Geldanamycin derivatives and neuroprotective effect on cultured P19-derived neurons.
Geldanamycin (1), an antifungal and anticancer ansamycin, was reported as a neurotrophic and neuroprotective substance against antineoplastic drugs, paclitaxel, vincristine, and cisplatin, on cultured dorsal root ganglion neurons from chick embryos. In this study, 1 in a large quantity, together with a known 17-O-demethylgeldanamycin (2), and a new 17-O-demethylgeldanamycin hydroquinone (3) were obtained from a mangrove Streptomyces sp. A series of O-alkyl and N-alkyl derivatives of 1 were prepared by modification of C-17 and/or C-19 on the quinone ring and were evaluated for in vitro activity against P19-derived neurons. Compound 1 and 19-O-methylgeldanamycin (7) at a very low dose (1nM) enhanced survival and neurite outgrowth of P19-derived neurons and prevented neurotoxicity of paclitaxel and vinblastine. Compound 7, possessing the lowest cytotoxicity and neurotoxicity, is serving as the most promising candidate in neurodegenerative therapy against neurotoxic anticancer drugs.
Tadtong
Sarin
S
Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME), Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Meksuriyen
Duangdeun
D
Tanasupawat
Somboon
S
Isobe
Minoru
M
Suwanborirux
Khanit
K
D000818:Animals; D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D002642:Chick Embryo; D005727:Ganglia, Spinal / Q000166:cytology; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; C001277:geldanamycin