Total synthesis and selective activity of a new class of conformationally restrained epothilones.
Stereoselective total syntheses of two novel conformationally restrained epothilone analogues are described. Evans asymmetric alkylation, Brown allylation, and a diastereoselective aldol reaction served as the key steps in the stereoselective synthesis of one of the two key fragments of the convergent synthetic approach. Enzyme resolution was employed to obtain the second fragment as a single enantiomer. The molecules were assembled by esterification, followed by ring-closing metathesis. In preliminary cytotoxicity studies, one of the analogues showed strong and selective growth inhibitory activity against two leukemia cell lines over solid human tumor cell lines. The precise biological mechanism of action and high degree of selectivity of this analogue remain to be examined.
Alhamadsheh
Mamoun M
MM
Department of Medicinal and Biological Chemistry, College of Pharmacy, The University of Toledo, Toledo, OH 43606, USA.
Gupta
Shuchi
S
Hudson
Richard A
RA
Perera
Lalith
L
Tillekeratne
L M Viranga
LM
D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000145:classification / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones / Q000138:chemical synthesis / Q000145:classification / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D034261:Epothilones