One-electron redox chemistry of amsacrine, mAMSA [9-(2-methoxy-4-methylsulphonylaminoanilino)acridinium], its quinone di-imine, and an analogue. A radiolytic study

Abstract

The redox chemistry of the clinical antileukemia drug mAMSA (amsacrine) and of its dimethylamino analogue (diAMSA) has been investigated by radiolytic methods. Steady-state and pulse radiolysis experiments show that upon one-electron oxidation both compounds give quinone di-imine radicals (mAQDI˙ and diAQDI˙) which disproportionate to the parent compounds and the corresponding quinone di-imines (mAQDI and diAQDI). One-electron reduction of the quinone di-imines give the same intermediate radicals which are not oxidized by oxygen. Nanosecond pulse radiolysis experiments show that the initial one-electron reduction of the quinone di-imines also occurs at the acridine ring, but is followed by rapid intramolecular electron transfer to the quinone di-imine side-chain. One-electron reduction of mAMSA occurs at the acridine ring and leads to acridan formation. The redox potential at pH 7.4 of the mAMSA–mAQDI˙ couple is calculated as 915 mV (versus n.h.e.), while the redox potential of the mAMSA–mAQDI couple is 415 mV. The analogue diAMSA shows a similar reversible redox chemistry but is much more readily oxidizable, with a calculated redox potential diAMSA–diAQDI˙ of 635 mV, and a redox potential diAMSA–diAQDI of 330 mV.