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

Valeriy A. Bacherikov, Ting Chao Chou, Hua J. Dong, Xiuguo Zhang, Ching Huang Chen, Yi W. Lin, Tsong J. Tsai, Rong Z. Lee, Leroy-Fong Liu, Tsann Long Su

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35 Citations (Scopus)

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-C2), O-butylene (O-C4), and methylene (C1) 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., 1-2 mg/kg (Q3D × 7) or 3 mg/kg (Q4D × 5); 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.

Original languageEnglish
Pages (from-to)3993-4006
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number12
DOIs
Publication statusPublished - Jun 2 2005
Externally publishedYes

Keywords

  • Acridines
  • Alkylating agents
  • Antitumour compounds
  • Chemotherapy
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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  • Cite this

    Bacherikov, V. A., Chou, T. C., Dong, H. J., Zhang, X., Chen, C. H., Lin, Y. W., Tsai, T. J., Lee, R. Z., Liu, L-F., & Su, T. L. (2005). Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: Synthesis and biological activity. Bioorganic and Medicinal Chemistry, 13(12), 3993-4006. https://doi.org/10.1016/j.bmc.2005.03.057