Stabilization of G-quadruplex DNA, inhibition of telomerase activity, and tumor cell apoptosis by organoplatinum(II) complexes with oxoisoaporphine

J Med Chem. 2015 Mar 12;58(5):2159-79. doi: 10.1021/jm5012484. Epub 2015 Feb 18.

Abstract

Two G-quadruplex ligands [Pt(L(a))(DMSO)Cl] (Pt1) and [Pt(L(b))(DMSO)Cl] (Pt2) have been synthesized and fully characterized. The two complexes are more selective for SK-OV-3/DDP tumor cells versus normal cells (HL-7702). It was found that both Pt1 and Pt2 could be a telomerase inhibitor targeting G-quadruplex DNA. This is the first report demonstrating that telomeric, c-myc, and bcl-2 G-quadruplexes and caspase-3/9 preferred to bind with Pt2 rather than Pt1, which also can induce senescence and apoptosis. The different biological behavior of Pt1 and Pt2 may correlate with the presence of a 6-hydroxyl group in L(b). Importantly, Pt1 and Pt2 exhibited higher safety in vivo and more effective inhibitory effects on tumor growth in the HCT-8 and NCI-H460 xenograft mouse model, compared with cisplatin. Taken together, these mechanistic insights indicate that both Pt1 and Pt2 display low toxicity and could be novel anticancer drug candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Aporphines / chemistry
  • Aporphines / pharmacology*
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cellular Senescence
  • Crystallography, X-Ray
  • DNA / chemistry*
  • Drug Resistance, Neoplasm / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Fluorescent Antibody Technique
  • G-Quadruplexes*
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Neoplasms / drug therapy
  • Neoplasms / pathology*
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Structure-Activity Relationship
  • Telomerase / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Aporphines
  • Enzyme Inhibitors
  • Organoplatinum Compounds
  • DNA
  • Telomerase