Last Updated: 04/06/07
Natural Products-Based Drug Discovery
Progress has been made in coupling cell-based, molecular-targeted high-throughput screens and crude natural product extracts for anticancer drug discovery. Screening campaigns of the DTP Natural Products Repository of some 70,000 extracts were carried out using three distinct molecular-targeted screens: the HIF-1a, CEBPa, and IkB kinase (IKK) signaling pathways.
HIF-1a is a key regulator of hypoxic cell signaling. CEBPa is a regulator of differentiation of myeloid and other cell types. The IKK signaling pathway is of particular importance in the pathogenesis of diffuse, large B-cell lymphomas.
High-throughput screening data were analyzed to identify active extracts to prioritize potential compounds for bioassay- directed isolation of active constituents. Selected extracts were then fractionated by high-pressure liquid chromatography in conjunction with spectroscopic monitoring to generate samples for testing in the molecular-targeted screen of interest. It has been possible to track activity through successive chemical separation steps and isolate chemical entities responsible for the activity. Camptothecin derivatives were isolated from a plant never before reported to produce such compounds.
This included a camptothecin derivative never before found in nature. Structure elucidation work is in progress for compounds isolated from all three screens.
Two novel antifungal compound series were reported in 2005. These represented the conclusion of work under a CRADA with SAIC for antimicrobial drug discovery. DTP Screening Technologies Branch (STB) investigators developed a novel fermentation process to produce the antitumor lead pleurotin and supported a large-scale plant recollection effort to isolate novel tropane alkaloids.
Meragelman TL, Tucker KD, McCloud TG, Cardellina JH 2nd, Shoemaker RH. Antifungal flavonoids from Hildegardia barteri. J Nat Prod 2005;68:1790–2.
Klausmeyer P, McCloud TG, Tucker KD, Cardellina JH 2nd, Shoemaker RH. Aspirochlorine class compounds from Aspergillus flavus inhibit azole-resistant Candida albicans. J Nat Prod 2005;68:1300–2.
Chin YW, Jones WP, Waybright TJ, McCloud TG, Rasoanaivo P, Cragg GM, Cassady JM, Kinghorn AD. Tropane aromatic ester alkaloids from a large-scale re-collection of Erythroxylum pervillei stem bark obtained in Madagascar. J Nat Prod 2006;69:414–7.
Shipley SM, Barr AL, Graf SJ, Collins RP, McCloud TG, Newman DJ. Development of a process for the production of the anticancer lead compound pleurotin by fermentation of Hohen-buehelia atrocaerulea. J Ind Microbiol Biotechnol 2006;33:463–8.
