Figure 1.

(a) Illustration of key events in the catalytic cycle of human Top1. Step 1: Top1 binds supercoiled DNA (scDNA; 5′-TA-3′ dinucleotide pair as target). Step 2: nucleophilic attack of the 3′-phosphate linking the TA pair (scissile strand) by Y723 (catalytic tyrosine residue) affords a covalent DNA–Top1 cleavage complex and nicked strand. Step 3: the intrinsic torque stored in scDNA drives ratchet-like rotation about the non-scissile strand until strand religation occurs with concomitant release of Y723. The turnover frequency¹ is up to 6000 min^–1. The relaxed DNA (rDNA) is then released⁴ by the enzyme in step 4. Interfacial poisons (IFPs) such as camptothecin (CPT) bind the nick site via 5′-TA-3′ intercalation and H-bonding to Top1 to form a ternary drug·scDNA–Top1 adduct, poisoning the enzyme. CICs operate differently by either blocking substrate recognition by Top1 (type 1 competitive inhibitor, CIC1) or, in principle, preventing the formation of the covalent cleavage complex by blocking the nucleophilic attack of the scissile strand by Y723 (type 2 competitive inhibitor, CIC2). (b) Structures of new cytotoxic pyrrole-based Au³⁺ macrocycles 1–5, free base macrocycle 6, and the Ni²⁺ analogue of 1, compound 7.