A highly GSH-sensitive SN-38 prodrug with an "OFF-to-ON" fluorescence switch as a bifunctional anticancer agent

Chem Commun (Camb). 2018 Aug 21;54(65):9031-9034. doi: 10.1039/c8cc05010d. Epub 2018 Jul 26.

Abstract

SN-38 (7-ethyl-10-hydroxy-camptothecin) is an active metabolite of irinotecan (CPT-11) and the most potent camptothecin analogue. In this study, 2,4-dinitrobenzene sulfonyl (DNS) was covalently conjugated as a GSH-sensitive trigger to 10'-OH of SN-38 to yield a GSH-sensitive prodrug, denoted as DNS-SN38, with virtually quenched fluorescence due to donor-excited photo-induced electron transfer (d-PeT). By investigating DNS-SN38's activation properties upon fluorescence restoration and cytotoxic potency against ovarian cancer cell lines (A2780 and m-Cherry + OCSC1-F2), its potential applicability as a useful chemotherapeutic agent was demonstrated.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemistry
  • Camptothecin / metabolism
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Fluorescence
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / metabolism
  • Fluorescent Dyes / pharmacology*
  • Glutathione / metabolism
  • Humans
  • Irinotecan
  • Kinetics
  • Mice
  • Microscopy, Confocal
  • Prodrugs / chemistry
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*

Substances

  • Antineoplastic Agents
  • Fluorescent Dyes
  • Prodrugs
  • Irinotecan
  • Glutathione
  • Camptothecin