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.

In vitro cytotoxic potential of newly synthesized furo[3,2-c]pyran-4-one derivatives in cultured human lymphocytes

“…Their compounds 10-13, 23, 25, and 27 showed potent inhibition against the SK-BR-3 breast cancer cell line. Neo-tanshinlactone was reported as a highly selective inhibitor of the growth of breast cancer cell lines SK-BR-3 (HER2 overexpressing breast cancer) and ZR-75-1 (estrogen receptor positive breast cancer) (Wang et al , 2006. The phellifuropyranone, 2-(3,4-dihydroxyphenyl)-6-(2 0 -(3,4-dihydroxyphenyl)-E-ethenyl)-furo [3,2-c]pyran-4-one, has antiproliferative activity against mouse melanoma cells and human lung cancer cells in vitro (Kojima et al 2008).…”

“…1) is a steroid-like tetracyclic natural product originally isolated from the traditional Chinese medicine Tanshen. Neo-tanshinlactone was reported as a highly selective inhibitor of the growth of breast cancer cell lines SK-BR-3 (HER2 over-expressing breast cancer) and ZR-75-1 (estrogen receptor positive breast cancer) Wang et al 2006). 6-Phenyl-4H-furo[3,2-c]pyran-4-one derivatives based on neo-tanshinlactone have shown potent inhibition against the SK-BR-3 breast cancer cell line (Dong et al 2010).…”

Development of New Estrogen Receptor-Targeting Therapeutic Agents for Tamoxifen-Resistant Breast Cancer

“…In addition, analog 42 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 (ER-negative) xenografts, as well as high selectivity against breast cancer cells compared with normal breast tissue-derived cell lines. Thus, 43–46 can serve as lead compounds for further development of clinical trial candidates for treatment of de novo tamoxifen-resistant breast cancer [67–69]. …”

Plant-derived natural product research aimed at new drug discovery

“…Therefore, G4 is an excellent candidate for further development toward anti-breast cancer clinical trials. More recent synthetic analog studies have ascertained certain structural features that are critical to the anticancer activity of this compound class and identified a compound (G5) with comparable or better anticancer activity [85].…”