Antitumor Agents. 272. Structure−Activity Relationships and In Vivo Selective Anti-Breast Cancer Activity of Novel Neo-tanshinlactone Analogues
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- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：March 11, 2010
- 年：2010
- 卷：53
- 期：5
- 页码：2299-2308
- 全文大小：924K
- 年卷期：v.53,no.5(March 11, 2010)
- ISSN：1520-4804
文摘
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.