Organic synthetic
Artificial ribonucleases
This group designed and synthesised an array of novel small synthetic molecules, mimicking the active centre of naturally occurring ribonucleases and capable of cleaving RNA. The conjugation of such cleaving constructs to antisense oligonucleotides could potentially produce artificial ribonucleases capable of cleaving their RNA targets in a sequence-specific manner. Apart from being useful tools in molecular biology, such chemical RNases can provide a new design platform for novel therapeutics affecting specific messenger RNAs and viral genomic RNAs. The project on structure-based iterative design of artificial ribonucleases is carried out in collaboration with the research groups of Professor Vlassov and Dr M Zenkova (Novosibirsk, Russia).
Academic staff
Bioreductive prodrugs as selective agents for cancer and other diseases
Bioreductive alkylating agents are prodrugs that were developed to target the hypoxic or the reductase-rich population of solid tumours. The mechanism of their selective activation is based on their ability to convert the oxidative mioety to their activated reduced species affording the cytotoxic agents that are able to alkylate DNA. Compounds that were designed using molecular modelling techniques were synthesised in the group's laboratories. Many of the compounds showed extremely good selectivity and potency either under hypoxic conditions or in the presence/over-expression of reductive enzymes in a number of tumour cell lines in vitro. The lead indolequinone compound, which when combined with a gene-directed enzyme prodrug therapy (GDEPT) approaches showed in vivo efficacy. Biomimetic and enzymatic activation of bioreductive agents resulted in their understanding of their mode of action in terms of activation and DNA alkylation. Based on these studies, novel delivery agents have been developed that can effectively release a potent (but not necessarily a cytotoxic) agent (eg enzyme inhibitors) under hypoxic/reductive conditions. This technology platform is currently being used to develop novel bioreductive-drug conjugates as delivery agents to target cancer and other diseases where hypoxia and/or reductive enzymes play a major physiological role.
Academic staff
- Dr Edwin Chinje
- Dr Kaye Williams
- Dr Rachel Cowen
- Professor Ian Stratford
Carbonic anhydrase (IX) inhibitors for selective cancer therapy
Tumour cells have a lower extracellular pH than normal cells, which is an intrinsic feature of the tumour phenotype. Transmembrane ion channels remove the protons to the exterior, caused by glycolytic pathway. The acidification of the extracellular milieu benefits tumour cells by degrading the matrix, promoting invasiveness. Moreover, the acidic condition, which is modulated by carbonic anhydrase (CA) isozymes, can limit the activity of anti-cancer drugs. Thus, by inhibiting the tumour specific CAIX isozyme, the bioavailability of anti-cancer agents such as doxorubicin is increased. The design and synthesis of novel CAIX inhibitors are currently being developed in the group's laboratories.
Academic staff