Synthesis of biologically active taxol analogues with modified phenylisoserine side chains.
Taxol (1) is a highly potent antitumor agent, exerting its mechanism of action by promoting the assembly of stable microtubules in cells. We are reporting on the first synthesis and biological evaluation of taxol derivatives with substituted phenyl rings at the C-13 N-benzoyl-(2'R,3'S)-3'-phenylisoserine side chain of taxol (1). Two taxol derivatives were synthesized, one possessing a N-(p-chlorobenzoyl)-(2'R,3'S)-3'-phenylisoserine side chain (2) and the other one a N-benzoyl-(2'R,3'S)-3'-(p-chlorophenyl)isoserine side chain (3). The synthesis of the novel phenylisoserine side chains was achieved through the asymmetric synthesis of 3-hydroxy-4-aryl-2-azetidinone derivatives via the ester enolate-imine cyclocondensation reaction. The 2-azetidinones 14 and 15 were acylated with p-chlorobenzoyl chloride and benzoyl chloride, respectively, to form the N-acyl beta-lactams 16 and 17. Subsequent coupling of 16 and 17 to 7-(triethylsilyl)baccatin III (6) in the presence of pyridine and DMAP afforded, after removal of the protecting groups, the desired taxol analogues 2 and 3 in excellent yields. The newly synthesized derivatives 2 and 3 were tested in the tubulin assembly assay and also evaluated for their cytotoxicity against B16 melanoma cells. It was found that the taxol derivatives 2 and 3 had activity comparable to taxol (1).
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
G I
GI
Georg
Z S
ZS
Cheruvallath
R H
RH
Himes
M R
MR
Mejillano
C T
CT
Burke
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002417:Cattle; D004354:Drug Screening Assays, Antitumor; D066298:In Vitro Techniques; D008546:Melanoma, Experimental / Q000188:drug therapy; D008870:Microtubules / Q000187:drug effects*; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017239:Paclitaxel