Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications

Chin Hui Kee; Azhar Ariffin; Khalijah Awang; Koichi Takeya; Hiroshi Morita; Salmaan Inayat Hussain; Kok Meng Chan; Pauline J. Wood; Michael D. Threadgill; Chuan Gee Lim; SeikWeng Ng; Jean Frédéric F. Weber; Noel F. Thomas

doi:10.1039/C0OB00296H

Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications†

Chin Hui Kee,^a Azhar Ariffin,^a Khalijah Awang,^a Koichi Takeya,^b Hiroshi Morita,^c Salmaan Inayat Hussain,^d Kok Meng Chan,^d Pauline J. Wood,^e Michael D. Threadgill,^e Chuan Gee Lim,^f SeikWeng Ng,^a Jean Frédéric F. Weber^g and Noel F. Thomas*^a

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* Corresponding authors

^a Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
E-mail: noelfthomas@um.edu.my
Fax: +603-79674193
Tel: +603-79674065

^b Department of Pharmacognosy, Tokyo University of Pharmaceutical and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo, Japan

^c Faculty of Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan

^d Faculty of Allied Health Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

^e Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, UK

^f Environmental and Bioprocess Technology Centre, SIRIM Berhad, Shah Alam, Malaysia

^g IKUS, Faculty of Pharmacy, Universiti Teknologi MARA, Shah Alam, Malaysia

Abstract

The syntheses of fourteen unusual o-carboxamido stilbenes by the Heck protocol revealed surprising complexity related to intriguing substituent effects with mechanistic implications. The unexpected cytotoxic and chemopreventive properties also seem to be substituent dependent. For example, although stilbene 15d (with a 4-methoxy substituent) showed cytotoxicity on HT29 colon cancer cells with an IC₅₀ of 4.9 μM, the 3,4-dimethoxy derivative (15c) is inactive. It is interesting to observe that the 3,5-dimethoxy derivative (15e) showed remarkable chemopreventive activity in WRL-68 fetal hepatocytes, surpassing the gold standard, resveratrol. The resveratrol concentration needed to be 5 times higher than that of 15e to produce comparable elevation of NQO1.

Organic & Biomolecular Chemistry

Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications†

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Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications

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