title: Site-specific and far-red-light-activatable prodrug of combretastatin A-4 using photo-unclick chemistry.
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.
authors: Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma 73117, USA.
authors: Moses
authors: M
authors: Bio
authors: Pallavi
authors: P
authors: Rajaputra
authors: Gregory
authors: G
authors: Nkepang
authors: Samuel G
authors: SG
authors: Awuah
authors: Abugafar M L
authors: AM
authors: Hossion
authors: Youngjae
authors: Y
authors: You
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D004396:Coloring Agents; D003432:Cross-Linking Reagents; D003624:Darkness; D017484:Dermatitis, Phototoxic / Q000473:pathology; D005456:Fluorescent Dyes; D008027:Light; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011166:Porphyrins / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis*; D013267:Stilbenes / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D003432:Cross-Linking Reagents; D005456:Fluorescent Dyes; D011166:Porphyrins; D011355:Prodrugs; D013267:Stilbenes; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; C022616:thiazolyl blue; C058728:fosbretabulin