Neovascularization Inhibitor Analogues Of 2-me Coumarin Skeleton And Biological Activity

2-Methoxyestradiol (2-ME,1) is a novel angiogenesis inhibitor, which is being investigated in PhraseⅠ-Ⅲclinical trials for treatment of various solid cancers, especially breast cancer, ovarian cancer, prostate cancer and multiple myeloma.In our recent researches,3-(p-hydroxyphenyl)-4-methyl-6-methoxy-7-hydroxy-coumarin (2a) was designed and synthesized as coumarin-core analogue of 2-ME. Preliminary bioactivity evaluation revealed that 2a could inhibit the proliferation of 50% uman Umbilical Vein Endothelial Cells (HUVECs) at 16.69μM (2-ME:IC50= 6.5μM).Based on the structure characteristic of 2a, a series of coumarins with modified functional groups at 3-position were designed and synthesized for investigating the SAR, including compounds with different substituents at para-position of 3-phenyl (2b-2g), analogues with 3-hydroxypyrrolidinyl or 3-hydroxypiperidyl substituent at 3-position (5 and 6), and a series of alkylated and acylated derivatives of 3-aminocoumarins, which were designed for expanding the diversity of these coumarin compounds.As results,7 compounds with different substituents at para-position of 3-phenyl, and 20 derivatives of 3-animocoumarins were synthesized. Some of the target compounds and intermediates were screened on Human Umbilical Vein Endothelial Cells (HUVECs), Human Endometrial Cancer Cells (RL95-2), Human Ovarian Cancer Cells (SKOV-3) and Human Breast Carcinoma Cells (MCF-7 and T-47D) with 2-ME as reference compound. The biological screening data indicated that 6 compounds (2a,2e,38,41,45,46) displayed anti-angiogenesis activity (the IC50 value was less than 100μM on HUVEC); the IC50 value of compounds 38 and 41 was 32.30μmol/L and 10.91μmol/L respectively.2 compounds (38 and 41) were effective on inhibiting the growth of SKOV-3 cells, the IC50 value was 9.43μmol/L and 22.20μmol/L respectively.3 compounds (2a,38 and 41) were effective on inhibiting the growth of T-47D cells, the IC50 value was 60.63μmol/L,28.64μmol/L and 17.25μmol/L respectively.A conclution could be made from the primary SAR, that the doule bond in the five-membered ring of 41 should play an important role for its anti-proliferation activities.