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

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.