37°C added to the basolateral surface. Simultaneously, the apical surface was bathed with cell permeant esters of PIP 3 (14a or 14b; 200 μM) or other vehicle. Following four rinses of apical and basolateral surfaces with Hank's buffer over a period of six minutes, the inserts were sequentially transferred at two minute intervals to fresh wells of a 24 well culture dish floating in a 37°C water bath. After twelve minutes, the inserts were transferred to wells containing 0.1 mM carbachol for the remainder of the experiment. After the experiment, the - 32 - contents of the wells and the inserts were transferreα to vials containing Ecoscint which were counted in a Packard scintillation counter. The data were analyzed as described by Venglarik, et al . Am . J. Physiol . 259 :C358-C364 (1990) yielding rate constants of nuclide efflux at two min intervals . Effects on chloride transport across T S1 monolayers: PIP 3 /AM by itself was able to mimic the action of EGF on a model of colonic epithelia. Di-C 12 PIP 3 /AM (14b) was more effective than di-C 8 PIP 3 /AM (14a) . Extracellular nonesterified PIP 3 had no effect, confirming that the site yof action was intracellular and that esterification was necessary for effective transmembrane delivery of PIP 3 in this system. Referring to FIG. 3, the inhibitory effects of EGF and PIP 3 /AM on chloride secretion are nonadditive. The T 84 monolayers were incubated for 30 minutes with 200 μM di-C 12 - PIP 3 /AM or other vehicle prior to mounting in Ussing- chambers. Chloride secretion was assessed as short circuit current (I sc ) , which was measured continuously at 4 second intervals. EGF (1 μM) was added to the basolateral surface of some chambers followed 15 minutes later by carbachol (100 μM) . Control runs were also stimulated with carbachol but not pretreated with EGF. In FIG. 3, each trace represents the average of six experiments. Referring to FIG. 3, the traces show the large I sc stimulated by carbachol (dotted line) and its nearly complete inhibition by pretreatment either with 1 μM EGF for 15 min (circles) or with 200 μM di-C 12 -PIP 3 /AM (14b) for 30 minutes (dashed line) . EGF and PIP 3 /AM were equally effective in reducing carbachol-stimulated peak I sc to 15% of the control. The combination of maximal doses of both - 33 - EGF and PIP 3 /AM (solid line) was no more effective than either alone. An inhibition of the carbachol-stimulated rise in [Ca 2+ ]i could inhibit I sc , but direct imaging of [Ca 2t ] in fura-2 -loaded T 84 monolayers failed to reveal any such effect of PIP 3 /AM. Transepithelial chloride fluxes can require opening of basolateral K + channels, whose function can be assayed by measuring efflux of preloaded 86 Rb * as a potassium ion surrogate. Referring to FIG. 4, the effects of PIP 3 /AM on 86 Rb + efflux from preloaded T θ4 colonic epithelia are shown. T 84 monolayers grown on Millipore inserts were pretreated with either di-C 12 -PIP 3 /AM (200 μM, circles) or vehicle (squares) for 30 minutes during labeling. The two traces for each set of conditions are replicate experiments . Monolayers were washed and the buffer in the basolateral reservoir was replaced every two minutes. Carbachol (100 μM) was added to the basolateral reservoir at the indicated time. Values are the calculated rate constants at the indicated time points for individual experiments. As shown in FIG. 4, di-C 12 -PIP 3 /AM (14a) did inhibit carbachol-stimulated 86 Rb + efflux by greater than 50 percent. The potassium ion channels are a likely target for the PIP 3 effect. Membrane-permeant esters of PIP 3 mimic the inhibitory effects of EGF both on chloride secretion and efflux through potassium ion channels. The data strongly suggest that a lipid product of PI-3 kinase mediates EGF- induced inhibition of chloride secretion in T 84 colonic epithelia. - 34 Other Embodiments All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the claims. What is claimed is: 35

Claims: Claims A compound of formula : wherein: R 1 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (O) CH 2 CH 3 , -CH 2 OC(0) (CH 2 ) 2 CH 3 , or a caging group; R 2 is H, -CH 2 OC(0)CH 3 , -CH 2 OC (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or -P(O) (OR 11 ) (X 2 R 12 ) , or a caging group; R 3 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , -P(0) (OR 13 ) (X 3 R 14 ) , or a caging group; R 4 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , -P(0) (OR 15 ) (X 4 R 16 ) , or a caging group; R s is H, -CH 2 OC(0)CH 3 , -CH 2 OC (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or a caging group; each of X 1 , X 2 , X 3 , and X 4 , is, independently, S or 0; each of R 6 , R 11 , R 12 , R 13 , R 14 , R 1S , and R 16 is, independently, H, -CH 2 0C(0) CH 3 , -CH 2 0C (0) CH 2 CH 3 , or -CH 2 0C(0) (CH 2 ) 2 CH 3 ; each of R 7 and R 8 is, independently, a saturated or unsaturated C 4 -C 22 group; Z is 0, CH 2 , or NH; and at least one of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R Sl6 IS • CH 2 0C(0)CH 3 , -CH 2 OC(0)CH 2 CH 3 , or -CH 2 0C(0) (CH 2 ) 2 CH 3 . - 36 2. The compound of claim 1, wherein R 2 is -P(0) (OR 11 ) (X 2 R 12 ) . 3. The compound of claim 1, wherein R 3 is -P(0) (OR 13 ) (X 3 R 14 ) . 4. The compound of claim 2, wherein R 3 is -P(0) (OR 13 ) (X 3 R 14 ) . 5. The compound of claim 1, wherein R 4 is -P(0) (OR 15 ) (X 4 R 16 ) . 6. The compound of claim 3, wherein R 4 is -P(0) (OR 15 ) (X 4 R 16 ) . 7. The compound of claim 4, wherein R 4 is -P(O) (OR 15 ) (X 4 R 16 ) . 8. The compound of claim 1, wherein Z is 0. 9. The compound of claim 1, wherein each of X 1 , X 2 , X 3 , and X 4 is 0. 10. The compound of claim 1, wherein the caging group is 2-nitrobenzyl, 1- (2 -nitrophenyl) ethyl, 4,5- dimethoxy-2-nitrobenzyl, 6-nitropiperonyl, 4- hydroxyphenacyl , or 7-hydroxycoumarin-4-ylmethyl. 11. The compound of claim 1, wherein each of R 7 and R 8 , independently, is a saturated or unsaturated C 4 -C 22 acyl, a C 4 -C 22 alkyl, a C 4 -C 22 alkenyl, or a C^- ^ polyene. 37 12. The compound of claim 1, wherein each of R 7 and R 8 , independently, is -C(O) (CH 2 ) m CH 3 where m is an integer between 4-20, inclusive, -C (0) - (CH 2 ) 7 CH=CH (CH 2 ) 7 CH 3 , -C(0) - (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 , -C(0) - (CH 2 ) 7 CH=CHCH 2 CH=CH (CH 2 ) 4 CH 3 , or -C(ϋ) - (CH 2 ) 2 (CH 2 CH=CH) 4 (CH 2 ) 4 CH 3 , wherein each double bond, independently, is in a cis or trans configuration. 13. The compound of claim 1, wherein each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is -CH 2 0C (0) CH 3 . 14. The compound of claim 1, wherein at least one of R 2 , R 3 , and R 4 is a phosphorus -containing group. 15. The compound of claim 1, wherein at least two of R 2 , R 3 , and R 4 are phosphorus -containing groups. 16. The compound of claim 1, wherein R 2 , R 3 , and R 4 are phosphorus-containing groups. 17. A pharmaceutical composition of the compound of claim 1. 18. The compound of claim 1 of the formula: 38 19. The compound of claim 18, wherein R 2 is -P(O) (OR 11 ) (X 2 R 12 ) . 20. The compound of claim 18, wherein R 3 is -P(O) (OR 13 ) (X 3 R 14 ) . 21. The compound of claim 19, wherein R 3 is -P(O) (OR 13 ) (X 3 R 14 ) . 22. The compound of claim 18, wherein R 4 is -P(O) (OR 15 ) (X 4 R 16 ) . 23. The compound of claim 20, wherein R 4 is -P(O) (OR 15 ) (X 4 R 16 ) . 24. The compound of claim 21, wherein R 4 is -P(O) (OR 15 ) (X 4 R 16 ) . 25. The compound of claim 18, wherein Z is 0. 26. The compound of claim 18, wherein each of X 1 , X 2 , X 3 , and X 4 is 0. 27. The compound of claim 18, wherein the caging group is 2-nitrobenzyl, 1- (2 -nitrophenyl) ethyl, 4,5- dimethoxy-2-nitrobenzyl, 6-nitropiperonyl, 4- hydroxyphenacyl , or 7-hydroxycoumarin-4-ylmethyl. 28. The compound of claim 18, wherein each of R 7 and R 8 , independently, is a saturated or unsaturated C 4 -C 22 acyl, a C 4 -C 22 alkyl, a C 4 -C 22 alkenyl, or a C 4 -C 22 polyene. 39 - 29. The compound of claim 18, wherein each of R 7 and R 8 , independently, is -C(O) (CH 2 ) m CH 3 where m is an integer between 4-20, inclusive, -C (0) - (CH 2 ) 7 CH=CH (CH 2 ) 7 CH 3 , -C(0) - (CH 2 ) 7 CH=CH(CH 2 ) 7 CH 3 , -C(0) - (CH 2 ) 7 CH=CHCH 2 CH=CH (CH 2 ) 4 CH 3 , or -C(0) - (CH 2 ) 2 (CH 2 CH=CH) 4 (CH 2 ) 4 CH 3 , wherein each double bond, independently, is in a cis or trans configuration. 30. The compound of claim 18, wherein each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is -CH 2 0C (0) CH 3 . 31. The compound of claim 18, wherein at least one of R 2 , R 3 , and R 4 are phosphorus-containing groups. 32. The compound of claim 18, wherein at least two of R 2 , R 3 , and R 4 are phosphorus-containing groups. 33. The compound of claim 18, wherein R 2 , R 3 , and R 4 are phosphorus-containing groups. 34. A pharmaceutical composition of the compound of claim 18. 35. The compound of claim 1 of the formula 40 - 36. The compound of claim 35, wherein R 4 is -P(0) (OR 15 ) (X 4 R 16 ) . 37. The compound of claim 35, wherein each of X 1 , X 2 , X 3 , and X 4 is 0. 38. The compound of claim 35, wherein the caging group is 2-nitrobenzyl, 1- (2 -nitrophenyl) ethyl, 4,5- dimethoxy-2-nitrobenzyl, 6-nitropiperonyl, 4- hydroxyphenacyl , or 7-hydroxycoumarin-4-ylmethyl . 39. The compound of claim 35, wherein each of R 7 and R 8 , independently, is a saturated or unsaturated C 4 -C 22 acyl, a C 4 -C 22 alkyl, a C 4 -C 22 alkenyl, or a C 4 -C 22 polyene. 40. The compound of claim 35, wherein each of R 7 and R 8 , independently, is -C(0) (CH 2 ) ra CH 3 where m is an integer between 4-20, inclusive, -C (0) - (CH 2 ) 7 CH=CH (CH 2 ) 7 CH 3 , -C (0) - (CH 2 ) 7 CH=CH (CH 2 ) 7 CH 3 , -C (0) - (CH 2 ) 7 CH=CHCH 2 CH=CH (CH 2 ) 4 CH 3 , or -C(0) - (CH 2 ) 2 (CH 2 CH=CH) 4 (CH 2 ) 4 CH 3 , wherein each double bond, independently, is in a cis or trans configuration. 41. The compound of claim 35, wherein each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is -CH 2 0C (0) CH 3 . 42. A pharmaceutical composition of the compound of claim 35. 41 43. A method of delivering a phosphoinositide to a cell comprising: includes contacting a cell with a membrane-permeant phosphoinositide; transporting the membrane-permeant phosphoinositide into the cell; and converting the membrane-permeant phosphoinositide to a phosphoinositide within the cell. - 42 - 44. The method of claim 43, wherein the membrane- permeant phosphoinositide is a compound of the formula: wherein : R 1 is H, -CH 2 OC(0)CH 3 , -CH 2 OC (O) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or a caging group; R 2 is H, -CH 2 OC(0)CH 3 , -CH 2 OC (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or -P(0) (OR 11 ) (X 2 R 12 ) , or a caging group; R 3 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , -P (0) (OR 13 ) (X 3 R 14 ) , or a caging group; R 4 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , -P(0) (OR 15 ) (X 4 R 16 ) , or a caging group; R 5 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or a caging group; each of X 1 , X 2 , X 3 , and X 4 , is, independently, S or O; each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, H, -CH 2 0C(0) CH 3 , -CH 2 0C(0) CH 2 CH 3 , or -CH 2 0C(0) (CH 2 ) 2 CH 3 ; each of R 7 and R 8 is, independently, a saturated or unsaturated C 4 -C 22 group; Z is 0, CH 2 , or NH; and at least one of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is -CH 2 OC(0)CH 3 , -CH 2 OC(0)CH 2 CH 3 , or -CH 2 0C(0) (CH 2 ) 2 CH 3 . 43 - 45. The method of claim 44, wherein Z is 0. 46. The method of claim 44, wherein each of X 1 , X 2 , X 3 , and X 4 is 0. 47. The method of claim 44, wherein each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is -CH 2 0C (0) CH 3 . 48. The method of claim 44, wherein at least one of R 2 , R 3 , and R 4 are phosphorus-containing groups. 49. The method of claim 44, wherein at least two of R 2 , R 3 , and R 4 are phosphorus-containing groups. 50. The method of claim 44, wherein R 2 , R 3 , and R 4 are phosphorus-containing groups. 51. The method of claim 44, wherein each of R 7 and R 8 , independently, is a saturated or unsaturated C 4 -C 22 acyl, a C 4 -C 22 alkyl, a C 4 -C 22 alkenyl, or a C 4 -C 22 polyene. 52. A method for identifying a biological process within a cell triggered by intracellular phosphoinositide, said method comprising: contacting a cell with a membrane-permeant phosphoinositide; transporting the membrane-permeant phosphoinositide into the cell; converting the membrane-permeant phosphoinositide to a phosphoinositide within the cell; and measuring an effect of the phosphoinositide on a biological process. 44 - 53. The method of claim 52, wherein the membrane- permeant phosphoinositide is a compound of the formula: wherein: R 1 is H, -CH 2 OC(0)CH 3 , -CH 2 OC (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or a caging group; R 2 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or -P(0) (OR 11 ) (X 2 R 12 ) , or a caging group; R 3 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , -P (0) (OR 13 ) (X 3 R 14 ) , or a caging group; R 4 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , -P (0) (OR 15 ) (X 4 R 16 ) , or a caging group; R 5 is H, -CH 2 OC(0)CH 3 , -CH 2 0C (0) CH 2 CH 3 , -CH 2 0C(0) (CH 2 ) 2 CH 3 , or a caging group; each of X 1 , X 2 , X 3 , and X 4 , is, independently, S or 0; each of R 6 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is, independently, H, -CH 2 0C (0) CH 3 , -CH 2 0C (0) CH 2 CH 3 , or -CH 2 0C(0) (CH 2 ) 2 CH 3 ; each of R 7 and R 8 is, independently, a saturated or unsaturated C 4 -C 22 group; Z is 0, CH 2 , or NH; and at least one of R 6 , R 11 , R 12 , R 13 , R 14 , R 1S , and R 16 is -CH 2 OC(0)CH 3 , -CH 2 OC(0)CH 2 CH 3 , or -CH 2 0C (0) (CH 2 ) 2 CH 3 . - 45 54. The method of claim 53, wherein Z is 0. 55. The method of claim 53, wherein each of X 1 , X 2 , X 3 , and X 4 is 0. 56. The method of claim 53, wherein each of R δ , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is -CH 2 0C (0) CH 3 . 57. The method of claim 53, wherein at least one of R 2 , R 3 , and R 4 are phosphorus-containing groups. 58. The method of claim 53, wherein at least two of R 2 , R 3 , and R 4 are phosphorus-containing groups. 59. The method of claim 53, wherein R 2 , R 3 , and R 4 are phosphorus-containing groups. 60. The method of claim 53, wherein each of R 7 and R 8 , independently, is a saturated or unsaturated C 4 -C 22 acyl, a C 4 -C 22 alkyl, a C 4 -C 22 alkenyl, or a C 4 -C 22 polyene. 46

Inventors: JIANG TAO, TSIEN ROGER Y, JIANG, TAO, TSIEN, ROGER, Y.
Applicants: JIANG TAO, TSIEN ROGER Y, UNIV CALIFORNIA, JIANG, TAO, THE REGENTS OF THE UNIVERSITY OF CALIFORNIA, TSIEN, ROGER, Y.
Application year: 1999
Main classification: C12Q1
IPC codes: A61K31, A61P43, C07F9, C12Q1