Synthetic Medicinal Chemistry of Natural Products.
Our research is mainly into chemical synthesis of target molecules which have interesting, novel, potent biological effects. We are especially looking at alkaloids as fundamental building blocks in synthetic medicinal chemistry. We also elucidate the structures and modes of action of toxins isolated and characterised from a variety of natural sources (e.g. garden plants, spiders, wasps, snakes, etc.). We are studying the modes of action of our designed, synthetic small molecules at DNA, and of toxins and their synthetic analogues at physiologically important ion channels (e.g. glutamate, acetylcholine, potassium, calcium). This is an active area of research both in the UK and internationally. We design and synthesize selective ligands for DNA and for therapeutically important proteins. We also isolate small molecule toxins and determine their chemical structures mainly by NMR techniques. We collaborate in inter-disciplinary studies with pharmacologists, biochemists and electrophysiologists. We have several close links with overseas research groups.
T M Norris, E Moya, I S Blagbrough, and M E Adams. (1996). Block of high-threshold calcium channels by the synthetic polyamines sFTX-3.3 and FTX-3.3. Molecular Pharmacology, 1996, 50, 939-946.
Polyamines and Polyamine Amides as ligands for Ion Channels, for DNA and RNA, and for Gene Therapy
We are designing and synthesising polyamines and polyamine amides based upon spider and wasp toxins as novel ligands for the control of physiologically important ion channels. We have shown that anti-cancer leads can be made by targeting DNA with novel polyamines-acridine conjugates. Our recent studies are into the packaging of genes using synthetic polyamine conjugates in order to achieve targeted gene therapy for the possible treatment of cancer and other genetic disorders. Recent aspects of this work have appeared in Pharmaceutical Sciences and in Chemical Communications. We collaborate closely with colleagues at Celltech Therapeutics and with Dr Ian S Haworth (Dept of Pharmaceutical Sciences, University of Southern California, Los Angeles).
M Fatehi, E G Rowan, A L Harvey, E Moya, and I S Blagbrough. (1997). Polyamine FTX-3.3
and polyamine amide sFTX-3.3 inhibit presynaptic calcium currents and acetylcholine
release at mouse motor nerve terminals. Neuropharmacology, 36,
185-194.
I S Blagbrough, S Carrington, and A J Geall. (1997). Polyamines and polyamine amides as
potent selective receptor probes, novel therapeutic lead compounds and synthetic vectors
in gene therapy. Pharmaceutical Sciences, 3, 223-233.
A J Geall, R J Taylor, M E Earll, M A W Eaton, and I S Blagbrough. (1998). Synthesis of
cholesterol-polyamine carbamates: pKa studies and condensation of calf thymus DNA. Chemical
Communications, 1403-1404.
I S Blagbrough, S Taylor, M L Carpenter, V Novoselskiy, T Shamma, and I S Haworth. (1998).
Asymmetric intercalation of N1-(acridin-9-ylcarbonyl)spermine at homopurine sites of
duplex DNA. Chemical Communications, 929-930.
Norditerpenoid Alkaloids from Delphinium and Aconitum as ligands for Ion Channels
In this interdisciplinary project, we are isolating toxic norditerpenoid alkaloids from garden plants. We are making semi-synthetic derivatives and have achieved a completely new and potent antagonist for neuronal nicotinic acetylcholine receptors that may be important for mapping key regions of the brain with exquisite specificity. We have also designed and synthesized the most active small molecule analogue of methyllycaconitine yet prepared, it is a tricyclic alkaloid, but we can make it in only a few steps. We are therefore interested in isolating natural products and in synthesising active and selective analogues, in collaboration with Dr Sue Wonnacott and Dr Adrian Wolstenholme (Dept Biology and Biochemistry) and Dr Michael G Rowan and Prof Barry V L Potter.
D J Hardick, I S Blagbrough, and B V L Potter (1996). Isotopic enrichment by asymmetric
deuteriation. An investigation of the synthesis of deuteriated (S)-(-)-methylsuccinic
acids from itaconic acid. Journal of the American Chemical Society, 118,
5897-5903.
D J Hardick, I S Blagbrough, G Cooper, B V L Potter, T Critchley, and S Wonnacott. (1996).
Nudicauline and elatine as potent norditerpenoid ligands at rat neuronal a-bungarotoxin
binding sites: importance of the 2-(methylsuccinimido)benzoyl moiety for neuronal
nicotinic acetylcholine receptor binding. Journal of Medicinal Chemistry, 39,
4860-4866.
W J Trigg, D J Hardick, G Grangier, S Wonnacott, T Lewis, M G Rowan, B V L Potter, and I S
Blagbrough. (1998). Selective probes for nicotinic acetylcholine receptors from
substituted AE-bicyclic analogs of methyllycaconitine. ACS Symposium Series, (Eds
D R Baker, J G Fenyes, G S Basarab, and D A Hunt), 686, 194-205.