Investigation relevant to the conformation of the 17-membered Pt(d(GpG)) macrocyclic ring formed by Pt anticancer drugs with DNA: Pt complexes with a Goldilocks carrier ligand.

Platinum anticancer drug DNA intrastrand cross-link models, LPt(d(G*pG*)) (G* = N7-platinated G residue, L = R4dt = bis-3,3′-(5,6-dialkyl)-1,2,4-triazine), and R = Me or Et), undergo slow Pt–N7 bond rotation. NMR evidence indicated four conformers (HH1, HH2, ΔHT1, and ΛHT2); these have different combinations of guanine base orientation (head-to-head, HH, or head-to-tail, HT) and sugar–phosphodiester backbone propagation relative to the 5′-G* (the same, 1, or opposite, 2, to the direction in B DNA). In previous work on LPt(d(G*pG*)) adducts, Pt–N7 rotation was too rapid to resolve conformers (small L with bulk similar to that in active drugs) or L was too bulky, allowing formation of only two or three conformers; ΛHT2 was not observed under normal conditions. The (R4dt)Pt(d(G*pG*)) results support our initial hypothesis that R4dt ligands have Goldilocks bulk, sufficient to slow G* rotation but insufficient to prevent formation of the ΛHT2 conformer. Unlike the (R4dt)Pt(5′-GMP)2 adducts, ROESY spectra of (R...