2. Academic Validation
  3. In Vivo and Mechanistic Studies on Antitumor Lead 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents

In Vivo and Mechanistic Studies on Antitumor Lead 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one and Its Modification as a Novel Class of Tubulin-Binding Tumor-Vascular Disrupting Agents

  • J Med Chem. 2017 Jul 13;60(13):5586-5598. doi: 10.1021/acs.jmedchem.7b00273.
Mu-Tian Cui 1,  Li Jiang 1,  Masuo Goto 2,  Pei-Ling Hsu 2,  Linna Li 3,  Qi Zhang 3,  Lei Wei 1,  Shou-Jun Yuan 3,  Ernest Hamel 4,  Susan L Morris-Natschke 2,  Kuo-Hsiung Lee 2 5,  Lan Xie 1 2
Affiliations

Affiliations

  • 1 Beijing Institute of Pharmacology and Toxicology , 27 Tai-Ping Road, Beijing 100850, China.
  • 2 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
  • 3 Beijing Institute of Radiation Medicine , 27 Tai-Ping Road, Beijing 100850, China.
  • 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, Maryland 21702, United States.
  • 5 Chinese Medicine Research and Development Center, China Medical University and Hospital , Taichung 40402, Taiwan.
PMID: 28653846 DOI: 10.1021/acs.jmedchem.7b00273
Abstract

7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (2), a promising Anticancer lead previously identified by us, inhibited tumor growth by 62% in mice at 1.0 mg/kg without obvious signs of toxicity. Moreover, compound 2 exhibited extremely high antiproliferative activity in the NIH-NCI 60 human tumor cell line panel, with low to sub-nanomolar GI50 values (10-10 M level). It also showed a suitable balance between aqueous solubility and lipophilicity, as well as moderate metabolic stability in vivo. Mechanistic studies using Mayer's hematoxylin and eosin and immunohistochemistry protocols on xenograft tumor tissues showed that 2 inhibited tumor cell proliferation, induced Apoptosis, and disrupted tumor vasculature. Moreover, evaluation of new synthetic analogues (6a-6t) of 2 indicated that appropriate 2-substitution on the quinazoline ring could enhance antitumor activity and improve druglike properties. Compound 2 and its analogues with a 4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin-2(1H)-one scaffold thus represent a novel class of tubulin-binding tumor-vascular disrupting agents (tumor-VDAs) that target established blood vessels in tumors.

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