Synthesis and antitumor activity of 5-(9-acridinylamino)anisidine derivatives.
A series of 5-(9-acridinylamino)anisidines were synthesized by condensing methoxy-substituted 1,3-phenylenediamines (10 and 11) with 9-chloroacridine derivatives to form 5-(9-acridinylamino)-m-anisidines (AMAs, 14a-e) and 5-(9-acridinylamino)-o-anisidines (AOAs, 15a-e). 5-(9-Acridinylamino)-p-anisidines (APAs, 17a-e) were synthesized by reacting 2-methoxy-5-nitroaniline (12) with 9-anilinoacridines, followed by reduction. The cytotoxic inhibition of growth of various human tumor cells in culture, inhibitory effects against topoisomerase II, and DNA interaction of these agents were studied. The structure-activity relationship studies revealed the following degree of potency: AOAs > AMAs > APAs. They also revealed that the newly synthesized derivatives bearing CONH(2)NH(2)NMe(2) and Me substituents at C4 and C5 positions of the acridine chromophore (i.e., AMA 14e, AOA 15e, and APA 17e) exhibited significant cytotoxicity against human tumor cell growth in vitro. AOA (15e) was the most potent among these derivatives, which resulted in 60% suppression of tumor volume at a dose of 20 mg/kg (Q2D x 9), intravenous injection on day 26 in nude mice bearing human breast carcinoma MX-1 xenografts.
Bacherikov
Valeriy A
VA
Laboratory of Bioorganic Chemistry, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Chang
Jang-Yang
JY
Lin
Yi-Wen
YW
Chen
Ching-Huang
CH
Pan
Wen-Yu
WY
Dong
Huajin
H
Lee
Rong-Zau
RZ
Chou
Ting-Chao
TC
Su
Tsann-Long
TL
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D023041:Xenograft Model Antitumor Assays
D000166:Acridines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II