Topoisomerase inhibitors and DNA alkylators are some of the most powerful anticancer compounds in use today. Although structurally diverse, they share several common design principles, which we are using to create diverse chemical biology tools and drug candidates that interact with DNA and its associated proteins.
Several complex natural products and their synthetic analogues have been developed as topoisomerase-IIα inhibitors (a). They stabilise the interaction of the enzyme with the DNA strand, forming an unusual ternary complex that results in double-stranded DNA breaks and eventually in cell death. We have selected the bare structural/pharmacophoric elements needed for bioactivity (eg. minor groove polar space-filling group A, oxygen-rich planar intercalator domain B, protein-interacting group C), to design a suite of simplified inhibitors that are more amenable to synthesis and prodrug use. We are also developing pharmacogenic prodrugs based on these structural features to create the topoisomerase inhibitor scaffold in cellulo following a photoisomerisation cascade. Lastly, we recently developed an exciting, fully reversible photoswitch system inspired by masking/unmasking the interaction pharmacophores A and B, which should allow us to reversibly dock/undock inhibitors or reporters to DNA and so place a range of DNA-dependent biological interactions under optical control.
DNA alkylators and crosslinkers (b) are a particularly potent and diverse class of cytotoxic agents, whose side-effects in healthy tissues are however particularly severe. We are working on triggered alkylators and crosslinkers as proof-of-principle for "smart" drugs that may reduce the side-effects of current treatments. Standard agents such as cisplatin may seem too small for chemical modification, but we are investigating extended ligand environments that can render the platinum complex photoresponsive; and the beautiful activity principle underlying the toxicity of the duocarmycins suggests several triggering systems that exploit specific tumoural biochemistry to create the alkylating cyclopropanyl species.