Antitumor agents. 272. Structure-activity relationships and in vivo selective anti-breast cancer activity of novel neo-tanshinlactone analogues.
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| 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 IC(50) values of 0.3, 0.2, 0.1, and 0.1 microg/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.
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| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 5 Pg. 2299-308 (Mar 11 2010) ISSN: 1520-4804 [Electronic] United States |
| PMID | 20148565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
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