Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1

Bernardo, Paul H.; Sivaraman, Thirunavukkarasu; Wan, Kah-Fei; Xu, Jin; Krishnamoorthy, Janarthanan; Song, Chun Meng; Tian, Liming; Chin, Jasmine S. F.; Lim, Diane S. W.; Mok, Henry Y. K.; Yu, Victor C.; Tong, Joo Chuan; Chai, Christina L. L.

doi:10.1351/PAC-CON-10-10-29

Pure Appl. Chem., 2011, Vol. 83, No. 3, pp. 723-731

http://dx.doi.org/10.1351/PAC-CON-10-10-29

Published online 2011-02-05

Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1

Paul H. Bernardo¹*, Thirunavukkarasu Sivaraman², Kah-Fei Wan³, Jin Xu¹, Janarthanan Krishnamoorthy⁴, Chun Meng Song⁵, Liming Tian¹, Jasmine S. F. Chin¹, Diane S. W. Lim¹, Henry Y. K. Mok⁴, Victor C. Yu⁶, Joo Chuan Tong^7,5 and Christina L. L. Chai^6,1*

¹ Institute of Chemical and Engineering Sciences, Agency for Science Technology and Research (A*STAR), 8 Biomedical Grove, #07-01 Neuros 138632, Singapore
² School of Chemical and Biotechnology, SASTRA University, Thanjavur-613401, TN, India
³ Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos 138670, Singapore
⁴ Department of Biological Sciences, National University of Singapore, 117543, Singapore
⁵ Institute for Infocomm Research, A*STAR, 1 Fusionopolis Way, No. 21-01 Connexis 138632, Singapore
⁶ Department of Pharmacy, Faculty of Science, National University of Singapore, 117543, Singapore
⁷ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, 117597 Singapore

Abstract: A small library of pyridine-based rhodanine analogues of BH3I-1 were synthesized and screened against B-cell lymphoma-extra large (Bcl-XL) and myeloid cell leukemia sequence 1 (Mcl-1) for the ability to displace 5-carboxyfluorescein-labeled Bak peptide (Flu‑Bak). Differences in selectivity toward Bcl-XL and Mcl-1 were observed, and the binding modes of selected compounds were studied further. The results may be useful in designing potent small-molecule inhibitors of Bcl-XL and Mcl-1 as well as selective Mcl-1 inhibitors.