Dr Malcom McCulloch
Lecturer of organic chemistry
Phone 0114 225 6020
The natural origins of therapeutic drugs: natural product scaffolds
What are natural products and where do they come from?
Natural products constitute a broad, fascinating set of naturally occurring molecules (secondary metabolites). They may be isolated from a wide range of biological sources including plants, fungi, bacteria, and animals. Historically, most natural products were obtained from terrestrial sources; however, in recent decades the field of marine natural products has bloomed, with numerous novel molecules being discovered from marine invertebrates, micro-organisms, and plants.
Natural product scaffolds are biologically privileged and of tremendous value in drug discovery
A significant percentage of therapeutic drugs have origins in natural products and natural products continue to play important roles in medicinal chemistry and drug discovery. There are numerous examples of medicines derived from natural products, including various antibiotics (e.g. -lactams), anti-cancer drugs (e.g. paclitaxol, Ixabepilone), immunosuppressant drugs (e.g. rapamycin), and cholesterol lowering agents (e.g. the statins). In most cases, the approved drugs resulting from natural products are derivatives: that is chemically modified variants based around a core molecular scaffold.
My research centres on utilising natural product scaffolds for the discovery of new therapeutic drugs, and as tool compounds to probe biological systems. Under this central theme, research goals fall under three related areas.
- Rational semi-synthesis. I am developing a concept I call lead-directed semi-synthesis. The goal is to generate rationally designed semi-synthetic compound libraries populated with lead-like and drug-like compounds. This will help address current needs within drug discovery.
- Neglected' antimicrobial natural products. A variety of natural products with interesting antimicrobial activity have never been subjected to serious medicinal chemistry investigations. My goal is to develop analogues of various `neglected` natural products, in order to identify the pharmacophores, develop more potent derivatives, and ultimately identify the mechanisms of action.
- Quinone derived natural products. Various quinone-derived natural products are continually being discovered and they often show notable biological activities. Selected examples of novel quinone-derivatives reported since 2011 include erythrazoles A and B (anticancer activity), and the abenquines (phosphodiesterase inhibitors, and activity against selected bacteria and fungi). I aim to synthesise these compounds and various analogues. A further aim of this research is to develop novel biomimetic synthetic methodology for the synthesis of benzoxazoles.
What skills do natural products chemists possess?
Most natural products chemists possess broad skills spanning organic chemistry, analytical chemistry, medicinal chemistry and pharmacognosy. Furthermore, many natural products chemist develop significant skills in, and knowledge of biology. Natural products chemists involved in the discovery of natural products use a range of chromatographic and other techniques to purify natural products; and a range of analytical techniques to solve their chemical structures (LCMS, NMR etc.). Chemists involved in the synthesis of natural products develop strong skills in organic synthesis and medicinal chemistry.
Peer reviewed journal articles
McCulloch, Malcolm W. B.; Haltli, Brad; Marchbank, Douglas H.; Kerr, Russell G. 'Evaluation of Pseudopteroxazole and Pseudopterosin Derivatives against Mycobacterium tuberculosis and other Pathogens'. Marine Drugs 2012, 10, 1711-1728.
McCulloch, Malcolm W. B.; Berrue, Fabrice; Haltli, Brad; Kerr, Russell G. 'One-pot Syntheses of Pseudopteroxazoles from Pseudopterosins: A Rapid Route to Non-natural Congeners with Improved Antimicrobial Activity', Journal of Natural Products, 2011, 74, 2250-256.
Berrue, Fabrice;* McCulloch, Malcolm W. B.;* Kerr, Russell G. 'Marine Diterpene Glycosides', Bioorganic and Medicinal Chemistry, 2011, 19, 6702-6719. *These authors contributed equally.
McCulloch, Malcolm W. B.; Bugni, Tim S.; Coombs, Gary S.; Concepion, Gisela P.; Harper, Mary Kay; Mangalindan, Gina C.; Mutizwa, M. Misha; Kaur, Simran; Veltri, Charles A; Virshup, David M.; Ireland, Chris M. 'Carteriosulfonic acids A-C, GSK3- inhibitors from a Carteriospongia sp.', Journal of Natural Products, 2009, 72, 1651-1656.
McCulloch, Malcolm W. B.; Coombs, Gary S.; Banerjee, Nikhil; Bugni, Tim S.; Cannon, Kendell M.; Harper, Mary Kay; Veltri, Charles A.; Virshup, David M.; Ireland, Chris M. 'Psammaplin A as a general activator of cell based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives', Bioorganic and Medicinal Chemistry, 2009, 17, 2189-2198.
Bugni, Tim S.; Harper, Mary Kay; McCulloch, Malcolm W. B.; Reppart, Jason; Ireland, Chris M. 'Fractionated marine invertebrate extract libraries for drug discovery', Molecules, 2008, 13, 1372-1383.
McCulloch, Malcolm W. B.; Barrow, Russell A. 'A metalation strategy for the construction of functionalized naphthalenes: the first synthesis of guieranone A', Tetrahedron Letters, 2005, 46, 7619-7621.
Book chapter contributions (peer reviewed)
Bugni, Tim S.; Harper, Mary K.; McCulloch, Malcolm W. B.; Whitson, Emily G. 'Advances in Instrumentation, Automation, Dereplication and Prefractionation' In Natural Product Chemistry for Drug Discovery, Buss, A. D.; Butler, M. S., Eds.; Royal Society of Chemistry: Cambridge, UK, 2010, pp 272-298.