2. Academic Validation
  3. Optimization of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines as tubulin polymerization inhibitors

Optimization of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines as tubulin polymerization inhibitors

  • Bioorg Med Chem. 2015 Sep 1;23(17):5740-7. doi: 10.1016/j.bmc.2015.07.016.
Sheng-Biao Wang 1,  Xiao-Feng Wang 1,  Bingjie Qin 1,  Emika Ohkoshi 2,  Kan-Yen Hsieh 3,  Ernest Hamel 4,  Mu-Tian Cui 1,  Dong-Qing Zhu 1,  Masuo Goto 2,  Susan L Morris-Natschke 2,  Kuo-Hsiung Lee 5,  Lan Xie 6
Affiliations

Affiliations

  • 1 Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
  • 2 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 4 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, MD 21702, USA.
  • 5 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
  • 6 Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. Electronic address: lanxieshi@yahoo.com.
PMID: 26242242 DOI: 10.1016/j.bmc.2015.07.016
Abstract

Thirteen new N-aryl 1,2,3,4-tetrahydroquinoline compounds (4a-f, 6a-c, and 8a-d) were synthesized and evaluated for antitumor activity and drug-like properties. Compound 4a exhibited high inhibitory potency with low nanomolar GI50 values of 16-20 nM in cellular assays, including excellent activity against the P-glycoprotein overexpressing cell line KBvin. Compound 4a inhibited colchicine binding to tubulin and tubulin assembly with an IC50 value of 0.85 μM, superior to the reference compound CA4 (1.2 μM) in the same assay. In addition, 4a also exhibited highly improved water solubility (75 μg/mL) and a suitable logP value (3.43) at pH 7.4. With a good balance between antitumor potency and drug-like properties, compound 4a could be a new potential drug candidate for further development. Current results on SAR studies and molecular modeling provided more insight about this class of compounds as tubulin polymerization inhibitors targeting the colchicine site.

Keywords

Colchicine binding inhibitors; Cytotoxic activity; N-Aryl 1,2,3,4-tetrahydroquinolines; Tubulin polymerization inhibitors.

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