SYNTHESIS, ANTITUMOR-ACTIVITY, AND DNA-BINDING PROPERTIES OF A NEW DERIVATIVE OF AMSACRINE, N-5-DIMETHYL-9-[(2-METHOXY-4-METHYLSULFONYLAMINO)PHENYLAMINO]-4-ACRIDINECARBOXAMIDE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (8) , 3245-3251
Abstract
The 4-(N-methylcarboxamido)-5-methyl derivative of amsacrine (NSC 249 992) was synthesized as part of a program aimed at optimizing solid tumor activity in this series. Physicochemical studies of this analog { N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-4-acridinecarboxamide; NSC 343 499} indicate a slightly increased lipophilicity (estimated log p = 1.10), a decreased acridine base strength (pKa 6.40), and a 16-fold-higher association constant for double-stranded calf thymus DNA (Ka 2.1 .times. 106 M-1 at 0.01 ionic strength). Like amsacrine, the drug binds to DNA by intercalation. Inhibition of cell growth was monitored by continuous drug exposure assays with a variety of rodent and human cell lines. The concentration for 50% inhibition varied from 6.7 nM (T-47D, a human breast carcinoma line) to 800 nM (P388/ADR, a murine { cell line resistant to Adriamycin). N-5-Dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino]-4-acridinecarboxamide was cytotoxic at growth-inhibitory concentrations and also induced cell cycle arrest in the G2 phase. It was active against [mouse] P388 leukemia following administration by p.o. [oral], i.v. or i.p. routes, and it was superior to amsacrine, daunorubicin and Adriamycin. It was curative towards i.v.-injected [mouse] Lewis lung tumor in a proportion of animals when treatment was started on day 1 or day 5 after tumor inoculation. It also produced highly significant life extensions against advanced tumors (treatment starting day 9 after i.v. inoculation or on day 8 after s.c. inoculation) and was comparable to cyclophosphamide in its effectiveness. It is a candidate drug for clinical trial.