An approach to the site-selective diversification of apoptolidin A with peptide-based catalysts.
We report the application of peptide-based catalysts to the site-selective modification of apoptolidin A (1), an agent that displays remarkable selectivity for inducing apoptosis in E1A-transformed cell lines. Key to the approach was the development of an assay suitable for the screening of dozens of catalysts in parallel reactions that could be conducted using only microgram quantities of the starting material. Employing this assay, catalysts (e.g., 11 and ent-11) were identified that afforded unique product distributions, distinct from the product mixtures produced when a simple catalyst (N,N-dimethyl-4-aminopyridine (10)) was employed. Preparative reactions were then carried out with the preferred catalysts so that unique, homogeneous apoptolidin analogues could be isolated and characterized. From these studies, three new apoptolidin analogues were obtained (12-14), each differing from the other in either the location of acyl group substituents or the number of acetate groups appended to the natural product scaffold. Biological evaluation of the new apoptolidin analogues was then conducted using growth inhibition assays based on the H292 human lung carcinoma cell line. The new analogues exhibited activities comparable to apoptolidin A.
Lewis
Chad A
CA
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, USA.
Longcore
Kate E
KE
Miller
Scott J
SJ
Wender
Paul A
PA
D017209:Apoptosis / Q000187:drug effects; D002384:Catalysis; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*
D018942:Macrolides; D010455:Peptides; C114125:apoptolidin