Synthesis Of Nitricoxide Releasing Cisplatin Prodrugs

Cisplatin, cis-diamminedichloridoplatinum(II), is the first member of a class of platinum-containing anti-cancer drugs with a wildly application. After administration,chloride ligand will be replaced by water to give the aquo complex cis-[PtCl(NH3)2(H2O)]+ inside cells. The Nucleophilic part of DNA replace the aqua ligand to form Pt-DNA complex. Both of the chloride ligands are capable of this reaction. By interfering with DNA replication, cisplatin kills cancer cells. Cisplatin have shortcomings include poor solubility, poor lipophilicity, high toxicity, severe side effects and easy to resistance. Those can be overcomed by oxidating cisplatin(?) into pro-cisplatin(?). Pro-cisplatin must be reduced to cisplatin within cells to be functional. Pro-cisplatin have two hydroxy ligands to be modified into different properties.Nitric oxide(NO) play important roles in the development of tumor. Low concentration of NO inhibit the growth of tumor while high concentration promote it.NO can interact with many chemotherapy drugs. There are evidence that NO donor drugs can enhance cisplatin efficacy against cancer cells. Organic nitrates is a kind of safety NO releasing drug wildly applied in clinic with antitumor property.Take these evidence that cisplatin and NO donor drugs have synergic reaction into consideration, a sereis of NO releasing pro-cisplatins with different NO releasing property were synthesized and confirmed by 1HNMR. First oxidate cisplatin(?) into hydroxy ligands containing pro-cisplatin(?), next carboxylate those hydroxy ligands with succinic anhydride, then bonding organic nitrate structures to carboxylated pro-cisplatin(?) by ester bond or amide bond. These structures were synthesized in the hope of finding structures with anticancer property similar or better than cisplatin.The 19 structures synthesized were evaluated in vitro with comparism of similar structures of pro-cisplatins without NO releasing property. MTT tests were carried out with human hepatocellular carcinoma Hep3 B cells and IC50 were calculatedaccordingly. Preliminary tests showed some of the NO releasing pro-cisplatin structures like A sereis and D sereis have similar anticancer property compared with cisplatin. The anticancer property of the NO releasing pro-cisplatins increase with the increase of NO releasing property. There is potential for them to be further investigated as anticancer drugs.