Synthesis And Bioactivities Of Novel Spiroheterocycle Heparanase Inhibitors

HS on cell surfaces modulates signal transduction to tumor cells by interacting with different growth factors. For example, fibroblast growth factor-2, vascular epidermal growth factor (VEGF), and heparin-binding epidermal growth factor such as growth factor (HB-EGF). Cell-surface and extracellular matrix HS plays a very important role in tumor metastasis. For the importance of HS in anti cancer, several kinds of HS mimetics have been synthesized and can act as anti-tumor agents. Among of them, DMBO(2-(2,6-difluorophenyl)-5-(4-methoxyphenyl)-l-oxa-3-azaspiro [5.5] Undecane) have been developed as a novel pyranoside mimetic compound, it exhibited strong anti anti-proliferation activity in vitro against tumor cells such as a highly metastatic murine osteosarcoma cell line LM8G7which secretes VEGF as well as two human ovarian cell lines, OVSAHO and SKOV-3that secrete TNF-a and HB-EGF respectively. Meanwhile, DMBO can act as a human heparanase inhibitor in vitro which possibly as a substrate mimetic.1,Given the DMBO has strong inhibition effects on cancer cells and heparanase, we synthetize thirteen new DMBO derivatives with different substitutents of two series which have never been reported. The thirteen new compounds are expected to be used as heparanase inhibitors and all these compounds have been characterized by IR,’H NMR,13C NMR and MS analysis, respectively.Through the optimization of reaction conditions,we synthetize the compounds successfully without any dehydration by-products.Most importantly, the conditions of the reaction we have optimized is mild and easy to handle with high yield2By means of1H NMR、UV-Vis and the theory of quantum chemistry, we investigate the effects of the substituent groups and solvent polarity on ring-chain tautomeric equilibrium and find out the factors and regularity that affect the equilibrium. Some of the synthetic compounds were evaluated for their heparanase inhibition activities. The in vitro bioactivity investigation suggested that most of the DMBO derivatives are capable of inhibiting heparanase with stong activity, especially compound14(IC50=4.47μM) exhibited the best inhibitory activity.