The rational design of anticancer platinum complexes: the importance of the structure-activity relationship

Curr Med Chem. 2009;16(18):2235-60. doi: 10.2174/092986709788453087.

Abstract

The ideal drug discovery process of new platinum based drugs should take into account three basic fundaments: on one side the mechanisms of action and the corresponding target biomolecules, on the other side, the possible mechanisms of resistance of cancer cells and their biochemical pathways and, finally, the pharmacokinetic and toxicity properties (ADMET) that will condition the clinical usefulness of the new drugs. At the end of this rational process always we face the necessity to design a molecule with a structure and certain physical and chemical properties. The structure is then a key fundamental issue when thinking of new anticancer platinum compounds. When analyzing the influence of molecular structure on anticancer activity it is useful to make the dissection of platinum complexes into different significant subunits or moieties, of the molecular structure. Thus, the following structural and electron dependent parameters are important to facilitate the comparison among platinum complexes: a) Nature of the non-labile ligand or carrier ligand (NLG); b) Nature of the labile ligand or leaving group (LG); c) Oxidation state of platinum atom; d) Type of atoms (connecting atoms X, Y, Z, W) that link ligands to platinum atom; e) Nature of the axial groups (AG) in platinum(IV) complexes; f) Nuclearity or number of Pt atoms in the platinum complexes; g) Formal charges present in the molecule and h) Intrinsic bioactivity of some ligands or bioactivity induced by molecules attached to ligands by linkers (in order to get a double mechanism of action or a parallel biological activity).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Drug Design*
  • Humans
  • Ligands
  • Neoplasms / drug therapy*
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / pharmacokinetics
  • Organoplatinum Compounds / pharmacology
  • Organoplatinum Compounds / therapeutic use
  • Platinum Compounds / chemistry*
  • Platinum Compounds / pharmacokinetics
  • Platinum Compounds / pharmacology
  • Platinum Compounds / therapeutic use
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Ligands
  • Organoplatinum Compounds
  • Platinum Compounds