Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage.
To improve the chemical stability and therapeutic efficacy of N-mustard, a series of phenyl N-mustard linked to DNA-affinic 9-anilinoacridines and acridine via a urea linker were synthesized and evaluated for antitumor studies. The new N-mustard derivatives were prepared by the reaction of 4-bis(2-chloroethyl)aminophenyl isocyanate with a variety of 9-anilinoacridines or 9-aminoacridine. The antitumor studies revealed that these agents exhibited potent cytotoxicity in vitro without cross-resistance to taxol or vinblastine and showed potent antitumor therapeutic efficacy in nude mice against human tumor xenografts. It also showed that 24d was capable of inducing marked dose-dependent levels of DNA cross-linking by comet assay and has long half-life in rat plasma.
Kapuriya
Naval
N
Institute of Biomedical Sciences, Laboratory of Bioorganic Chemistry, Academia Sinica, Taipei 115, Taiwan.
Kapuriya
Kalpana
K
Zhang
Xiuguo
X
Chou
Ting-Chao
TC
Kakadiya
Rajesh
R
Wu
Yu-Tse
YT
Tsai
Tung-Hu
TH
Chen
Yu-Ting
YT
Lee
Te-Chang
TC
Shah
Anamik
A
Naliapara
Yogesh
Y
Su
Tsann-Long
TL
D000166:Acridines / Q000737:chemistry; D000677:Amsacrine / Q000031:analogs & derivatives* / Q000737:chemistry; D000816:Aniline Mustard / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D014508:Urea / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000166:Acridines; D000970:Antineoplastic Agents; D000677:Amsacrine; C022202:9-anilinoacridine; D014508:Urea; D004247:DNA; D000816:Aniline Mustard