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 IC50 values ranging from 0.002 to 0.7 μM, 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 1–2 mg/kg (Q3D × 7) or 3 mg/kg (Q4D × 5) via intravenous injection.