Double-component diazeniumdiolate derivatives as anti-cancer agents

Bioorg Med Chem. 2020 Apr 15;28(8):115405. doi: 10.1016/j.bmc.2020.115405. Epub 2020 Mar 3.

Abstract

In this study, we synthesized a series of double-component O2-aryl diazeniumdiolate (DDNO) derivatives, of which each molecule can release up to four nitric oxide molecules. These compounds showed cytotoxic activities to cancer cells, such as human leukemia, breast cancer and lung cancer. Among them, compound 1 (DDNO-1) showed the highest specific activity to human leukemia cells. It induced cell apopotosis and arrest cell cycle of G2/M phase. The JNK and p38 protein kinases were activated by compound 1 to induce cancer cell apoptosis. Compound 1 also increased pro-apoptotic Bax level, which is a same function compared to a reported NO donor, JS-K. More interestingly, it decreased the level of an anti-apoptotic member Bcl-2, which is an opposite effect compared to JS-K. Compound 1 could be developed as a new anti-cancer agent since it increases the Bax/Bcl-2 ratio to overcome the drug resistance.

Keywords: Anti-cancer agent; Bcl-2 inhibitor; Diazeniumdiolate derivatives; G2/M phase arrest; Leukemia; Nitric oxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Azo Compounds / chemistry*
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Molecular Structure

Substances

  • Antineoplastic Agents
  • Azo Compounds
  • diazeniumdiolate