Structure-activity studies of phenanthroindolizidine alkaloids as potential antitumor agents.
Five phenanthroindolizidine alkaloids (PA) were chemically synthesized and seven were isolated from Tylophora atrofolliculata. To facilitate future drug design of phenanthroindolizidine alkaloids as potential antitumor agents, we have explored the structure-activity relationships (SAR) of this class of compounds. We demonstrated that DCB-3503 and tylophorinidine (PA-7) were among the most active compounds against tumor growth both in vitro and in vivo. In the hepatocellular carcinoma cell line HepG2, the GI(50)s of DCB-3503 and PA-7 were 35+/-5 nM and 11+/-5 nM, respectively. DCB-3503 and PA-7 significantly inhibited HepG2 tumor growth in nude mice at a dose of 9 mg/kg given by intraperitoneal (ip) injections twice a day every third day for a total of four cycles (P<0.05 for DCB-3503 and P<0.01 for PA-7). Their potent antitumor activities correlated with their potent NF-kappaB-inhibitory effects and their cyclin D1 down-regulatory effects.
Gao
Wenli
W
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Bussom
Scott
S
Grill
Susan P
SP
Gullen
Elizabeth A
EA
Hu
You-Cai
YC
Huang
Xueshi
X
Zhong
Sanbao
S
Kaczmarek
Conrad
C
Gutierrez
Julio
J
Francis
Samson
S
Baker
David C
DC
Yu
Shishan
S
Cheng
Yung-Chi
YC
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D007212:Indolizines / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D010618:Phenanthrolines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D010618:Phenanthrolines; C521640:phenanthroindolizidine