Design, synthesis, and biological evaluation of neo-tanshinlactone and its analogs as potent antibreast cancer agents

My research in Dr. K. H. Lee's laboratory is to discover novel plant-derived natural products with antibreast cancer activity and then modify these new lead compounds to develop still more potent antitumor agents.; In the course of a search for antitumor agents from traditional Chinese medicine, neo-tanshinlactone (1) was isolated and synthesized for the first time and was evaluated against several human cancer cell lines. Compound 1 showed selective inhibitory activity against two estrogen receptor positive human breast cancer cell lines. Compound 1 is 10-fold more potent and 20-fold more selective against ER+ breast cancer in vitro as compared to tamoxifen citrate. Interestingly, compound 1 is also a potent inhibitor of an estrogen receptor negative, HER-2 over-expressing breast cancer cell line. Therefore, compound 1 is a novel antibreast cancer agent in vitro and is worthy of further development as an antibreast cancer drug candidate.; Neo-tanshinlactone's unique specific activity encouraged us to explore novel neo-tanshinlactone analogs as potential antibreast cancer agents. We first synthesized 21 analogs without an A ring (25--45). None of them showed cytotoxicity against several tumor cell lines, but they did show in vitro antitumor promoter activity. Compounds 22 and 39, the most active compounds in the in vitro assay, also showed strong antitumor promoter activity in an in vivo assay. We next synthesized neo-tanshinlactone analogs with different D rings (A--C series compounds). A series compounds showed better activity than B and C series. Compound 60 showed similar activity as tamoxifen with an ED50 of 4.0 mug/mL against MCF-7 and ZR-75-1 (ER+) and 10.3 and 7.5 mug/mL against MDA MB-231 and HS 587-1 (ER-), respectively. Compound 61 showed similar activity as compound 1 with ED50 values of 0.45 and 0.18 mug/mL against MCF-7 and ZR-75-1 (ER+) and 10.3 and 7.5 mug/mL against MDA MB-231 and HS 587-1 (ER-), respectively. We concluded that the methyl and ethyl groups at the 4-position of ring A can increase the activity dramatically, while the chlorine and methoxy groups at the 6-position of ring B do not affect the activity significantly. The furan/dihydrofuran ring is critical for the activity and the methyl furan ring resulted in better activity than hydroxyl dihydrofuran and furan rings. The activity of these compounds does not seem to correlate with ER-status or EGFR/HER2 status. The mechanism of action should be further investigated.; In conclusion, we developed a novel synthetic procedure for the general preparation of neo-tanshinlactone (1) and its analogs. The procedure is particularly useful because of the very promising antibreast cancer activity shown by 1 and analogs such as 61. The synthetic method is well suited to the preparation of additional analogs for extensive SAR studies.