Natural Products as Leads for Drug Development

Natural products extracts are, on the one hand, very attractive feedstock for high throughput screens, because they provide unique and very broad chemical diversity to the screening process, permitting the sampling of far more "chemical space" than conventional combinatorial libraries. On the other hand, these same extracts represent substantial challenges to screeners and lead processors. Screeners must contend with complex mixtures with poor solubility and considerable pigmentation, along with widespread to ubiquitous "nuisance compounds" that provide false or uninteresting positive responses in many assay systems. The capacity and speed of conventional HTS arrays can provide a large number of hits or leads to a processing laboratory, resulting in considerable pressure to evaluate such leads quickly and efficiently and identify any meaningful, promising development candidates in those complex mixtures.

The first challenge for natural products chemists is to adapt and engage existing and emerging technological and tactical advances to expedite the process of dereplication and lead identification; research to develop new strategies and the technology to make them work is also a critical part of the approach. Once a lead compound is identified, compound development, through structure modification, analog synthesis or combinatorial chemistry, must follow, if the lead is to be moved forward expeditiously in the development pipeline. Until or unless a practical synthetic route to the candidate compound can be established, adequate supplies of the compound must be obtained from the natural source, in order to facilitate further development.

Credentials

John Cardellina earned baccalaureate degrees in Chemistry and Russian from the Pennsylvania State University (1968) and a Ph.D. in Organic Chemistry from the University of Hawaii (1979). He has worked in the pharmaceutical and dietary supplement industries and held academic appointments at Montana State University and the University of Maryland's Center of Marine Biotechnology. Prior service at the National Cancer Institute includes research in the Laboratory of Medicinal Chemistry and the Laboratory of Drug Discovery Research and Development. Research interests center on novel natural products, their pharmacological activity, structure-activity relationships, and synthesis and structure modification. Current emphasis is on antitumor, antiviral and antimicrobial natural products from microorganisms, terrestrial plants and marine macroorganisms.

Recent Publications

NCBI PubMed listing of publications by John Cardellina.

Hallock, Y.F., Sowder, R.C., II, Pannell, L.K., Hughes, C.B., Johnson, D.G., Gulakowski, R., Cardellina, J.H., II, and Boyd, M.R. Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa. J. Org. Chem. 65: 124-128, 2000.

Gustafson, K.R., Walton, L.K., Sowder, R.C., II, Pannell, L.K., Cardellina, J.H., II, and Boyd, M.R.: New circulin macrocyclic polypeptides from Chassalia parvifolia. J. Nat. Prod. 63: 176-178, 2000.

Rashid, M.A., Gustafson, K.R., Cardellina, J.H., II, and Boyd, M.R.: A new podophyllotoxin derivative from Bridelia ferrugianea. Nat. Prod. Lett. 14: 285-292, 2000.

Groweiss, A., Cardellina, J.H., II, and Boyd, M.R.: HIV-Inhibitory prenylated xanthones and flavones from Maclura tinctoria. J. Nat. Prod. 63: 1537-1539, 2000.

Rashid, M.A., Gustafson, K.R., Cardellina, J.H., II, and Boyd, M.R.: Absolute stereochemistry and anti-HIV activity of minquartynoic acid, a polyacetylene from Ochanostachys amentacea. Nat. Prod. Lett. 15: 21-26, 2001.

Cardellina, J.H., II: Challenges and opportunities confronting the botanical dietary supplement industry. J. Nat. Prod. 65: 1073-1084, 2002.

Cardellina, J.H., II: Mineral content of dietary supplements: A factor in quality assessment. J. Am. Nutr. Assoc. 5: 44-45, 2002.