Molecular Modelling Analysis of the Metabolism of Dacarbazine

 Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, C42, The University of Sydney, PO Box 170, Lidcombe, NSW 1825, Australia.Telephone: +61 2 9351 9522 Fax: +61 2 9351 9520 E-mail : f.huq@fhs.usyd.edu.au.

Abstract: Dacarbazine (DTIC) that is routinely used in the treatment of malignant melanoma, Hodgkin’s disease, renaladenocarcinoma, soft tissue sarcoma, solid tumours and malignant lymphomas, is a produg that is metabolized in the liver to produce the active species responsible for causing DNA methylation. Hydroxylation one of the methyl groups first produces HMMTIC that yields the unstable metabolite MTIC following the loss of the hydroxymethyl moiety as formaldehyde. Spontaneous cleavage of MTIC produces AIC, and the methylating agent MHAZ. The methylation of DNA is believed to be responsible for both antineoplastic activity and carcinogenicity. The adverse effects of DTIC include nausea, vomiting, myelosuppression, flu-like syndrome and facial flushing. In this study, molecular modelling analyses have been carried out using the program Spartan ’02 to investigate the relative stability of DTIC and its metabolites, to locate the positions of negative electrostatic potential and the HOMOS with high electron density as applied to DTIC and its metabolites, with the aim of providing a better understanding of toxicity due to the drug. The results of  analyses show that DTIC and its metabolites differ significantly in their kinetic lability with most having relatively small LUMO-HOMO energy differences and hence quite labile. The results of the analyses also show that most of the metabolites may be subject to electrophilic attack at a number of sites. The location of HOMOs with high electron density close to O, C and in between the two nitrogen atoms of MDAZH indicates that the reaction with the molecule may take place at a number of sites. The presence of  HOMOs with high electron density close to O, C and in between the two nitrogen atoms of MDAZH indicate that the electrophilic attack on the molecule may take place at a number of sites.

Key words: Dacarbazine, antitumour activity, Hodgkin’s disease, methylation, molecular modelling

<<<