Study On The Design,Synthesis And Biological Activity Of Functional Antitumor Platinum(?) Prodrugs

Platinum(?)-based complexes like cisplatin and oxaliplatin are well known the mainstay of chemotherapy regimens on clinic.Although a huge success has been achieved by platinum(?)drugs,several defects such as severe side effects and drug resistance restrict their applications.To overcome these drawbacks,platinum(?)complexes,exhibiting kinetic inertness compared with their platinum(?)counterparts,have been investigated for the antitumor application due to their unique mechanisms.Repair of lesions in DNA is an established mechanism of resistance to antitumor DNA-damaging drugs.As one of the classic DNA alkylating agents,chlorambucil has been mainly used to treat many types of tumors.Herein we designed and synthesized a series of platinum(?)complexes with a “joint action” to damage DNA by conjugation of chlorambucil with platinum-based drugs.This new type of platinum(?)complexes were stable under the physiological condition and could be easily reduced to their platinum(?)equivalents and release chlorambucil in the presence of ascorbic acid.By taking a joint action to enhance the damage of DNA,the conjugates displayed potent antitumor activity against all the tested cancer cell lines,and notably could overcome cisplatin resistance at certain degree,thereby induced cell apoptosis significantly in both SGC7901 and SGC7901/CDDP cells.Further investigation indicated that 2-19 and 2-21 possessed stronger ability to damage DNA by causing DNA double-strand breaks,which consequently inhibited DNA replication and arrested the cell cycle.Mechanism researches revealed that 2-19 suppressed the drug resistance by the improvement of the platinum uptake in cancer cells and DNA platination as well as generating the inhibition of PARP-1 protein which could suppress the DNA repair.Cancer is a disease with complicated pathogenesis,and cancer-associated inflammation often occurrs along with the tumor growth and metastatic progression.Wogonin,a natural product that possesses wide biological activities,is now in phase I clinical test as an anticancer agent in China.Herein we reported a series of novel platinum(?)conjugates by tethering wogonin to the axial position of platinum(?)complexes to via a linker group.Novel platinum(?)conjugates not only inherited the genotoxicity from cisplatin,but also obtained the COX inhibitory property from wogonin.Further mechanistic investigation revealed that the wogonin-Pt conjugates caused the accumulation of ROS,decreased the mitochondrial membrane potential(??m),activated the p53 pathway and then induced apoptosis.Thus,3-13 and 3-16 not only displayed excellent anticancer activity,but also overcame the resistance in SGC7901/CDDP cells and attenuated the toxicity to HUVEC cells.Moreover,in vivo studies revealed that 3-16 could inhibit the tumor growth and exhibit nearly no toxic effect.High expression level of androgen receptor(AR)is a major characteristic of castration-resistant prostate cancer(CRPC),which is difficult to diagnose and cure.Taking the high level AR of CRPC as the target,we firstly reported three Pt(?)-based prodrugs targeting AR.Competitive experiments showed that AR-Pt(?)conjugates all displayed decent AR binding affinity and antagonist activity against androgen receptor.Among them,4-22 is a three-in-one hybrid containing an AR binding ligand,a cisplatin unit and a coumarin moiety.Based on the decent AR binding affinity,4-22 selectively accumulated more in LNCaP(AR+)cells than in PC-3(AR-)cells,thereby exhibited excellent anticancer activity superior to cisplatin.Further mechanistic research revealed that 4-22 could arrest the cell cycle at S phase and increase the apoptosis dramaticlly.In brief,the AR-targeted theranostic agent successfully improved AR-overpressed tumor selectivity of cisplatin and offered a promising strategy to treat CRPC.Human NAD(P)H:quinone oxidoreductase isozyme I(NQO1),a cytoprotective 2-electron-specific reductase was found at unusually high activity levels in cancer cells.Here we described a series of NQO1 targeting platinum(?)prodrugs by conjugating a quinone propionic acid.Researches showed that this kind of platinum(?)complexes had potential to be dual stimuli-activatable prodrugs due to the reported reducing capacity by VC and stimuli-activated characteristic by NQO1 which was over-expressed in numerous cancer cells.Besides,we synthesized a theranostic prodrug 5-12 by tethering a coumarin motiety.Prodrug 5-12 could selectively accumulate in NQO1-overexpressed cancer cells and exhibit strong fluorescence after reduction,showing a promising theranostic effect.Due to their unique combined action mechanism,prodrugs 5-11 and 5-12 not only possessed potent and selective anticancer activities superior to cisplatin both in vitro and in vivo,but also overcame the resistance.Thus,this work may offer a new stratagy for the construction of targeting theranostic anticancer agents.