TY - JOUR
T1 - Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization
AU - Herdman, Christine A.
AU - Devkota, Laxman
AU - Lin, Chen Ming
AU - Niu, Haichan
AU - Strecker, Tracy E.
AU - Lopez, Ramona
AU - Liu, Li
AU - George, Clinton S.
AU - Tanpure, Rajendra P.
AU - Hamel, Ernest
AU - Chaplin, David J.
AU - Mason, Ralph P.
AU - Trawick, Mary Lynn
AU - Pinney, Kevin G.
N1 - Funding Information:
The authors are grateful to the National Cancer Institute of the National Institutes of Health (Grant No. 5R01CA140674 to K.G.P., M.L.T., and R.P.M.), the Cancer Prevention and Research Institute of Texas (CPRIT, Grant No. RP140399 to K.G.P., M.L.T., and R.P.M.), and OXiGENE, Inc. (Grant to K.G.P. and M.L.T.) for their financial support of this project, and to the NSF for funding the Varian 500 MHz NMR spectrometer (Grant No. CHE-0420802 ). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. The authors would also thank Dr. James Karban and Dr. Michelle Nemec (Director) for the use of the shared Molecular Biosciences Center at Baylor University, Dr. Alejandro Ramirez (Mass Spectrometry Core Facility, Baylor University) and Dr. Kevin Klausmeyer and Marissa Penney (X-ray analysis). The authors are grateful to Mr. Tyler Goddard (Baylor University) for his contributions to the synthesis of certain analogues, and to Jeni Gerberich (UTSW) and Dr. Li Li (UTSW) for valuable technical assistance. Imaging was facilitated with the assistance of Resources of the Harold C. Simmons Cancer Center supported through an National Institutes of Health National Cancer Institute Cancer Center Support Grant [Grant 1P30 CA142543 ], specifically, the Southwestern Small Animal Imaging Resource, and Live Cell Imaging Resource. The IVIS Spectrum was purchased with support of 1S10RR024757.
Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/12/15
Y1 - 2015/12/15
N2 - The discovery of 3-methoxy-9-(3′,4′,5′-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5 μM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1 μM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.
AB - The discovery of 3-methoxy-9-(3′,4′,5′-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5 μM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1 μM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.
KW - Benzosuberene analogues
KW - Inhibitors of tubulin polymerization
KW - Small-molecule synthesis
KW - Vascular disrupting agents
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U2 - 10.1016/j.bmc.2015.10.012
DO - 10.1016/j.bmc.2015.10.012
M3 - Article
C2 - 26775540
AN - SCOPUS:84949529872
SN - 0968-0896
VL - 23
SP - 7497
EP - 7520
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 24
ER -