Cyclopropyl-Epo A 17 as well as the corresponding Epo B analog were identified to be equipotent with Epo A and B; e.g., IC50?s for 17 and cyclopropyl-Epo B towards the human colon carcinoma cell lineHCT-116 are 1.four and 0.7 nM, respectively.These findings re-confirmed the Vicriviroc structure selleck chemicals notion the oxirane ring method in epothilones merely serves to stabilize the correct bioactive conformation from the macrocyclic skeleton in lieu of acting as being a reactive electrophile or maybe a hydrogen bond acceptor.As proven inside a later examine by Buey et al., the replacement from the epoxide moiety by a cyclopropane ring also creates enhanced binding to stabilized microtubules in vitro.Bis-substitution of your oxygen-replacing carbon in cyclopropyl-Epo B by bulky bromine substituents leads to decreased activity, however the resulting analog is still even more potent than Epo D against the HCT-116 cell line.Along with cyclopropyl-epothilones, the BMS group has also devised a strategy for your conversion of Epo A to a whole range of analogs incorporating a aziridine ring in spot in the epoxide moiety.
As illustrated in Scheme 6, the optimized route to these compounds entails regioselective epoxide ring-opening with MgBr2 ? Et2O followed by bromide displacement with azide ion, Mitsunobu-based inversion of configuration at C12, activation with the 12-hydroxyl group like a mesylate and eventually aziridine ring formation acipimox by means of azide reduction underneath Staudinger disorders.The resulting N-unsubstituted twelve,13-aziridinyl-Epo A 21 has been converted into a series ofN-substituted derivatives by way of alkylation, acylation, carbamoylation, or sulfonylation.A variety of of those derivatives show antiproliferative actions which are comparable with as well as superior to that of Epo A..Most recently, a folate conjugate in the N- -derivative of 21 has become advanced by BMS to two Phase I/II clinical studies; these scientific studies had been terminated as of July 2010.Bromohydrin 18 has also been elaborated into 12-cyano-Epo A 24 which was anticipated for being extra acid-stable compared to the organic item Epo B.As outlined in Scheme 7, oxidation of 18 with pyridinium chlorochromate furnished bromo ketone 23, whose treatment with KCN led to cyanohydrin formation and concomitant epoxide ring closure.Deprotectionwith CF3COOH then supplied the target structure 24.Interestingly, chlorohydrins one, two, and seven are already reported not to undergo epoxide formation even below strongly basic disorders , in contrast for the facile formation on the epoxide ring through the cyanohydrin of ketone 23.The antiproliferative action of 12-cyano-Epo A is comparable with that of Epo A mother or father compound Epo B).Modifications of your ester moiety One on the most clear modifications on the epothilone scaffold will be the hydrolysis of your ester bond to produce the corresponding seco acid.