Synthesis of triphenylphosphonium dibenzothiophene S-oxide derivatives and their effect on cell cycle as photodeoxygenation-based cytotoxic agents

Bioorg Chem. 2020 Dec:105:104442. doi: 10.1016/j.bioorg.2020.104442. Epub 2020 Oct 29.

Abstract

Photodeoxygenation of Dibenzothiophene-S-oxide (DBTO) in UV-A light produces atomic oxygen [O(3P)] and the corresponding sulfide, dibenzothiophene (DBT). Recently, DBTO has been derivatized to study the effect of UV-A light-driven photodeoxygenation in lipids, proteins, and nucleic acids. In this study, two DBTO derivatives with triphenylphosphonium groups were synthesized to promote mitochondrial accumulation. The sulfone analogs of these derivatives were also synthesized and used as fluorescent mitochondrial dyes to assess localization in mitochondria of HeLa cells. These derivatives were then used to study the effect of photodeoxygenation on MDA-MB-231 breast cancer cell line using cell viability assays, cell cycle phase determination tests, and RNA-Seq analysis. The DBTO derivatives were found to significantly decrease cell viability only after UV-A irradiation as a result of generating corresponding sulfides that were found to significantly affect gene expression and cell cycle.

Keywords: Atomic Oxygen; Heterocyclic oxides; Mitochondria-targeting; O((3)P); Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Base Sequence
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cytotoxins / chemical synthesis*
  • Cytotoxins / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / ultrastructure
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / pharmacology
  • Oxygen / chemistry
  • Oxygen / metabolism
  • Photochemical Processes
  • Reactive Oxygen Species / chemistry
  • Reactive Oxygen Species / metabolism
  • Thiophenes / chemistry
  • Ultraviolet Rays

Substances

  • Antineoplastic Agents
  • Cytotoxins
  • Organophosphorus Compounds
  • Reactive Oxygen Species
  • Thiophenes
  • Oxygen
  • dibenzothiophene