Structure optimization and molecular dynamics studies of new tumor-selective s-triazines targeting DNA and MMP-10/13 for halting colorectal and secondary liver cancers

J Enzyme Inhib Med Chem. 2024 Dec;39(1):2423174. doi: 10.1080/14756366.2024.2423174. Epub 2024 Nov 8.

Abstract

A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. 7a and 7g surpassed doxorubicin against HCT-116 cells regarding potency (IC50 = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). 7g was potent against liver cancer (HepG-2; IC50 = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). 7g surpassed NNGH against MMP-10 (IC50 = 0.205 μM) and MMP-13 (IC50 = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.

Keywords: 1,2,3-triazole-tethered s-triazines; Colorectal cancer; DNA targeting; MMP-10/13 inhibition; molecular dynamics.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects
  • Cell Proliferation* / drug effects
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Dose-Response Relationship, Drug*
  • Drug Screening Assays, Antitumor*
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / pathology
  • Matrix Metalloproteinase 10* / metabolism
  • Matrix Metalloproteinase 13* / metabolism
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / chemistry
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Structure-Activity Relationship
  • Triazines* / chemical synthesis
  • Triazines* / chemistry
  • Triazines* / pharmacology

Substances

  • Antineoplastic Agents
  • Triazines
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 10
  • Matrix Metalloproteinase Inhibitors
  • MMP10 protein, human

Grants and funding

The author(s) reported there is no funding associated with the work featured in this article.