From triazines and triazenes to temozolomide

Abstract

NEW DRUGS don't just 'happen' by a process of spontaneous generation: rather, their emergence into the clinical spotlight is acheived in a tentative series of evolutionary nudges, with the 'fitness' of the candidate molecule moulded by the selection forces imposed by laboratory and clinical environments. As in most human endeavours inquisitiveness and awareness are the catalysts to innovation, but luck plays a major role, especially when contrasting but complementary research strands converge at the right time in the right place. So it was with the discovery of temozolomide which is a story of a symbiotic relationship between two cultures; on the one hand the laboratory sciences of chemistry and pharmacology and on the other the clinical sciences which impose the ultimate test of efficacy does the drug actually work in patients, or not. The ancestor molecules of the bicyclic nucleus of temozolomide were originally synthesised in the early 1960s at Nottingham University and their structural similarity to temozolomide itself will be obvious (Fig. 1). The pyrazolo-l,2,4-triazines proved to have modest inhibitory properties against the mouse sarcoma 180 and a methylcholanthrene-induced rat sarcoma [1 ], but at the time there was no mechanism for evaluating the clinical potential of these leads. A series of imidazo-l,2,4triazinones and 1,2,3-benzotriazinones prepared at Aston University in the 1970s were completely lacking in antitumour activity against the available tumour models of the day, the L1210 and P388 leukaemias of the NCI. Despite these disappointments, the experience gained in exploring the chemical properties of these reactive close relatives of temozolomide was the essential foundation stone in the whole programme [2]. In 1978 the pharmaceutical company May & Baker agreed to fund a programme of inquisitive chemistry extending the foregoing studies at Aston and a pharmacy research student Robert Stone was recruited and given the simple instruction by his academic and industrial supervisors: Make some