Biomimetic Synthesis of Complex Natural Products The goals of the proposed continuing research program are to develop novel synthetic methods and biomimetic approaches to important classes of bioactive agents, as well as to evaluate compounds in strategic biological collaborations. Approaches include catalytic, asymmetric photocycloadditions using chiral trifluoroethanol catalysis guided by excited state computational analysis, syntheses of bioactive natural products using oxidative dearomatization with bis(?-oxo)dicopper(III) complexes including efforts towards catalytic asymmetric oxidations, and reductive isomerization of ?-alkynyl enones to vinyl allenones and subsequent cycloadditions to access vinylallene-derived natural products. The Principal Investigator, Professor John Porco, and his colleagues will use these new methodologies to synthesize bioactive natural products including the antitumor agents aglaiastatin, sorbicillactone A, chloropestolide A, and the antivira agent humulone. In collaborative studies with investigators at Boston University, the National Cancer Institute (NCI), the Novartis Institutes for BioMedical Research, McGill University, and the Whitehead Institute, Porco and his colleagues will assay the biological activity of the produced compounds. This proposed effort is organized into three core projects with the following aims: """""""" Develop catalytic asymmetric photocycloadditions of 3-hydroxyflavones and achieve asymmetric syntheses of the aglains foveoglin A and perviridisin B and the rocaglates aglaiastatin and aglaroxin. """""""" Complete asymmetric syntheses of (-)-sorbicillactone A, bisvertinolone and isobisvertinol, sorbifuranones A and C, and humulone and variants. """""""" Complete asymmetric syntheses of the antitumor natural products iso-A82775C, pestalofones B and C, chloropestolide A, and chloropupukeananin. This work will carry forward a highly productive research program for Professor Porco and his coworkers. Through their continued collaborations with biological researchers to assess bioactive natural products and derivatives, this new project will lead to the translation of such compounds into evaluation in clinical setting.

Public Health Relevance

Biomimetic Synthesis of Complex Natural Products The goals of the proposed continuing research program are to develop novel synthetic methods and biomimetic approaches to access important classes of bioactive agents and to explore fundamental questions of compound mechanism of action in strategic biological collaborations. The relevance to public health of the planned studies entails identification of novel, biologically active agents for use as pharmacological therapies for both viral illnesses and human cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM073855-09
Application #
8761517
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2006-02-01
Project End
2018-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Boston University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Qi, Chao; Xiong, Yuan; Eschenbrenner-Lux, Vincent et al. (2016) Asymmetric Syntheses of the Flavonoid Diels-Alder Natural Products Sanggenons C and O. J Am Chem Soc 138:798-801
Chu, Jennifer; Cencic, Regina; Wang, Wenyu et al. (2016) Translation Inhibition by Rocaglates Is Independent of eIF4E Phosphorylation Status. Mol Cancer Ther 15:136-41
Kärkäs, Markus D; Porco Jr, John A; Stephenson, Corey R J (2016) Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis. Chem Rev 116:9683-747
Bhattacharya, Bidisha; Chatterjee, Sujoy; Devine, William G et al. (2016) Fine-tuning of macrophage activation using synthetic rocaglate derivatives. Sci Rep 6:24409
Gandin, Valentina; Masvidal, Laia; Hulea, Laura et al. (2016) nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs. Genome Res 26:636-48
Gervais, Anais; Lazarski, Kiel E; Porco Jr, John A (2015) Divergent Total Syntheses of Rhodomyrtosones A and B. J Org Chem 80:9584-91
Qin, Tian; Iwata, Takayuki; Ransom, Tanya T et al. (2015) Syntheses of Dimeric Tetrahydroxanthones with Varied Linkages: Investigation of ""Shapeshifting"" Properties. J Am Chem Soc 137:15225-33
Stone, Steven D; Lajkiewicz, Neil J; Whitesell, Luke et al. (2015) Biomimetic kinetic resolution: highly enantio- and diastereoselective transfer hydrogenation of aglain ketones to access flavagline natural products. J Am Chem Soc 137:525-30
Liu, Shufeng; Wang, Wenyu; Brown, Lauren E et al. (2015) A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway. EBioMedicine 2:1600-6
Wolfe, Andrew L; Singh, Kamini; Zhong, Yi et al. (2014) RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513:65-70

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