Antitumor agents 279. Structure-activity relationship and in vivo studies of novel 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs as potent and selective anti-breast cancer agents |
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Authors: | Dong Yizhou Nakagawa-Goto Kyoko Lai Chin-Yu Kim Yoon Morris-Natschke Susan L Lee Eva Y-H P Bastow Kenneth F Lee Kuo-Hsiung |
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Institution: | a Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA b Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA c Department of Biological Chemistry, University of California, Irvine, CA 92697-4037, USA d Department of Developmental & Cell Biology, University of California, Irvine, CA 92697-4037, USA e Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan |
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Abstract: | 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 μg/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED50 0.73 μg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED50 1.7 and 0.85 μg/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 Brca1f11/f11p53f5&6/f5&6Crec mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands. |
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Keywords: | 2-(Furan-2-yl)naphthalen-1-ol analogs Structure-activity relationships Anti-breast tumor agents |
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