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: Xihong Wang, Kyoko Nakagawa-Goto, Kenneth F Bastow, Ming-Jaw Don, Yun-Lian Lin, Tian-Shung Wu, Kuo-Hsiung Lee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 18 Pg. 5631-4 (Sep 07 2006) ISSN: 0022-2623 [Print] United States
• PMID: 16942038 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 4-ethyl-17-methyl-11,15-dioxacyclopenta(a)phenanthren-12-one
• Antineoplastic Agents
• Furans
• Heterocyclic Compounds, 4 or More Rings
• Pyrones
• neotanshinlactone

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Female
• Furans (chemical synthesis, chemistry, pharmacology)
• Heterocyclic Compounds, 4 or More Rings (chemical synthesis, chemistry, pharmacology)
• Humans
• Pyrones (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship