Wortmannin-Rapamycin Conjugate

Phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) act synergistically in promoting cancer. Wortmannin is a potent inhibitor of PI3K enzymes, while rapamycin blocks mTOR Complex 1 TORC1. Wortmannin-rapamycin conjugate consists of analogs of 17-hydroxy wortmannin and rapamycin conjugated via a prodrug linker. Hydrolysis of the prodrug linker in vivo releases the inhibitors. The wortmannin-rapamycin conjugate inhibits the growth of HT-29 colon tumors and A498 renal tumors in mice better than rapamycin alone. Also, the conjugate, when given in combination with the VEGF-blocker bevacizumab, produces substantial regression of larger A498 tumors. Finally, the wortmannin-rapamycin conjugate is tolerated better than an equivalent mixture of the inhibitors.Formal Name: 1-(4S,4aR,5R,6aS,7S,9aR,E)-1-(((3-(dimethylamino)propyl)(methyl)amino)methylene)-7,11-dihydroxy-4-(methoxymethyl)-4a,6a-dimethyl-2,10-dioxo-1,2,4,4a,5,6,6a,7,8,9,9a,10-dodecahydroindeno[4,5-h]isochromen-5-yl acetate 8-(7E,15E,17E,19E)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34aS-hexadecahydro-9R,27-dihydroxy-3S-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10R,21S-dimethoxy-6R,8,12R,14S,20,26R-hexamethyl-23S,27R-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone octanedioate. CAS Number: 1067892-47-0. Molecular Formula: C88H131N3O23. Formula Weight: 1598.9. Purity: >98%. Formulation: (Request formulation change), A crystalline solid. Solubility: DMF: 30 mg/ml, DMSO: 20 mg/ml, Ethanol: 5 mg/ml. lambdamax: 256, 267, 277, 289, 318, 411 nm. SMILES: O=C(O[C@H]1[C@H](OC)C[C@H](C[C@@H](C)[C@@](CC([C@H](C)/C=C(C)/[C@@H](O)[C@@H](OC)C([C@H](C)C[C@H](C)/C=C/C=C/C=C(C)/[C@@H](OC)C[C@](O2)([H])CC[C@@H](C)[C@]2(O)C3=O)=O)=O)([H])OC([C@]4([H])CCCCN4C3=O)=O)CC1)CCCCCCC(O[C@H]5CC[C@]6([H])[C@]5(C)C[C@@H](OC(C)=O)C([C@]([C@@H](COC)OC(/C7=C/N(C)CCCN(C)C)=O)(C)C7=C8O)=C6C8=O)=O. InChi Code: InChI=1S/C88H131N3O23/c1-51-28-21-20-22-29-52(2)66(106-15)46-60-35-33-57(7)88(104,114-60)82(100)83(101)91-41-26-25-30-63(91)85(103)111-67(47-64(93)53(3)43-56(6)78(97)81(108-17)77(96)55(5)42-51)54(4)44-59-34-37-65(68(45-59)107-16)110-72(94)31-23-18-19-24-32-73(95)112-70-38-36-62-74-76(69(109-58(8)92)48-86(62,70)9)87(10)71(50-105-14)113-84(102)61(75(87)80(99)79(74)98)49-90(13)40-27-39-89(11)12/h20-22,28-29,43,49,51,53-55,57,59-60,62-63,65-71,78,81,97,99,104H,18-19,23-27,30-42,44-48,50H2,1-17H3/b22-20+,28-21+,52-29+,56-43+,61-49+/t51-,53-,54-,55-,57-,59+,60+,62+,63+,65-,66+,67+,68-,69-,70+,71-,78-,81+,86+,87+,88-/m1/s1. InChi Key: GVMCLKAVNVFURS-UXLLMVCWSA-N.