Some of the most promising leads for powerful therapeutic agents have arisen from marine sponges. Aside from providing an environmentally friendly avenue to these compounds, chemical synthesis enables the development of analogs with improved bioactivity and regularly leads to fundamental discoveries in chemistry, biology and medicine. The pyrrole-imidazole alkaloids are a diverse family of marine sponge derived natural products with reported bioactivity including: anticancer, antibiotic, antiviral, antihistiminic, antimuscarinic and potential leads for cystic fibrosis and Alzheimer's disease. This proposal encompasses both the chemical and biological aspects of several members of this natural product class, including its most complex members. Thus, enantioselective syntheses of sceptrin, oxysceptrin, nakamuric acid, ageliferin, nagelamide, axinellamine, massadine, and palau'amine are proposed. The overall aim is to provide useful amounts of these natural products using concise synthetic sequences and biomimetic cascade reactions. Upon achieving practical syntheses of these compounds we will study their structure activity relationships and mechanism of action through collaborations. The biological studies will be carried out in collaboration with leaders in the fields of cancer (Professor Bob Abraham, Burnham Institute), viral (Professor Raymond Schinazi, Emory), neuropharmacology (Professor George Siggins, Scripps) and physiology (Dr. Lee Sweeny, Penn State Med. Center). ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM073949-01
Application #
6908565
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$278,850
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Horn, Evan J; Rosen, Brandon R; Chen, Yong et al. (2016) Scalable and sustainable electrochemical allylic C-H oxidation. Nature 533:77-81
Michaudel, Quentin; Ishihara, Yoshihiro; Baran, Phil S (2015) Academia-industry symbiosis in organic chemistry. Acc Chem Res 48:712-21
Ma, Zhiqiang; Wang, Xiaolei; Wang, Xiao et al. (2015) ORGANIC SYNTHESIS. Response to Comment on ""Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence"". Science 349:149
Feng, Yu; Holte, Dane; Zoller, Jochen et al. (2015) Total Synthesis of Verruculogen and Fumitremorgin A Enabled by Ligand-Controlled C-H Borylation. J Am Chem Soc 137:10160-3
Rosen, Brandon R; Werner, Erik W; O'Brien, Alexander G et al. (2014) Total synthesis of dixiamycin B by electrochemical oxidation. J Am Chem Soc 136:5571-4
Rodriguez, Rodrigo A; Barrios Steed, Danielle; Kawamata, Yu et al. (2014) Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology. J Am Chem Soc 136:15403-13
Ma, Zhiqiang; Wang, Xiaolei; Wang, Xiao et al. (2014) Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence. Science 346:219-24
Rodriguez, Rodrigo A; Pan, Chung-Mao; Yabe, Yuki et al. (2014) Palau'chlor: a practical and reactive chlorinating reagent. J Am Chem Soc 136:6908-11
O'Hara, Fionn; Baxter, Ryan D; O'Brien, Alexander G et al. (2013) Preparation and purification of zinc sulfinate reagents for drug discovery. Nat Protoc 8:1042-7
Zhou, Qianghui; Ruffoni, Alessandro; Gianatassio, Ryan et al. (2013) Direct synthesis of fluorinated heteroarylether bioisosteres. Angew Chem Int Ed Engl 52:3949-52

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