Structure Guided Design, Synthesis, and Biological Evaluation of Novel Benzosuberene Analogues as Inhibitors of Tubulin Polymerization.

Autor:	Niu H; Department of Chemistry and Biochemistry , Baylor University , One Bear Place, No. 97348 , Waco , Texas 76798-7348 , United States., Strecker TE; Department of Chemistry and Biochemistry , Baylor University , One Bear Place, No. 97348 , Waco , Texas 76798-7348 , United States., Gerberich JL; Department of Radiology , The University of Texas Southwestern Medical Center , 5323 Harry Hines Boulevard , Dallas , Texas 75390-9058 , United States., Campbell JW 3rd; Department of Radiology , The University of Texas Southwestern Medical Center , 5323 Harry Hines Boulevard , Dallas , Texas 75390-9058 , United States., Saha D; Department of Radiology Oncology, Division of Molecular Radiation Biology , The University of Texas Southwestern Medical Center , 2201 Inwood Road , Dallas , Texas 75390-9187 , United States., Mondal D; Department of Chemistry and Biochemistry , Baylor University , One Bear Place, No. 97348 , Waco , Texas 76798-7348 , United States., Hamel E; Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis , National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health , Frederick , Maryland 21702 , United States., Chaplin DJ; Department of Chemistry and Biochemistry , Baylor University , One Bear Place, No. 97348 , Waco , Texas 76798-7348 , United States.; Mateon Therapeutics, Inc. , 701 Gateway Boulevard, Suite 210 , South San Francisco , California 94080 , United States., Mason RP; Department of Radiology , The University of Texas Southwestern Medical Center , 5323 Harry Hines Boulevard , Dallas , Texas 75390-9058 , United States., Trawick ML; Department of Chemistry and Biochemistry , Baylor University , One Bear Place, No. 97348 , Waco , Texas 76798-7348 , United States., Pinney KG; Department of Chemistry and Biochemistry , Baylor University , One Bear Place, No. 97348 , Waco , Texas 76798-7348 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2019 Jun 13; Vol. 62 (11), pp. 5594-5615. Date of Electronic Publication: 2019 May 24.
DOI:	10.1021/acs.jmedchem.9b00551
Abstrakt:	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 both as 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:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu