The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

摘要

A multiparameter model of the diffusion, antiproliferative assays IC 50 and aerobic and hypoxic clonogenic assays for a wide range of neutral and radical anion forms of tirapazamine (TPZ) analogues has found: a) extravascular diffusion is governed by the desolvation, lipophilicity, dipole moment and molecular volume; b) hypoxic assay properties of the TPZ analogues show dependencies on the electron affinity, lipophilicity and dipole moment and desolvation; c) aerobic properties are mainly dependent on the electron affinity, involving free radicals in the extracellular matrix. The model shows that ligand water desolvation and lipophilicity are the dominant processes governing the DNA intercalation of TPZ analogues, consistent with DFT modelling of the complexes formed by TPZ analogues with neutral and N-protonated acridine moieties which intercalate with the guanine DNA nucleobases. It is shown that TPZ can form stable complexes with cucurbit[7]uril as a precursor to proof of principle of improved TPZ delivery to tumours.