Antitumor Agents. 272. Structure-Activity Relationships and In Vivo Selective Anti-Breast Cancer Activity of Novel Neo-tanshinlactone Analogues

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

来源：Journal of Medicinal Chemistry, 2010, 53(5): 2299-2308.

DOI：10.1021/jm1000858

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 mu g/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than I 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 it 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.

• 出版日期2010-3-11
• 单位中国医科大学