Christopher Moody - Overview
The overall theme to our work is the relationship
between molecular structure and biological activity, particularly in the
areas of chemotherapy of cancer. To this end we are involved in the chemical
synthesis (developing new synthetic methodology where necessary) and evaluation
of a wide range of compounds with potential as therapeutic agents. Specific
projects include:
Thiopeptide Antibiotics
The thiopeptide antibiotics are a class of sulfur containing modified
cyclic peptides characterised by several common structural features. Most
of the thiopeptide antibiotics inhibit protein synthesis in bacteria,
and share a common mode of action. The thiopeptides have been demonstrated
to be active against Gram-positive bacteria and anaerobes, including pathogens
resistant to antibiotics currently in use, and also have potential as
growth inhibitors of the human malaria parasite. In addressing the synthesis
of thiopeptides, we propose to develop new routes to the various heterocyclic
rings which form the macrocyclic structure.
Chemotherapy of Cancer
Bioreductive anticancer agents based on heterocyclic quinones and
targeted delivery of tumour growth inhibitors
The term bioreductive drug was coined to describe anticancer agents which
are inactive in their own right, but upon metabolic reduction are transformed
into a cytotoxic species which can interact with biomolecules. Such drugs
are being developed as selective cytotoxins for the hypoxic regions of
solid tumours. The basis of our work is that bioreductive activation is
also a highly specific delivery mechanism for targeting a variety of processes
important for tumour growth. Thus, bioreduction of a quinone Q–D in the
hypoxic region of a tumour could result in the formation of a reactive
intermediate followed by elimination of another biologically active molecule
DH. Hence DH is only released within hypoxic regions of tumours. Additionally
we can engineer the quinones to be excellent substrates for NAD(P)H-quinone
oxidoreductase (DT-diaphorase) and thus target tumours rich in this enzyme,
thereby providing drug activation by a hypoxia independent mechanism.
Inhibitors of angiogenesis
Angiogenesis, a complex multistep event, is a pre-requisite for tumours
to grow beyond the minimum volume. Although the control of angiogenesis
is complex with many factors involved, there is considerable evidence
that VEGF is a major contributor to solid tumour growth by the promotion
of both angiogenesis and vascular permeability. Our proposed approach
is to investigate specifically activated blockers of VEGF and angiogenesis.
To do this we propose to take advantage of the properties of the quinones
developed in our own laboratory, and therefore build compounds which incorporate
proven inhibitors which are released in tumours upon metabolic activation.
Bioactive Natural Products
We are interested in a range of naturally occurring compounds with interesting
biological activity. For example, the benzoquinone antibiotics such as
geldanamycin act by binding to Hsp90; it is also a substrate for NAD(P)H-quinone
oxidoreductase (NQO1). Marine organisms are a rich source of structurally
diverse natural products many of which have potent biological activity.
One compound of great interest is diazonamide A, a structurally unique
secondary metabolite. The structure of the natural product comprises a
complex arrangement of aromatic and heteroaromatic rings, and we are developing
a total synthesis of diazonamide using a number of approaches.
