Synthesis,Characterization And Antitumor Activity Of Novel Binuclear Platinum(â…¡) Complexes

Cancers seriously affect human health and have brought great challenges to human life. Platinum-based drugs have occupied an important position due to the superior anti-tumor activity. Among them, cisplatin, carboplatin and oxaliplatin are the typical representatives in platinum-based drugs on marker. Platinum-based drugs have outstanding advantages in clinical application and no cross-resistance with other anticancer drugs. However, these drugs have serious side effects such as ototoxicity, renal toxicity, neurotoxicity and gastrointestinal reactions as well as low bioavailability. Therefore, developing novel platinum drugs is a direction of the development of platinum drugs in the future.It is widely considered that Trans-1R,2R-cyclohexanediamine, the chiral ligands of oxaliplatin, is an important component which plays the antitumour role. Moreover, bi- and multi-nuclear platinum-based drugs can form multi-point bonding with DNA. This bonding force makes DNA more devastating and more difficult repaired due to the bi-and multi-nuclear platinum drugs’ non-classical structure-activity relationship. In addition, many planar aromatic molecules with inserted DNA effect can form hydrogen bonding with DNA, thereby increasing interactions between drugs and DNA. Curcumin is the slightly acidic phenols dione, it is extracted from turmeric and also a main component which turmeric plays pharmacological action. It is shown that the antitumor activity of curcumin is closely related with the unsaturated ketone chain in curcumin’s structure in many studies. Based on above considerations, my master’s thesis is divided into two parts:Part one:The synthesis, characterization and antitumor activity of binuclear platinum complexes with (1R,1’R,2R,2’R)-N1,N1’-(1,3-phenylene bis (methylene)) cyclohexane-1,2-diamine as a carrier group.Based on Trans-1R,2R-cyclohexanediamine of chiral ligand of oxaliplatin, isophthalaldehyde of planar aromatic molecules with inserted effects as well as seven leaving group altering the distribution of drugs water and ester, we designed and synthesized seven binuclear platinum complexes and tested cell cytotoxicities in vitro by MTT assay. Results indicated that seven complexes had good antitumor activity. Among them, a binuclear platinum complex P7 with leaving group of 3-hydroxy-cyclobutane-1,1-dicarboxylic acid showed better antitumor activity than carboplatin against HepG-2 and A549 cell lines, and close cytotoxicity to oxaliplatin against HCT-116 cell line. It may be very promising for becoming a lead compound in development of the platinum drug in the future.Part two:Synthesis and characterization of tetradentate ligand with 1,6-diethoxy-containing 1,5-diene-3,4-dione chainThe unsaturated ketone chain of curcumin is an important part that curcumin exert antitumor effect. However, to some extent, it is not stable. Therefore, according to the unsaturated ketone chain of curcumin, tetradentate ligand with more stable unsaturated ketone chain, 1,6-diethoxy-1,5-diene-3,4-dione chain and Trans-1R,2R-cyclohexanediamine were designed and synthesized. The solitary electron of nitrogen atom of amino in Trans-1R,2R-cyclohexanediamine could form co-electron yoke effect with 1,6-diethoxy-1,5-diene-3,4-dione chain and this conjugation structure made tetradentate ligand more stable than curcumin. In addition, compared with the existing tetradentate ligand, the tetradentate ligand with two amino groups and ketone carbonyl group had novel chemical structure and showed better solubility. It would probably be developed as a potential platinum intermediate.