The competitive renewal proposal describes a research program directed at the total synthesis of naturally occurring antibiotics and designed antibacterial agents. The proposed work represents continuation of our NIH-funded (AI55475) research activities and will specifically involve molecular design and synthetic work toward thiostrepton (1), nocathiacin I (2), marinomycin A (3) and abyssomycin C (4c) and their analogs. In the thiostrepton project, we plan to optimize a biologically active lead compound representing the didehydropiperidine domain of the molecule that we have discovered during our successful total synthesis of this antibiotic. In the nocathiacin I project we will follow our recently developed methodology for W-hydroxyindole synthesis to achieve a total synthesis of the natural product and apply the technology to the construction of designed analogs for the purposes of SAR studies. The total synthesis of marinomycin A is designed to test the scope and limitations of the palladium-catalyzed cross-coupling and olefin metathesis reactions. The designed total synthesis of abysommycin C relies on a biosynthetic hypothesis cascade and is expected to deliver other members of the class, including designed analogs for biological evaluation. Overall, this research program aims to generate new knowledge for the treatment of anti- infective diseases, advance the art of chemical synthesis as applied to drug design and development, and, possibly, result in the synthesis of new potential antibacterial agents. ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Peters, Kent
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Scripps Research Institute
La Jolla
United States
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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; 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
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
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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