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 Jin Dong, Xiuguo Zhang, Ching Huang Chen, Yi Wen Lin, Tsong Jen Tsai, Rong Zau Lee, Leroy F. Liu, Tsann Long Su

Research output: Contribution to journalArticlepeer-review

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

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