title: Antitumor agents. 254. Synthesis and biological evaluation of novel neo-tanshinlactone analogues as potent anti-breast cancer agents.
abstract: In our previous study, neo-tanshinlactone (1) showed potent and selective anti-breast cancer activity. To explore the SAR of 1, nine analogues (15-18, 24-28) were designed and synthesized. Together with 1 and tamoxifen (TAM), all newly synthesized compounds and some intermediates were evaluated for in vitro anticancer activity against several human tumor cell lines. Compounds without a ring D did not show promising activity, while compounds with a methylated furan ring D showed better activity than those with unsubstituted furan or hydroxy-dihydrofuran rings. Among all newly synthesized compounds, compound 15 with an ethyl group at the 4-position showed the best activity and selectivity with ED50 values of 0.45 and 0.18 microg/mL against MCF-7 and ZR-75-1 (ER+) and 13.5 and 10.0 microg/mL against MDA MB-231 and HS 587-1 (ER-), respectively. Furthermore, 15 also showed potent activity against SK-BR-3 (ER-, HER2+) with an ED50 value of 0.10 microg/mL. Our preliminary SAR studies showed that a methylated furan ring D and the C-4 substituent in ring A are critical for anti-breast cancer activity. Further development of 1 and 15 as anti-breast cancer drug candidates is warranted.
authors.affiliation: Natural Products Research Laboratories, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Xihong
authors.initials: X
authors.lastname: Wang
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Ming-Jaw
authors.initials: MJ
authors.lastname: Don
authors.forename: Yun-Lian
authors.initials: YL
authors.lastname: Lin
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C514072:4-ethyl-17-methyl-11,15-dioxacyclopenta(a)phenanthren-12-one; D000970:Antineoplastic Agents; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; D011753:Pyrones; C494351:neotanshinlactone