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Biography
My career has been built upon a strong experimental bench apprenticeship in organic chemistry. I did not retire from active personal experimental work until I was over 50. Throughout, I have supervised teams of graduate students leading to successful PhD completions of (currently) >60 students. Since 1980 I have been Director of the Cancer Research Campaign (CRC: now Cancer Research UK) Experimental Cancer Chemotherapy Research Group firstly at Aston University and then (since 1992) at the University of Nottingham. At the last count I have published >300 papers in refereed journals.
Prior to 1980 the main focus of my work was developing novel routes to the synthesis of heterocyclic compounds. This is reflected in publications from the mid 1960s which elaborate on the chemistry of cyclic and acyclic systems with NNN bonds (1,2,3-triazines and 1,3-disubstituted triazenes) as well as bicyclic systems with bridgehead N atoms. All the early original work was published in esteemed mainstream chemistry journals especially J. Chem. Soc., Perkin Trans. 1. The focus of my work since 1980 has been the identification of what, I would assert, are the most precious commodities in drug discovery cancer research: novel molecules with novel biological properties. Through my familiarity with the literature of chemistry, cancer biology and pharmacology, I have developed antennae attuned to recognise what are potentially cunning molecules. (Note: what to other scientific constituencies might be more imaginative and stunning molecules derived from natural product scaffolds may not be optimal for the purpose in hand.) In the special context of a relatively small research group, the real scientific elegance of our work has derived from inventing molecules with three qualities: ease of synthesis; ability to perturb a biological mechanism not previously challenged in clinical trials; and pharmaceutical robustness. This is reflected in a changing emphasis in publications after 1980 to include journals such as Biochemistry, Cancer Research and J. Medicin. Chem. which publish interdisciplinary studies spanning the chemical, physical and biological sciences. The success of this transition was recognised by the receipt of the Royal Society of Chemistry (RSC) Interdisciplinary Research Award (1991) and recently the RSC George and Christine Sosnovsky Award for chemical contributions to cancer research (2002). Also the approach has led to milestone achievements in anti-cancer drug discovery signified by the British Association of Cancer Research (BACR) Tom Connors Award Lecture (2002). The series of papers 'Structural Studies on Bioactive Compounds' records the development of three small molecules for clinical trial: all of these projects led to molecules which were first in their class. N-methylformamide (NMF, 1) was the first small molecule differentiating agent to enter clinical trial; the immunomodulatory and antiviral agent bropirimine (2) which triggers cytokine cascades; and the lipophilic dihydrofolate reductase inhibitor MZPES (3). Despite spectacular responses in head and neck cancer NMF was withdrawn because it elicited hepatotoxicity probably through generation of an bioelectrophilic intermediate. Bropirimine is now on the market in Japan as Remisar™. MZPES, the first aromatic azide ever to enter the clinic for any indication, produced bizarre neurotoxicities because it inhibited histamine metabolism in the brain. Recently, work on this series has led to detailed studies on the synthesis and mode of action of diaminopyrimidines with antitumour and anti-Pneumocystis carinii activity. The series of papers 'Antitumour Imidazotetrazines' encompasses results
Research Summary
Nottingham e-mail address: Malcolm.Stevens@nottingham.ac.uk