Design, Synthesis and Photochemical Reactivation of Caged Prodrugs of 8-Hydroxyquinoline-Based Enzyme Inhibitors

Abstract

8-Hydroxyquinoline (HQ)-based compounds have recently been proposed as potential candidates for drugs for treating human immunodeficiency virus (HIV), cancer, neurodegenerative diseases (Alzheimer’s and Parkinson’s disease), and parasitic and bacterial infections. However, HQ itself and its derivatives might be toxic due to their intrinsic affinity for metal cations in living systems. One possible strategy for suppressing the toxicity and side effects of drugs with metal chelation properties, such as HQ, would be masking the critically important moieties with protecting groups that can be subsequently removed under specific conditions. In our previous work, we reported that HQ analogs are potent and selective inhibitors (K_i values=0.16–29 µM) of aminopeptidase from Aeromonas proteolytica (AAP) (EC 3.4.11.10), a dinuclear Zn²⁺ peptidase. Based on this background information, HQ sulfonates were synthesized as prodrugs of HQ-based AAP-inhibitors that can be reactivated by photochemical cleavage of the S–O bond in the sulfonate groups. The findings indicate that HQ sulfonates containing methanesulfonyl and 2-aminoethanesulfonyl groups are essentially stable under physiological conditions and undergo photolysis to regenerate the corresponding HQ compounds that function as AAP inhibitors. This methodology could be applied to the design of similar types of Zn²⁺ hydrolase inhibitors and prodrugs.