Structure Modifications And SARs Of Taxol's C-2 Position

Paclitaxel ( = Taxol), an antitumor agent isolated from bark of pacificyew Taxus breviforlia originally, has been considered as one of the mosteffective drugs for its unique action mechanism and anti-cancer activity. It isused at present for the treatment of breast, lung, and ovarian carcinomas,and also for AIDS-related Kaposi's sarcoma. But its resource andwater-solubility are the drawbacks in this drug's development.Structure activity relationship (SAR) studies of paclitaxel analogues aremost active in recent years. By structure modifications on pactitaxel, manyanalogues are synthesized with better water solubility and more active. Aknown taxoid 7-epi-10-deacetylpaclitaxel 23 was used as the startingmaterial. By selectively cleaving the C-13 side chain, several modificationson the core structure, the mixture 2-mesylate 20 & 1,2-epoxide 21 wereobtained.The 1,2-epoxide 21 arose from intramolecular attack on the 2-mesylate20 by the 1-hydroxyl, then the nucleophile could attack on the 1,2-expoxide21. Several nucleophiles were used to afford 2α-N, O, S-linked baccatinsfrom compounds 20 & 21.OAc OOTESHO OMsOOAcOOAc OOTESO OOAcSN2 OSN2OAc OOTESHO OOAcONuNuHOOAcOOHS AcOOOXOPhOH32 R = Bz, X = HRNH33 R = Boc, X = H34 R = Bz, X = O35 R = Boc, X = O HOOAcOOHXAcOOOOPhOH40 R = Bz, X =ORNH41 R = Boc, X = O42 R = Bz, X = N43 R = Boc, X = NThe new synthesis route of compound 49 were founded, and thereaction's process was presumed.HOOAcOOTESHOAcOOTESO48OOAcOOTESOAcOOTESOOS49MsClEt3N / TolueneMsClHOOAcOOTESOAcOOTESOSOO-OOAcOOTESOAcOOTESOSOO甲基迁移B--CH3OAnd a new type of compounds (54a and 54b) were associated with2,2,4-trimethyl-3-hydroxy-4-cyclohexenecarboxylate and (S)-Isoserinederivatives. The space location of compound 51 's C-3 hydroxyl group wasidentified.OHO OHOHO ON OPhOTESR51 52a b OOOOOHNHR54a: R= Bz5533ba:: RR == BBzoc54b: R= Boca: CH2N2 b: LHMDS, then HF/PyThe cytotoxicity and tubulin polymerization activity of paclitaxel'sanalogues were tested. We discussed SAR of paclitaxel's analogs at thebinding sites in paclitaxel.Then the low activities of those analogs wasrationalized by computational simulations. The compound 35'sconformation was studies with 2D-NMR technique. The conformationdifferences of 35 and paclitaxel explain that the abnormal signals ofcompound 35's NMR spectra.化合物结构一览表HOOAcOOTESS AcOOO28HOOAcOOTESS AcOOHO29HOOAcOOTESS AcOOOO30HOOAcOOTESS AcOOHOO 31HOOAcOOHS AcOOOOPhOHBzNH32HOOAcOOHS AcOOOOPhOHBocNH33HOOAcOOHS AcOOOOPhOHBzNH34OHOOAcOOHS AcOOOOPhOHBocNH35OHOOAcOOTESO AcOOO36HOOAcOOTESO AcOOHO37HOOAcOOTESHN AcOOO38HOOAcOOTESHN AcOOHO39HOOAcOOHO AcOOOOPhOHBzNH40HOOAcOOHO AcOOOOPhOHBocNH41HOOAcOOHHN AcOOOOPhOHBzNH42HOOAcOOHHN AcOOOOPhOHBocNH43HOOAcOOTESO AcOOTESO46OOAcOOTESOAcOOTESO47HOOAcOOTESHO AcOOTESO48OOAcOOTESO AcOOTESOO S49OOOOOHBocNH54aOOOOOHNH54bBz...