Design, Synthesis And Preliminary Activity Of Matrix Metalloproteinase Inhibitors

The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidase involved in the degradation and remodeling the extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). To date, at least 28 structurally related members have been identified in the mammal MMPs gene family, While MMP-2 (gelatinase A) is proved to play key roles in the processes of tumor growth, invasion, metastasis and angiogenesis. And have been associated with an aggressive malignant phenotype and poor prognosis in patients with cancer. As a result, it is believed that the growth and metastasis can be controlled by MMP inhibitors (MMPIs) which are expected to be useful for the treatment of cancer.Base on the 3D structures of known MMPIs and binding modes of these compounds in complex with MMPs, we designed and synthesized 4 series of quinoxalione compounds with the help of Chem3D Ultra 7.0 program. Preliminary activity assay was carried out both in vitro and in vivo.The first series of compounds were synthesized starting from 1,4-Dithia-7-azaspiro[4,4]nonane-8-carboxylic acid through a reaction sequence including sulfonylation, condensation, hydrolysis and so on. The structures of target compounds were identified by IR, ESI-MS and HNMR spectra.The second and third series of compounds were synthesized starting from 1,2-diaminobenzene through a reaction sequence including cyclization, N-substitute, hydrolysis, condensation, and so on. The structures of target compounds were identified by IR, HR-MS and HNMR spectra. The fourth series of compounds were synthesized starting from 1,2-diaminobenzene through a reaction sequence including cyclization, N-substitute, hydrazinolysis and so on. The structures of target compounds were identified by IR, ESI-MS and HNMR spectra.The fifth series of compounds were synthesized starting from 3,4-difluoroaniline through a reaction sequence including N-protection, nitration, de-protection, hydrogenation reduction, cyclization, N-substitute, hydrazinolysis and so on. The structures of target compounds were identified by IR, ESI-MS and HNMR spectra.Preliminary activity assay was carried out both in vitro and in vivo. Inhibiting activities of compounds on gelatinase (MMP-2) were measured by using succinylated gelatin as substrate. The test results demonstrated that most of these inhibitors showed significant anticancer activities. And some compounds were assayed for their anti-proliferation activity towards HL-60, K562 cell and SKOV3 cell. MTT method was employed. The result showed that the designed compounds did have anti-proliferation activity towards K562 cell and SKOV3 cell.In conclusion, five series of novel pyrrolidine scaffold-based MMP inhibitors were designed and synthesized. Preliminary enzyme activity assay and anti-proliferation assays of SKOV3 and K562 cell showed most compounds possess potential inhibitory activity. These compounds are promising lead compounds for application prospect and developing new generation of MMP inhibitors as antitumor agents.