In Vitro and In Silico Studies on Cytotoxic Properties of Oxythiamine and 2'-Methylthiamine

Int J Mol Sci. 2024 Apr 15;25(8):4359. doi: 10.3390/ijms25084359.

Abstract

It is important to search for cytostatic compounds in order to fight cancer. One of them could be 2'-methylthiamine, which is a thiamine antimetabolite with an additional methyl group at the C-2 carbon of thiazole. So far, the cytostatic potential of 2'-methylthiamine has not been studied. We have come forward with a simplified method of synthesis using commercially available substrates and presented a comparison of its effects, as boosted by oxythiamine, on normal skin fibroblasts and HeLa cancer cells, having adopted in vitro culture techniques. Oxythiamine has been found to inhibit the growth and metabolism of cancer cells significantly better than 2'-methylthiamine (GI50 36 and 107 µM, respectively), while 2'-methylthiamine is more selective for cancer cells than oxythiamine (SI = 180 and 153, respectively). Docking analyses have revealed that 2'-methylthiamine (ΔG -8.2 kcal/mol) demonstrates a better affinity with thiamine pyrophosphokinase than thiamine (ΔG -7.5 kcal/mol ) and oxythiamine (ΔG -7.0 kcal/mol), which includes 2'-methylthiamine as a potential cytostatic. Our results suggest that the limited effect of 2'-methylthiamine on HeLa arises from the related arduous transport as compared to oxythiamine. Given that 2'-methylthiamine may possibly inhibit thiamine pyrophosphokinase, it could once again be considered a potential cytostatic. Thus, research should be carried out in order to find the best way to improve the transport of 2'-methylthiamine into cells, which may trigger its cytostatic properties.

Keywords: OCT1; cell growth inhibition; molecular docking; molecular dynamics; thiamine antimetabolites.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation*
  • Oxythiamine* / chemistry
  • Oxythiamine* / metabolism
  • Oxythiamine* / pharmacology
  • Thiamine / analogs & derivatives
  • Thiamine / chemistry
  • Thiamine / pharmacology

Substances

  • Oxythiamine
  • Thiamine
  • Antineoplastic Agents

Grants and funding

The research was founded with a scientific subsidy of the Medical University in Białystok B.SUB.24.384. Analyses were performed in the Center of Synthesis and Analysis BioNanoTechno of the University of Białystok. The equipment in the center was funded by the EU as a part of the Operational Program Development of Eastern Poland 2007–2013, projects: POPW.01.03.00-20-034/09-00 and POPW.01.03.00-20-004/11. This study was supported by the Ministry of Education and Science, Poland, as a part of subsidies for maintaining the research potential granted to the Faculty of Biology (SWB-8) and the Faculty of Chemistry of the University of Białystok. The authors would like to thank the Computational Center of the University of Bialystok (Grant GO-008) for providing access to the supercomputer resources and the NAMD program. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.