Antitumor agents. 272. Structure-activity relationships and in vivo selective anti-breast cancer activity of novel neo-tanshinlactone analogues

Yizhou Dong, Qian Shi, Huei Chen Pai, Chieh Yu Peng, Shiow Lin Pan, Che Ming Teng, Kyoko Nakagawa-Goto, Donglei Yu, Yi Nan Liu, Pei Chi Wu, Kenneth F. Bastow, Susan L. Morris-Natschke, Arnold Brossi, Jing Yu Lang, Jennifer L. Hsu, Mien Chie Hung, Eva Y H P Lee, Kuo Hsiung Lee

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57 Citations (Scopus)

Abstract

Neo-tanshinlactone (1) and its previously reported analogues, such as 2, are potent and selective in vitro antibreast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of antibreast agents. Several derivatives (19-21 and 24) exerted potent and selective antibreast cancer activity with IC50 values of 0.3,0.2,0.1, and 0.1 μg/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analogue 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.

Original languageEnglish
Pages (from-to)2299-2308
Number of pages10
JournalJournal of Medicinal Chemistry
Volume53
Issue number5
DOIs
Publication statusPublished - Mar 11 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Dong, Y., Shi, Q., Pai, H. C., Peng, C. Y., Pan, S. L., Teng, C. M., Nakagawa-Goto, K., Yu, D., Liu, Y. N., Wu, P. C., Bastow, K. F., Morris-Natschke, S. L., Brossi, A., Lang, J. Y., Hsu, J. L., Hung, M. C., Lee, E. Y. H. P., & Lee, K. H. (2010). Antitumor agents. 272. Structure-activity relationships and in vivo selective anti-breast cancer activity of novel neo-tanshinlactone analogues. Journal of Medicinal Chemistry, 53(5), 2299-2308. https://doi.org/10.1021/jm1000858