Trimethoxy Trityl Groups as a Potent Substituent for Anti-cancer Cytidine Analog Prodrugs

Chihiro Ito, Kazuaki Taguchi, Yoshie Moroi, Yuki Enoki, Ryoh Tokuda, Keishi Yamasaki, Shuhei Imoto, Kazuaki Matsumoto

Research output: Contribution to journalArticlepeer-review

Abstract

Methoxy trityl groups are acid-responsive protecting groups that are routinely used in the process of nucleoside analog synthesis. This study investigated the potential of methoxy trityl groups, monomethoxy trityl (MMT), dimethoxy trityl (DMT), and trimethoxy trityl (TMT), as acid-responsive substituents for designing anti-cancer cytidine analog prodrugs. For this purpose, we synthesized six gemcitabine (GEM) derivatives, which were modified either 4-(N)- or 5′-(O)-sites with MMT, DMT, and TMT, as candidates for anti-cancer cytidine analog prodrugs. In vitro dissociation test of methoxy trityl groups clearly showed that the acid responsivity of the methoxy trityl moieties was in the order TMT>DMT>MMT. Furthermore, the rate of 5′-(O)-methoxy tritylation was higher than that of 4-(N)-methoxy tritylation. Along with high acid-responsivity, trimethoxy trityl-O-GEM (TMT-O-GEM) showed superior cytotoxicity against 2D cultured human breast cancer cells (MCF-7 and MDA-MB-231) and human pancreatic cancer cells (AsPC-1) compared to other methoxy-tritylated GEM derivatives. Moreover, TMT-O-GEM suppressed the growth of MCF-7 spheroids compared with trimethoxy trityl-N-GEM (TMT-N-GEM). Both TMT-O-GEM and TMT-N-GEM were negligibly deprotected and metabolized in mouse or human serum after 72 h, indicating that trimethoxy tritylation inhibits deamination by cytidine deaminase. These results indicate that 5′-(O)-trimethoxy tritylation is a potent approach for the development of anti-cancer cytidine analog prodrugs.

Original languageEnglish
JournalJournal of Pharmaceutical Sciences
DOIs
Publication statusAccepted/In press - 2022

Keywords

  • Cancer
  • Deoxyribonucleic acid
  • Molecular modeling
  • Prodrug
  • pH

ASJC Scopus subject areas

  • Pharmaceutical Science

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