Site-specific and far-red-light-activatable prodrug of combretastatin A-4 using photo-unclick chemistry

Moses Bio, Pallavi Rajaputra, Gregory Nkepang, Samuel G. Awuah, Abugafar M.L. Hossion, Youngjae You

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Although tissue-penetrable light (red and NIR) has great potential for spatiotemporally controlled release of therapeutic agents, it has been hampered because of the lack of chemistry translating the photonic energy to the cleavage of a chemical bond. Recently, we discovered that an aminoacrylate group could be cleaved to release parent drugs after oxidation by SO and have called this "photo-unclick chemistry". We demonstrate its application to far-red-light-activated prodrugs. A prodrug of combretastatin A-4 (CA4) was prepared, CMP-L-CA4, where CMP is dithiaporphyrin, a photosensitizer, and L is an aminoacrylate linker. Upon irradiation with 690 nm diode laser, the aminoacrylate linker of the prodrug was cleaved, rapidly releasing CA4 (>80% in 10 min) in CDCl3. In tissue culture, it showed about a 6-fold increase in its IC50 in MCF-7 after irradiation, most likely because of the released CA4. Most significantly, CMP-L-CA4 had better antitumor efficacy in vivo than its noncleavable (NC) analog, CMP-NCL-CA4. This is the first demonstration of the in vivo efficacy of the novel low-energy-light-activatable prodrug using the photo-unclick chemistry.

Original languageEnglish
Pages (from-to)3936-3942
Number of pages7
JournalJournal of Medicinal Chemistry
Volume56
Issue number10
DOIs
StatePublished - May 23 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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