THEO CHEM ELSEVIER Journal of Molecular Structure (Theochem) 389 (1997) 191-198 The antineoplastic behaviour of nitrosoureas: an ab initio study Arpita Yadav, Vinod Kumar Singh Department of Chemistry, Indian Institite of Technology, Kanpur 208016, India Received 5 June 1995; revised 24 April 1996 Abstract The present study is an attempt towards answering the basic question, ‘What contributes to the antineoplastic behaviour of nitrosoureas?’ In other words, ‘What is the active species generated in vivo which is responsible for the alkylation of DNA nucleic acid bases and what is the site of alkylation ?’ Ab initio MO calculations have been performed on possible active species generated in vivo and their interactions with guanine and cytosine have been studied in detail. The results indicate that the generation of the vinyl carbocation and its complexation with guanine and cytosine is responsible for the antineoplastic behaviour of the nitrosoureas. Detailed intermolecular interaction calculations have also been performed to study some recently proposed mechanisms for sequence specific reactions where the alkylation takes place before the dissociation of nitrosourea. Keywords: Ab initio calculation; Antineoplastic behaviour; Nitrosourea zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJ 1. Introduction A malignant neoplasm (cancer) is a proliferation of cells which are no longer under the control of the organism. It grows unrestricted and progressively invades the vital organs of the body, thus contributing to malignancy. Surgery and X-ray therapy provided the only means for attacking a malignant disease in the past. The current medical literature shows that lately chemotherapy is employed in almost all the cases despite the agony that all the antineoplastic agents are non specific and highly toxic for the patient. A variety of antineoplastic agents are in clinical use [l-3], for example, alkylating agents, antimetabo- lites, nitrosoureas, plant alkaloids, antibiotics, enzymes, hormones and radioactive isotopes. These are chemically different compounds and their modes of action are also varied. A glimpse of previous work in this area can be had from refs. [4] and [5]. Further, many leading theore- tical chemists have summarized the general cell biol- ogy aspects of carcinogenesis, i.e., the initiation and proliferation of malignant cells [6-81. The water environment in malignant cells has been studied by Jhon and Lowdin [9]. Broth and Vasilescu [lo] have studied the electrostatic properties and conformation of the radioprotector and anticancer drug I-102. Pull- man [ll] has studied in detail the role of quinones as antitumor agents. Sapse and Snyder [ 121 have studied the syn and anti conformers of simple nitrosoureas and their intramolecular proton transfer probability in regard to their activity. Reynolds and Thomson [13,14] have studied in detail the mechanistic aspects of chemical carcinogenesis by N-nitrosamines. The present study deals with the antineoplastic behaviour of nitrosoureas which occupy a unique 0166-1280/97/$17.00 Copyright 0 1997 Elsevier Science B.V. All rights reserved PIZ SO166-1280(96)04638-6