Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: synthesis and biological activity.

Abstract

A series of N-mustard derivatives of 9-anilinoacridine was synthesized for antitumor and structure-activity relationship studies. The alkylating N-mustard residue was linked to the C-3' or C-4' position of the anilino ring with an O-ethylene (O-C(2)), O-butylene (O-C(4)), and methylene (C(1)) spacer. All of the new N-mustard derivatives exhibited significant cytotoxicity in inhibiting human lymphoblastic leukemic cells (CCRF-CEM) in culture. Of these agents, (3-(acridin-9-ylamino)-5-{2-[bis (2-chloroethyl)amino]ethoxy}phenyl)methanol (10) was subjected to antitumor studies, resulting in an approximately 100-fold more potent effect than its parent analogue 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) in inhibiting the growth of human lymphoblastic leukemic cells (CCRF-CEM) in vitro. This agent did not exhibit cross-resistance against vinblastine-resistant (CCRF-CEM/VBL) or Taxol-resistant (CCRF-CEM/Taxol) cells. Remarkably, the therapeutic effect of 10 at a dose as low as one tenth of the Taxol therapeutic dose [i.e., 1-2mg/kg (Q3Dx7) or 3mg/kg (Q4Dx5); intravenous injection] on nude mice bearing human breast carcinoma MX-1 xenografts resulted in complete tumor remission in two out of three mice. Furthermore, 10 yielded xenograft tumor suppression of 81-96% using human T-cell acute lymphoblastic leukemia CCRF-CEM, colon carcinoma HCT-116, and ovarian adenocarcinoma SK-OV-3 tumor models.

• Authors: Valeriy A Bacherikov, Ting-Chao Chou, Hua-Jin Dong, Xiuguo Zhang, Ching-Huang Chen, Yi-Wen Lin, Tsong-Jen Tsai, Rong-Zau Lee, Leroy F Liu, Tsann-Long Su
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 13 Issue 12 Pg. 3993-4006 (Jun 02 2005) ISSN: 0968-0896 [Print] England
• PMID: 15911312 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkylating Agents
• Antineoplastic Agents
• Amsacrine
• 9-anilinoacridine

Topics

• Alkylating Agents (chemistry)
• Amsacrine (analogs & derivatives, chemical synthesis, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Humans
• Mice
• Mice, Nude
• Neoplasms (drug therapy, pathology)
• Remission Induction
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays