Synthesis and evaluation of the anti-proliferative and NF-κB activities of a library of simplified tylophorine analogs.
Tylophorine and many related phenanthropiperidine alkaloids are extraordinarily potent anti-proliferative agents. Despite their impressive anti-cancer activity, clinical development of these alkaloids has been hampered by their poor solubility and neurological side effects. Although it has been suggested that developing polar phenanthropiperidines will mitigate these undesired properties, the lack of practical methods for the synthesis of such analogues has limited this effort. Here, we present a concise synthetic approach to N-substituted phenanthropiperidines, which enabled a systematic investigation of structure-activity relationships at an underexplored region of the tylophorine scaffold. This work suggests that ring E of tylophorine is essential for the anti-proliferative activity of the 6,7,10,11-tetramethoxy-1,2,3,4-tetrahydrodibenzo[f,h]isoquinoline core scaffold.
Department of Medicinal Chemistry and the Institute for Therapeutics Discovery & Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
Micah J
MJ
Niphakis
Bryant C
BC
Gay
Kwon Ho
KH
Hong
Nicholas P
NP
Bleeker
Gunda I
GI
Georg
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007212:Indolizines / Q000737:chemistry* / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D016328:NF-kappa B; D010616:Phenanthrenes; C004218:tylophorine