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Synthetic Analogues of the Microtubule-Stabilizing Sponge Alkaloid Ceratamine A Are More Active than the Natural Product.

TitleSynthetic Analogues of the Microtubule-Stabilizing Sponge Alkaloid Ceratamine A Are More Active than the Natural Product.
Publication TypeJournal Article
Year of Publication2010
AuthorsNodwell, M, Zimmerman, C, Roberge, M, Andersen, RJ
JournalJournal of Medicinal Chemistry
Volume53
Pagination7843 - 7851
Date Published2010///
ISBN Number0022-2623
Keywordssynthetic analog microtubule stabilizer sponge alkaloid ceratamine natural product
Abstract

Desbromoceratamine A (3) exhibits significantly less potent activity than the natural product ceratamine A (1) in a cell-based assay for antimitotic activity. Synthesis of the ceratamine A analog 4 has shown that replacing the bromine atoms in the natural product with Me groups generates an analog that is more active than natural ceratamine A (1). Further enhancement of the antimitotic activity of the ceratamine pharmacophore has been achieved in the synthetic analog 33, which has both bromine atoms replaced with Me groups and an addnl. Me substituent on the amino nitrogen at C-2. An efficient synthetic route has been developed to 33 that should enable the first in vivo evaluation of the new ceratamine microtubule-stabilizing pharmacophore and has provided several addnl. analogs for structure-activity relationship evaluation. [on SciFinder(R)]