Replacement of a Thiourea-S with an Amidine-NH Donor Group in a Platinum−Acridine Antitumor Compound Reduces the Metal’s Reactivity with Cysteine Sulfur

Abstract

The reactivity of two DNA-targeted platinum-acridine conjugates with cysteine sulfur was studied. The conjugate containing an amidine-NH donor group cis to the chloride leaving group showed considerably reduced reactivity with N-acetylcysteine compared to the prototypical derivative containing a thiourea-S linkage. The opposite scenario has been observed previously in reactions with nucleobase nitrogen. Possible consequences of the unique target-selective tuning of the substitution chemistry for the pharmacodynamic properties and biological activity of these agents are discussed.