Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 1, Pages 52-57Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.11.077
Keywords
2-(Furan-2-yl)naphthalen-1-ol analogs; Structure-activity relationships; Anti-breast tumor agents
Categories
Funding
- National Cancer Institute [CA-17625]
- NATIONAL CANCER INSTITUTE [R01CA017625] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI077417] Funding Source: NIH RePORTER
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In our ongoing modification study of neo-tanshinlactone (1), we discovered 2-(furan-2-yl)naphthalen-1-ol (FNO) derivatives 3 and 4 as a new class of anti-tumor agents. To explore structure-activity relationships (SAR) of this scaffold, 18 new analogs, 6-12 and 14-24, were designed and synthesized. The C11-esters 7 and 12 displayed broad anti-tumor activity (ED50 1.1-4.3 mu g/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED50 0.73 mu g/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED50 1.7 and 0.85 mu g/mL, respectively, against MDA-MB-231). The SAR results demonstrated that the substitutions from the ring-opened lactone ring C of 1 are critical to the anti-tumor potency as well as the apparent tumor-tissue type selectivity. Treatment with 3 in Brca1(f11/f11)p53(f5&6/f5&6)Cre(c) mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands. (C) 2010 Elsevier Ltd. All rights reserved.
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