(E)-N'-Arylidene-2-(4-oxoquinazolin-4(3H)-yl) acetohydrazides: Synthesis and evaluation of antitumor cytotoxicity and caspase activation activity

J Enzyme Inhib Med Chem. 2019 Dec;34(1):465-478. doi: 10.1080/14756366.2018.1555536.

Abstract

In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds. In term of caspase activation activity, several compounds were found to exhibit potent effects, (e.g. compounds 7 b, 5n, and 5l). Especially, compound 7 b activated caspases activity by almost 200% in comparison to that of PAC-1. Further docking simulation also revealed that this compound potentially is a potent allosteric inhibitor of procaspase-3.

Keywords: Acetohydrazides; caspase activation; cytotoxicity; quinazolin-4(3H)-one.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Molecular Docking Simulation
  • Molecular Structure
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Hydrazines
  • Quinazolines
  • Caspases

Grants and funding

We acknowledge the principal financial support from the National Foundation for Science and Technology of Vietnam (NAFOSTED, Grant number 104.01-2017.06). The work was also partly supported by a grant funded by the Korean Government (NRF, Grant number 2017R1A5A2015541) and a small grant from Hanoi University of Pharmacy. P.T. Hai acknowledges the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research.