title: 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.
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 (ED(50) 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 (ED(50) 0.73 μg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED(50) 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 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.
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Dong
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Lai
authors.forename: Yoon
authors.initials: Y
authors.lastname: Kim
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Eva Y-H P
authors.initials: EY
authors.lastname: Lee
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D009281:Naphthalenes / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C557259:2-(furan-2-yl)naphthalen-1-ol; D000970:Antineoplastic Agents; D005663:Furans; D009281:Naphthalenes