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.

Figure 1

Structures of compound 1 and PT-ACRAMTU (2) with structural differences highlighted.

Figure 2

Progress of the reactions of compound 1 (open circles) and compound 2 (filled circles) with one equivalent of N-acetylcysteine (N-AcCys) at 25 °C monitored by ¹H NMR spectroscopy. The data shown is the mean of two experiments. The solid line (for 1) represents a curve fit assuming second-order conditions, [Pt]/[Pt]₀ = (1 + k [Pt]₀ t)⁻¹; (t_1/2 = 180 min). The dashed trend line (for 2) has no physical significance.

Figure 3

Positive-ion electrospray mass spectra of adducts I (A) and II (B) showing peaks for the molecular ions, [I]⁺ (m/z 725.2) and [II-2H]²⁺ (m/z 643.7, z = 2), and fragment ions resulting from in-source collisionally activated dissociation (CAD). The insets illustrate the observed fragmentation patterns. The discrepancy between the calculated and observed m/z values for some of the platinum containing ions is due to distorted Pt isotope patterns.

Scheme 1

Reactivity of Compounds 1 and 2 with N-Acetylcysteine (N-AcCys)