Bioengineering functional copolymers. XXI. Synthesis of a novel end carboxyl-trithiocarbonate functionalized poly(maleic anhydride) and its interaction with cancer cells

Bioorg Med Chem. 2012 Aug 15;20(16):5053-61. doi: 10.1016/j.bmc.2012.05.058. Epub 2012 Jun 5.

Abstract

A novel carboxyl-trithiocarbonate functionalized polymer with a highly selective antitumor activity was synthesized by a reversible addition-fragmentation chain transfer (RAFT) polymerization of maleic anhydride (MA) with benzoyl peroxide as an initiator and S-1-dodecyl-S-(α,α'-dimethyl-α"-acetic acid)trithiocarbonate as a RAFT agent with the aim to design and synthesize an effective anticancer agent with minimum side effects. The structure, molecular weights and composition of synthesized polymers were investigated by (1)H ((13)C) NMR, MALDI-TOF-MS and GPC analyzes. It was demonstrated that RAFT polymerization of MA was accompanied by a partially controlled decarboxylation of anhydride units and the formation of conjugated double bond fragments in backbone macromolecular chains. The mechanism of interaction of pristine RAFT agent and PMA-RAFT polymer with cancer (HeLa human cervix carcinoma) and normal (L929 Fibroblast) cells was investigated by using a combination of chemical, biochemical, statistical, spectroscopic (SEM and fluorescence inverted microscope) and real-time analysis (RTCA) methods. PMA-RAFT exhibited higher and selective cytotoxicity, apoptotic and necrotic effects toward HeLa cells at relatively low concentrations (around 7.5-75 μg mL(-1), IC(50) = 11.183 μg mL(-1)) and toward Fibroblast cells at high concentrations (IC(50) > 100 μg mL(-1)). The observed highly selective antitumor activity render PMA-RAFT polymers as promising candidates for the utilization in cancer chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Bioengineering*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Fibroblasts / drug effects
  • Fibroblasts / pathology
  • HeLa Cells
  • Humans
  • Maleic Anhydrides / chemical synthesis
  • Maleic Anhydrides / chemistry
  • Maleic Anhydrides / pharmacology*
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Polymers / chemical synthesis
  • Polymers / chemistry
  • Polymers / pharmacology*
  • Structure-Activity Relationship
  • Thiones / chemistry*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Maleic Anhydrides
  • Polymers
  • Thiones
  • polymaleic anhydride
  • trithiocarbonic acid