COMPARISON OF THE INVIVO AND INVITRO ANTILEUKEMIC ACTIVITY OF MONOSUBSTITUTED DERIVATIVES OF 4'-(9-ACRIDINYLAMINO)METHANESULFON-META-ANISIDIDE

  • 1 January 1982
    • journal article
    • research article
    • Vol. 22  (2) , 486-492
Abstract
The growth-inhibitory activity of 4''-(9-acridinylamino)methanesulfon-m-anisidide and 47 acridine-monosubstituted derivatives was measured using cultures of L1210 murine leukemia cells grown for 3 days in the presence of each drug. The results were compared with previously published in vivo antitumor activity and physicochemical properties related to DNA binding, acridine base strength, stability to chemical attack by thiols and lipophilicity. Multiple-parameter regression equations show that both dose potency and host toxicity in mice were related to a combination of in vitro activity and a nonlinear (quadratic) term in lipophilicity. The in vitro activity could in turn be modeled as a combination of terms representing DNA binding, ability to quench the fluorescence of DNA-bound ethidium, stability to thiolysis and lipophilicity. Apparently, the terms for thiolytic stability and lipophilic-hydrophilic balance described the availability of the drug to the cell. The DNA binding constant determined what proportion of the available drug was bound to DNA, the proposed target site. The remaining terms could reflect changes in the geometry of drug-DNA binding, which in turn affect the intrinsic activity of these drugs when bound at their site of action.

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