This is a competitive renewal of our grant application 5R01AI055475-09 (titled Synthesis of Antibiotics). We are expanding the scope of our investigations to include broad spectrum antiviral agents as well as compounds that may be useful in the battle against tuberculosis and malaria, the two most prevalent infectious diseases on a global scale. Specifically, we propose the total synthesis and biological evaluation of five classes of naturally occurring anti-infective agents: hirsutellones (antitubercular), beilschowskysin (antimalarial), viridicatumtoxins (antibacterial), epidithiodiketopiperazines (antiviral and antibacterial), and nocathiacins (antitumor antibiotics). We recently reported a total synthesis of hirsutellone B. In addition to continuing our analoging efforts, we plan to prepare hirsutellones A, C, and F from synthetic hirsutellone B or an advanced synthetic intermediate through bioinspired pathways. These efforts recently led to a total synthesis of hirsutellone C. Our ongoing total synthesis of beilschowskysin will feature a Nozaki-Hiyama-Kishi coupling to forge a macrocyclic precursor, a novel CAN-promoted oxidation of a furan, and a [2+2] photocycloaddition cascade for the stereoselective construction of the unusual cyclobutane core. We propose a convergent synthesis of viridicatumtoxins A and B that will employ a Tsuji reaction for the stereospecific installation of an all-carbon quaternary stereocenter. Our strategy should be amenable to the synthesis of truncated viridicatumtoxin analogs that closely resemble clinically important tetracyclines. We are working on a concise synthesis of the epidithiodiketopiperazines aranotin and acetylaranotin that employs an inverse electron demand Diels-Alder cycloaddition to form a cyclohexene ring, which may be transformed directly into the unusual 7-membered ring divinyl ether through a singlet oxygen ene and Criegee rearrangement cascade. We also propose a novel method for the introduction of the disulfide bridge and its diselenide analog that we plan to feature in a total synthesis of epicorazine A and its diselenide analog. Our interest in the nocathiacins inspired the development of a novel method for the construction of N-hydroxyindoles, which has been applied to the construction of an advanced nocathiacin system. We are continuing to pursue the completion of the total synthesis of nocathiacin III. The target molecules, synthetic fragments, and designed analogs to be synthesized in the course of these projects will be tested against relevant pathogens, including drug-resistant strains. In some cases, synthetic analogs and probes also may be useful for studies aimed at elucidating the mechanism of action of the compound class. The significance of the proposed work lies both in the enablement of anti-infectives research as well as in the development of new synthetic strategies and methods as enabling technologies for other drug discovery and development programs. Therefore, the work is expected to have a broad and positive impact on chemistry, biology, and medicine.

Public Health Relevance

The project is directed toward the discovery and development of new anti-infective agents through the total synthesis of naturally occurring anti-infective compounds, molecular design and chemical synthesis of analogs of these substances, and biological investigations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI055475-12
Application #
8476193
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Xu, Zuoyu
Project Start
2002-09-30
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$488,217
Indirect Cost
$167,018
Name
Rice University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
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
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, Kyriacos C; Valiulin, Roman A (2013) Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents. Org Biomol Chem 11:4154-63
Nicolaou, K C; Nilewski, Christian; Hale, Christopher R H et al. (2013) Total synthesis and structural revision of viridicatumtoxin B. Angew Chem Int Ed Engl 52:8736-41
Nicolaou, K C; Yu, Ruocheng; Shi, Lei et al. (2013) General synthetic approach to functionalized dihydrooxepines. Org Lett 15:1994-7
Nicolaou, K C; Hale, Christopher R H; Ebner, Christian et al. (2012) Synthesis of macroheterocycles through intramolecular oxidative coupling of furanoid ýý-ketoesters. Angew Chem Int Ed Engl 51:4726-30
Nicolaou, K C; Valiulin, Roman A; Pokorski, Jonathan K et al. (2012) Bio-inspired synthesis and biological evaluation of a colchicine-related compound library. Bioorg Med Chem Lett 22:3776-80
Nicolaou, K C; Adsool, Vikrant A; Hale, Christopher R H (2011) An expedient synthesis of a functionalized core structure of bielschowskysin. Angew Chem Int Ed Engl 50:5149-52
Nicolaou, K C; Kiappes, J L; Tian, Weiwei et al. (2011) Synthesis of the carboline disaccharide domain of shishijimicin A. Org Lett 13:3924-7
Nicolaou, K C; Simmons, Nicholas L; Chen, Jason S et al. (2011) Total synthesis and biological evaluation of marinopyrrole A and analogues. Tetrahedron Lett 52:2041-2043

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