This grant application describes a program directed towards the total synthesis of the novel thiopeptide antibiotic thiostrepton. Produced by several bacterial strains including streptomyces azureus, this naturally-occurring substance is characterized by a novel molecular architecture which includes three highly complex molecular domains: a didehydropiperidine ring system possessing a quaternary center bearing three carbons and a nitrogen; a potentially sensitive thiazoline ring; and a unique quinaldic acid system. The originally proposed total synthesis will feature not only a highly convergent and flexible approach to the assembly of thiostrepton, but moreover the projected route will end with three novel cyclization reactions to complete the most challenging portions of the molecule. Moreover and given the daring nature of this bold approach an alternative, safer strategy for the construction of the macrocyclic rings is proposed. As such, this work is expected to impact positively the areas of new synthetic methodologies and strategies for complex molecule construction. Furthermore, the use of synthesized fragments and thiostrepton itself as chemical biology tools to probe the interactions of small molecules with RNA should help set the stage for drug discovery programs utilizing small organic compounds to selectively target RNA or RNA-protein complexes. The disease areas likely to benefit most from the proposed investigations are bacterial-caused diseases and malaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055475-02
Application #
6668699
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Tseng, Christopher K
Project Start
2002-09-30
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$463,000
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Nicolaou, K C; Liu, Guodu; Beabout, Kathryn et al. (2017) Asymmetric Alkylation of Anthrones, Enantioselective Total Synthesis of (-)- and (+)-Viridicatumtoxins B and Analogues Thereof: Absolute Configuration and Potent Antibacterial Agents. J Am Chem Soc 139:3736-3746
Nicolaou, K C; Pulukuri, Kiran Kumar; Rigol, Stephan et al. (2017) Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents. J Am Chem Soc 139:15868-15877
Nicolaou, K C; Pulukuri, Kiran Kumar; Yu, Ruocheng et al. (2016) Total Synthesis of ?(12) -Prostaglandin J3 : Evolution of Synthetic Strategies to a Streamlined Process. Chemistry 22:8559-70
Nicolaou, K C; Wang, Yanping; Lu, Min et al. (2016) Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations. J Am Chem Soc 138:8235-46
Nicolaou, K C; Pulukuri, Kiran Kumar; Rigol, Stephan et al. (2016) Synthesis and Biological Investigation of ?(12)-Prostaglandin J3 (?(12)-PGJ3) Analogues and Related Compounds. J Am Chem Soc 138:6550-60
Oresic Bender, Kristina; Ofori, Leslie; van der Linden, Wouter A et al. (2015) Design of a highly selective quenched activity-based probe and its application in dual color imaging studies of cathepsin S activity localization. J Am Chem Soc 137:4771-7
Nicolaou, K C; Shah, Akshay A; Korman, Henry et al. (2015) Total Synthesis and Structural Revision of Antibiotic CJ-16,264. Angew Chem Int Ed Engl 54:9203-8
Nicolaou, K C; Nilewski, Christian; Hale, Christopher R H et al. (2015) Synthesis and biological evaluation of dimeric furanoid macroheterocycles: discovery of new anticancer agents. J Am Chem Soc 137:4766-70
Nicolaou, K C; Shi, Lei; Lu, Min et al. (2014) Total synthesis of myceliothermophins?C, D, and E. Angew Chem Int Ed Engl 53:10970-4
Nicolaou, K C; Hale, Christopher R H; Nilewski, Christian et al. (2014) Total synthesis of viridicatumtoxin B and analogues thereof: strategy evolution, structural revision, and biological evaluation. J Am Chem Soc 136:12137-60

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