Combretastatin A4-β-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy

  • ACS Med Chem Lett. 2017 Jan 20;8(2):211-214. doi: 10.1021/acsmedchemlett.6b00427.
Tomohiro Doura  1 ,  Kazuaki Takahashi  1 ,  Yasumitsu Ogra  1 ,  Noriyuki Suzuki  1
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, Chiba University , 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
PMID: 28197314 DOI: 10.1021/acsmedchemlett.6b00427
Abstract

Chemotherapy for ovarian Cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian Cancer prodrug monotherapy (PMT), we designed and synthesized two β-galactose-conjugated CA4s (CA4-βGals), CA4-βGal-1 and CA4-βGal-2. CA4 was liberated from CA4-βGals by β-galactosidase, an enzyme more strongly expressed in ovarian Cancer cells than normal cells. CA4-βGal-2, which has a self-immolative benzyl linker between CA4 and the β-galactose moiety, was more cytotoxic to ovarian Cancer cell lines than CA4-βGal-1 without a linker. Therefore, CA4-βGal-2 can serve as a platform for the design and manufacture of prodrugs for ovarian Cancer PMT.

Keywords
Antitumor agent; combretastatin A4; ovarian cancer; prodrug monotherapy; tubulin polymerization inhibitor; β-galactosidase.