Potent Chlorambucil-Platinum(IV) Prodrugs

Int J Mol Sci. 2022 Sep 9;23(18):10471. doi: 10.3390/ijms231810471.

Abstract

The DNA-alkylating derivative chlorambucil was coordinated in the axial position to atypical cytotoxic, heterocyclic, and non-DNA coordinating platinum(IV) complexes of type, [PtIV(HL)(AL)(OH)2](NO3)2 (where HL is 1,10-phenanthroline, 5-methyl-1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane). The resultant platinum(IV)-chlorambucil prodrugs, PCLB, 5CLB, and 56CLB, were characterized using high-performance liquid chromatography, nuclear magnetic resonance, ultraviolet-visible, circular dichroism spectroscopy, and electrospray ionization mass spectrometry. The prodrugs displayed remarkable antitumor potential across multiple human cancer cell lines compared to chlorambucil, cisplatin, oxaliplatin, and carboplatin, as well as their platinum(II) precursors, PHENSS, 5MESS, and 56MESS. Notably, 56CLB was exceptionally potent in HT29 colon, Du145 prostate, MCF10A breast, MIA pancreas, H460 lung, A2780, and ADDP ovarian cell lines, with GI50 values ranging between 2.7 and 21 nM. Moreover, significant production of reactive oxygen species was detected in HT29 cells after treatment with PCLB, 5CLB, and 56CLB up to 72 h compared to chlorambucil and the platinum(II) and (IV) precursors.

Keywords: 56MESS; 5MESS; DNA; PHENSS; ROS; chlorambucil; cytotoxicity; platinum(II); platinum(IV).

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Carboplatin
  • Cell Line, Tumor
  • Chlorambucil / pharmacology
  • Cisplatin / chemistry
  • Female
  • Humans
  • Male
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology
  • Ovarian Neoplasms*
  • Oxaliplatin
  • Platinum / chemistry
  • Prodrugs* / chemistry
  • Prodrugs* / pharmacology
  • Reactive Oxygen Species

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Prodrugs
  • Reactive Oxygen Species
  • Oxaliplatin
  • Chlorambucil
  • Platinum
  • Carboplatin
  • Cisplatin

Grants and funding

The authors thank Western Sydney University for its financial support. A.D.A. and M.G.E. were supported through an Australian Postgraduate Award.