Stereoselective Synthesis And Biological Evaluation Of Ramelteon Derivatives And The Discovery Of Novel Multi-target Anti-cancer Agents

The doctoral dissertation is divided into two parts. Part Ⅰ:the stereoselective synthesis of ramelteon and the design, synthesis and biological evaluation of its derivatives. Part II:multi-target drug design based on hybridization of traditional anti-cancer drugs and anti-HDAC agents.(1) Ramelteon is the first melatonin receptors agonist for the treatment of circadian rhythm sleep disorders. Currently, most reported total synthesis of ramelteon mainly involved catalytic asymmetric hydrogenation, which has unavoidable defects such as expensive metals and phosphorus ligands. From the view of medicinal chemistry, it is very difficult to synthesize 6-or/and 7-substituted chiral derivatives through present known methods. Therefore, it is necessary to find an efficient approach for the medicinal modification of ramelteon.We developed a new synthetic approach of ramelteon with high efficiency and enantioselectivity based on asymmetric Michael addition. In addition, using the similar method, we designed and synthesized a series of ramelteon analogues. Among all these synthesized compounds, compounds 1-68b, 1-70a, 1-75a, 1-78a exhibited powerful MT2 agonistic activity (EC50< 50 nM) as well as wonderful MT2 selectivity (more than 2200-fold). This work provides highly selective MT2 agonists which could serve as useful tool compounds for the functional study.(2) Cancer is one of the most serious life-threatening diseases. Traditional anti-cancer drugs are frequently used as important chemotherapy treatments for a variety of cancers. Almost all traditional cytotoxic agents are associated with severe toxicities and other undesirable side effects. Great achievements have been made in targeted medicines. However, the effectiveness of these agents has been hindered by poor response rates and acquired drug resistance. A new strategy to overcome these limitations is to design a single molecule with inhibitory activities for multiple cancer targets. This strategy can directly block key signalling pathways as well as attenuate multiple compensatory pathways.We selected podophyllotoxin and colchicine as parent compounds to investigate novel multi-target anti-cancer agents. By introducing HDAC zinc binding group and an appropriate linker, we successfully developed a number of multi-target agents. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. PPT-SAHA hybrids exhibited potent HDAC inhibitory and antiproliferative activities. Further optimization of this series resulted in the PPT-SAHA-like hybrid series, which had remarkably improved anti-HDAC activity. Compound 2-30d displayed the best HDAC inhibitory activity which was 10-to 20-fold more potent than SAHA. The zinc-binding group was found to play a significant role in the cytotoxicity. Compound 2-38 showed better antiproliferative activity than etoposide and MGCD0103. Subsequently, we developed a new series of microtubulin-HDAC dual inhibitor based on the molecular symmetry of PPT. Compounds 3-14a and 3-14c exhibited powerful cytotoxicity and the IC50 values of these compounds are between 19-40 nM. Besides, we designed a new series of colchicine-SAHA hybrids. Most of these compounds displayed good antiproliferative activity against a variety of cancer cell lines. According to our past experience, we investigated different zinc-binding groups. The introduction of anilides as ZBGs resulted in increased antiproliferative activity. Compound 4-14a showed the most potent in vitro anti-cancer activity.This work provides new idea for the design and optimization of multi-target drug, and builds important foundation for further exploration.