Structure Guided Design, Synthesis, and Biological Evaluation of Novel Benzosuberene Analogues as Inhibitors of Tubulin Polymerization
Autor: | Mary Lynn Trawick, Tracy E. Strecker, Ernest Hamel, Jeni Gerberich, Deboprosad Mondal, James W. Campbell, Kevin G. Pinney, David J. Chaplin, Haichan Niu, Ralph P. Mason, Debabrata Saha |
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Rok vydání: | 2019 |
Předmět: |
Male
Chemistry Techniques Synthetic 01 natural sciences Article 03 medical and health sciences chemistry.chemical_compound Protein structure Coumarins Tubulin Cell Line Tumor Drug Discovery Animals Humans Bioluminescence imaging Colchicine Tubulin polymerization Benzosuberene Protein Structure Quaternary IC50 030304 developmental biology Combretastatin 0303 health sciences Chemistry Combinatorial chemistry Rats 0104 chemical sciences 010404 medicinal & biomolecular chemistry Cell culture Drug Design Molecular Medicine Protein Multimerization |
Zdroj: | J Med Chem |
ISSN: | 1520-4804 0022-2623 |
Popis: | A promising design paradigm for small-molecule inhibitors of tubulin polymerization that bind to the colchicine site draws structural inspiration from the natural products colchicine and combretastatin A-4 (CA4). Our previous studies with benzocycloalkenyl and heteroaromatic ring systems yielded promising inhibitors with dihydronaphthalene and benzosuberene analogues featuring phenolic (KGP03 and KGP18) and aniline (KGP05 and KGP156) congeners emerging as lead agents. These molecules demonstrated dual mechanism of action, functioning as both potent vascular disrupting agents (VDAs) and as highly cytotoxic anticancer agents. A further series of analogues was designed to extend functional group diversity and investigate regioisomeric tolerance. Ten new molecules were effective inhibitors of tubulin polymerization (IC(50) < 5 µM) with seven of these exhibiting highly potent activity comparable to CA4, KGP18, and KGP03. For one of the most effective agents, dose-dependent vascular shutdown was demonstrated using dynamic bioluminescence imaging in a human prostate tumor xenograft growing in a rat. |
Databáze: | OpenAIRE |
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