Structure-Based Design, Synthesis and Biological Evaluation of Novel 6-Substituted 10-Chloro-12h-Thiochromeno[2,3-C]Quinolin-12-One Derivatives as Potential Anticancer Agents

Background: Topoisomerase inhibitors are important and clinically effective drugs, while DNA, DNA-topoisomerase complex and/or topoisomerase-interactive compounds that disrupt DNA duplication mechanisms have yet to be proven useful in the clinic. Anthraquinone-based drugs have been shown to process strong antiperliferative properties, are used for treatment of varied oncology. During the pathogenesis of cancer, the topoisomerase, telomerase, and cytotoxicity play key roles in tumor angiogenesis, tumor growth, metastasis and drugs resistance. In recent years, several known anti-cancer compounds (eg.TAS-103, XR11576, and intoplicine) which were entered Phase II and Phase III clinical trials were mainly found that the activity of tetracyclic core pharmacophore may be better than the traditional tricyclic anthraquinone structure. Thus, to design, synthesis and evaluate a series of tetracyclic heterocyclic derivative for the core small molecular structure as anti-cancer drugs is a tendency to development. Purpose: In order to find stronger DNA binding, a series of tetracyclic and heterocyclic small molecules will be design and their polypharmacology activities evaluation. In this three years study, we plan to further investigate whether the target small molecules exhibit an anti-cancer effect through inhibition of topoisomerase, telomerase and tumor growth inhibition properties. Method: Studies include the preparation of starting materials, design and synthesis target compounds, moreover the underlying mechanisms involved and SARs and their polypharmacology activities are also investigated. Progresses of the studies are planned as: 1st year: (1) To design and synthesize various analogues of thiochromeno[2,3-c]quinolin-12-one derivatives and identify the basic anti-cancer activity in cell based assays. (2) To primary evaluate the anti-cancer activities of these synthetic compounds by MTT assay in vitro. (3) Effects of these potential anti-cancer compounds on alongside cytotoxicity tests with matched pairs of enzyme resistant, sensitive cells and cell lines are also investigated. 2nd year: (1) To evaluate the therapeutic effects of these potential small molecules on DNA binding, telomerase activities and hTERT expression between G-quadruplex stabilization and telomerase inhibition. (2) To further evaluate the topoisomerase and anti-cancer activities of these potential compounds in vitro. 3rd year: To study the effects of novel derivatives on DNA binding, telomerase activities, hTERT expression, and topoisomerase inhibition. By comparing profiles of biological assay including the NCI-60 cell line assay, we will identify targets for small molecules development and lead optimization, which provide a rational basis for the SARs and through the pharmacological studies. Anticipated results: The study will lead to obtain potential target small molecules for development of more efficient and safer anti-cancer drugs.