@article{9caf61e6a7124339b1e5dc1e444544fa,
title = "Structure Guided Design, Synthesis, and Biological Evaluation of Novel Benzosuberene Analogues as Inhibitors of Tubulin Polymerization",
abstract = "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 (IC50 < 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.",
author = "Haichan Niu and Strecker, {Tracy E.} and Gerberich, {Jeni L.} and Campbell, {James W.} and Debabrata Saha and Deboprosad Mondal and Ernest Hamel and Chaplin, {David J.} and Mason, {Ralph P.} and Trawick, {Mary Lynn} and Pinney, {Kevin G.}",
note = "Funding Information: The authors are grateful to the Cancer Prevention and Research Institute of Texas (CPRIT, Grant RP140399 to K.G.P., M.L.T., R.P.M.; Grant RP170696 to K.G.P., M.L.T.; Grant RP140285 to R.P.M.; Grant RP120670-C3 to D.S.), the National Cancer Institute of the National Institutes of Health (Grant 5R01CA140674 to K.G.P., M.L.T., R.P.M.), Mateon Therapeutics, Inc. (grant to K.G.P., M.L.T.), and the University Research Committee (URC) and the Vice Provost for Research at Baylor University (M.L.T.) for financial support of these projects. The authors further acknowledge resources associated with the UT Southwestern Small Animal Imaging Resource (SW-SAIRP), supported in part by the Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant, 1P30CA142543, and the Department of Radiology. The IVIS Spectrum was acquired with the assistance of NIH Shared Instrumentation Grant S10RR024757. Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",
year = "2019",
month = jun,
day = "13",
doi = "10.1021/acs.jmedchem.9b00551",
language = "English (US)",
volume = "62",
pages = "5594--5615",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "11",
}