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

Abstract

To cite this version:Clifford Fong. 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. [Research Report] Eigenenergy. 2017, pp.2017 -2017 International Journal of Computational Biology and Drug Design: In press 2017 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.Clifford W. Fong Eigenenergy, Adelaide, South Australia. AbstractA 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 that: (a) extravascular diffusion is governed by the desolvation, lipophilicity, dipole moment and molecular volume, similar to passive and facilitated permeation through the blood brain barrier and other cellular membranes, (b) hypoxic assay properties of the TPZ analogues show dependencies on the electron affinity, as well as lipophilicity and dipole moment and desolvation, similar to other biological processes involving permeation of cellular membranes, including nuclear membranes, (c) aerobic properties are dependent on the almost exclusively on the electron affinity, consistent with electron transfer involving free radicals being dominant with little or no drug permeation of membranes, and most likely occurring in the extracellular matrix. Application of the model to the DNA binding equilibrium constants of TPZ analogues with acridine or acridine-like moieties show that ligand water desolvation and lipophilicity are the dominant processes governing the DNA intercalation of TPZ analogues. This conclusion is 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.A quantum mechanical study has shown that TPZ can form stable complexes with cucurbit [7]uril as a precursor to proof of principle of improved TPZ delivery to tumours.Keywords: Tirapazamine analogues, intra-tumoural diffusion, anti-cancer, hypoxia, cytotoxicity, DNA binding, cucurbiturils, quantum mechanics Abbreviations Tirapazamine TPZ, free energy of water desolvation ΔG desolv,CDS , lipophilicity free energy ΔG lipo,CDS , cavity dispersion solvent structure of the first solvation shell CDS, multicellular layers MCL, extracellular matrix ECM, diffusion through support membrane D s , diffusion through multicellular layer D MCL , cucurbit[n]urils CB, cucurbit [7]urils, CB [7], highest occupied molecular orbital HOMO, lowest unoccupied molecular orbital LUMO, density functional molecular orbital theory DFT, adiabatic electron affinity AEA, cisplatin CisPt, ratio aerobic property:hypoxic property HCR, aerobic aer, hypoxic hyp, DNA binding equilibrium constant K DNA, multiple correlation coeffici...