Synthesis of 9,9-dialkyl-4,5-diazafluorene derivatives and their structure-activity relationships toward human carcinoma cell lines.
A homologous set of 9,9-dialkyl-4,5-diazafluorene compounds were prepared by alkylation of 4,5-diazafluorene with the appropriate alkyl bromide and under basic conditions. The structures of these simple organic compounds were confirmed by spectroscopic techniques (FTIR, NMR, and FABMS). Their biological effects toward a panel of human carcinoma cells, including Hep3B hepatocellular carcinoma, MDAMB-231 breast carcinoma, and SKHep-1 hepatoma cells, were investigated; a structure-activity correlation was established with respect to the length of the alkyl chain and the fluorene ring structure. The relationship between the mean potency [log(1/IC(50))] and alkyl chain length was systematically studied. The results show that compounds with butyl, hexyl, and octyl chains exhibit good growth inhibitory effects toward these three human carcinoma cell lines, and the 9,9-dihexyl-4,5-diazafluorene further exhibits antitumor activity in athymic nude mice Hep3B xenograft models. For the structurally related dialkylfluorenes that lack the diaza functionality, in vitro cytotoxicity was not observed at clinically relevant concentrations.
Wang
Qiwei
Q
Department of Chemistry and Centre for Advanced Luminescence Materials, Hong Kong Baptist University, Waterloo Road, Kowloon Tong, Hong Kong, PR China.
Yuen
Marcus Chun-Wah
MC
Lu
Guo-Liang
GL
Ho
Cheuk-Lam
CL
Zhou
Gui-Jiang
GJ
Keung
Oi-Mei
OM
Lam
Kim-Hung
KH
Gambari
Roberto
R
Tao
Xiao-Ming
XM
Wong
Raymond Siu-Ming
RS
Tong
See-Wai
SW
Chan
Kit-Wah
KW
Lau
Fung-Yi
FY
Cheung
Filly
F
Cheng
Gregory Yin-Ming
GY
Chui
Chung-Hin
CH
Wong
Wai-Yeung
WY
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D005260:Female; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005449:Fluorenes