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Design, Synthesis, and Preclinical Evaluation of New 5,6- (or 6,7-) Disubstituted-2-(fluorophenyl)quinolin-4-one Derivatives as Potent Antitumor Agents

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Li-Chen Chou†^#, Meng-Tung Tsai†^#, Mei-Hua Hsu†, Sheng-Hung Wang‡, Tzong-Der Way§, Chi-Hung Huang

, Hui-Yi Lin†, Keduo Qian

, Yizhou Dong

, Kuo-Hsiung Lee

, Li-Jiau Huang*†, and Sheng-Chu Kuo*†

^† Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan

^‡ Institute of Cellular and Organismic Biology, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan

^§ School of Biological Science and Technology, China Medical University, Taichung, Taiwan

Taiwan Advance Biopharm, Inc., 12F, No. 25, Lane 169, Kangning Street, Xizhi City, Taipei 221, Taiwan

Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, United States

J. Med. Chem., 2010, 53 (22), pp 8047–8058

DOI: 10.1021/jm100780c

Publication Date (Web): October 25, 2010

*To whom correspondence should be addressed. For L.-J.H.: phone, +886-4-22053366-5609; fax, +886-4-22030760; e-mail, ljhuang@mail.cmu.edu.tw. For S.-C.K.: phone, +886-4-22030760; fax, +886-4-22030760; e-mail, sckuo@mail.cmu.edu.tw., #

L.-C. Chou and M.-T. Tsai contributed equally to this work.

Section:

Heterocyclic Compounds (One Hetero Atom)

Abstract

Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1−P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC₅₀ of 0.03−8.2 μM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1−P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.

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This article has been cited by 1 ACS Journal articles (1 most recent appear below).

One-Pot Approach to 2,3-Disubstituted-2,3-dihydro-4-quinolones from 2-Alkynylbenzamides
Noriko Okamoto, Kei Takeda, Minoru Ishikura, and Reiko Yanada
The Journal of Organic Chemistry2011 76 (21), 9139-9143
- One-Pot Approach to 2,3-Disubstituted-2,3-dihydro-4-quinolones from 2-Alkynylbenzamides
  Noriko Okamoto, Kei Takeda, Minoru Ishikura, and Reiko Yanada
  The Journal of Organic Chemistry2011 76 (21), 9139-9143
  Concise and efficient syntheses of various trans-2,3-disubstituted-2,3-dihydro-4-quinolones have been achieved via tandem Hofmann-type rearrangement of 2-alkynylbenzamides, nucleophilic addition of alcohols to the isocyanate intermediates, intermolecular [...
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