1005192-33-5

Upstream product

• 1005192-34-6 4-[(2-{1-acetoxy-3-[(2-azido-3-methyl-pentanoyl)-(3-methyl-butyryloxymethyl)-amino]-4-methyl-pentyl}-thiazole-4-carbonyl)-amino]-2-methyl-5-phenyl-pentanoic acid 
• 19220-93-0 pentafluorophenyl acetate 

Relevant academic research and scientific papers

TUBULYSIN D ANALOGUES

The present invention provides novel tubulysin analogues, methods of making and methods of using such analogues and conjugates thereof. The essential features for the potent cytotoxicity of tubulysin D have been established for the first time by the synthesis and evaluation of a series of analogues. By identifying functionality that surprisingly is not necessary for activity, highly potent cell-growth inhibitors have been developed that are smaller and considerably more stable than tubulysin D.

Design, synthesis, and biological properties of highly potent tubulysin D analogues

Ten analogues of tubulysin D were synthesized and assayed against established mammalian cell lines, including cancer cells measuring inhibition of cell growth by an MTT assay. These experiments establish for the first time the essential features for the potent cytotoxicity of tubulysin D. The activities of analogues 2 to 5 demonstrate that numerous modifications may be introduced at the C-terminus of the natural product with only modest loss in activity, while the activities of analogues 6 to 8 suggest that a basic amine must be present at the N-terminus to maintain activity. Most surprisingly, analogue 10 establishes that replacement of the chemically labile O-acyl N,O-acetal with the stable N-methyl group results in almost no loss in activity. In aggregate, these structure-activity relationships enable the design of analogues such as 11 that are smaller and considerably more stable than tubulysin D but that maintain most of its potent cell-growth inhibitory activity.