Potent antitumor N-mustard derivatives of 9-anilinoacridine, synthesis and antitumor evaluation.
A series of 9-anilinoacridine N-mustard derivatives, in which the alkylating N-mustard residue was linked to the C-3' or C-4' position of the anilino ring with an O-ethylene spacer, was synthesized and evaluated for cytotoxicity against human lymphoblastic leukemic cells (CCRF-CEM) in culture. The results showed that all of the new compounds exhibited potent cytotoxicity with IC(50) values ranging from 0.002 to 0.7 microM, which were as potent or significantly more potent than 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA). Compound 9 did not exhibit cross-resistance against both vinblastine-resistant (CCRF-CEM/VBL) and taxol-resistant (CCRF-CEM/taxol) cells. Additionally, compound 9 demonstrated potent antitumor effect in nude mice bearing human breast carcinoma MX-1 xenografts, resulting in complete tumor remission in two out of three mice at the maximal dose of 1-2mg/kg (Q3Dx7) or 3mg/kg (Q4Dx5) via intravenous injection.
Laboratory of Bioorganic Chemistry, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Valeriy A
VA
Bacherikov
Ting-Chao
TC
Chou
Hua-Jin
HJ
Dong
Ching-Huang
CH
Chen
Yi-Wen
YW
Lin
Tsong-Jen
TJ
Tsai
Tsann-Long
TL
Su
D000677:Amsacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D000677:Amsacrine; C022202:9-anilinoacridine; D014747:Vinblastine; D017239:Paclitaxel