Design, Synthesis And Antitumor Evaluation Of Platinum(Ⅳ) Complexes With Double Acting Mechanism

Platinum(Ⅳ)compounds with unique advantages as antitumor drugs including high activities,low toxicities,low drug-resistance,high bioavailability,satisfactory pharmacokinetic properties and remarkable tumor targeting properties have aroused wide attention of researchers.Great attention have been attracted to the exploration of platinum(Ⅳ)new complexes,and many remarkable achievements have been obtained.Platinum compounds are of much potential to be developed as the next generation of platinum anticancer drugs with oral administration.Naphthalimide or coumarin as axial ligands were incorporated into platinum system to prepare 14 target compounds and their bioactivities as antitumor agents were evaluated.1.5 naphthalimide platinum(Ⅳ)target compounds with cisplatin core were were designed and synthesized starting from cisplatin and 1,8-naphthalic anhydride.The in vitro results indicated that some target compounds displayed good antitumor activities especially compounds 67 b and 67 e which are superior to positive controls cisplatin and oxaliplatin.The linkages between naphthalimide and cisplatin core and the substituents on naphthalimide exhibited remarkable influences on their activities.Hence,compound 67 e displayed significantly superior antitumor activities.The mechanism investigation revealed that the incorporation of naphthalimide as DNA targeting functional moiety to platinum(Ⅳ)system endowed naphthalimide platinum(Ⅳ)complexes with double DNA interaction capacities.Naphthalimide platinum(Ⅳ)complex could bind with DNA and induce untwisting of dsDAN.Meanwhile,the naphthalimide platinum(Ⅳ)complex would undergo reduction in reductive milieu and release platinum(Ⅱ)complex which could rapidly combine with DNA and cause remarkable damage of tumor cells.The double interaction mechnism of naphthalimide platinum(Ⅳ)with DNA to cause cell apoptosis was probably the reason for their overcoming of drug resistance.Furthermore,naphthalimide platinum(Ⅳ)complex could effectively combine with HSA in blood via electrostatic and Vander Waals interactions.Moreover,the target compounds 67 b and 67 e displayed lower toxicities and high safety than reference drug oxaliplatin in vivo.2.Oxaliplatin and naphthalimide were employed as raw materials to design and synthesis naphthalimide platinum compounds with oxaliplatin core.The bioactivities results of the 5 target compounds in vitro indicate that all naphthalimide platinum(Ⅳ)compounds possessed moderate to effective antitumor competence against all tested tumour cells including resistant cell lines.Especially compound 71 b exhibited the most prominent activities with was comparable or even better than cisplatin and oxaliplatin,and fully overcame the resistance of cisplatin.The SAR discussion disclosed that the linkage between naphthalimide and oxaliplatin core displayed great impacts on activities,and the three carbon linker seemed more favourable than other ones for this series of compounds.The further introduction of amino and nitro moieties onto naphthalimide fragment led no remarkable enhancement of antitumor abilities.The mechanism evaluation infered that the title compounds could interact with dsDNA in platinum(Ⅳ)form and cause DNA lesion which was distinguished from classical platinum(Ⅳ)compounds.The further reduction to divalent form in reducing microenvironment would release platinum(Ⅱ)complexes and induce remarkable secondary damage to DNA.The double DNA damage mechanism was favorable for their overcoming of cisplatin resistance.Furthermore,naphthalimide platinum(Ⅳ)complex could combine with HSA via electrostatic and Vander Waals interactions which could enhance the stability and be favourable for the storage and delivery of drugs in blood.Additionally,the construction of naphthalimide platinum(Ⅳ)drugs effectively improved the cellular and DNA accumulation in comparison with the precursory platinum(Ⅱ)drug.The in vivo assay demonstrated that the target compound 71 b had low toxicity and enhanced safety in contrast to oxaliplatin.3.A series of coumarin derived platinum(Ⅳ)complexes with coumarin axial ligands were prepared with oxaliplatin and coumarin as raw materials.The evaluation of their antitumor activities in vitor and in vivo as well the antitumor mechanism is under way.