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)
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
Project End
Budget Start
Budget End
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
Lajkiewicz, Neil J; Cognetta 3rd, Armand B; Niphakis, Micah J et al. (2014) Remodeling natural products: chemistry and serine hydrolase activity of a rocaglate-derived ?-lactone. J Am Chem Soc 136:2659-64
Boyce, Jonathan H; Porco Jr, John A (2014) Asymmetric, stereodivergent synthesis of (-)-clusianone utilizing a biomimetic cationic cyclization. Angew Chem Int Ed Engl 53:7832-7
Grenning, Alexander J; Boyce, Jonathan H; Porco Jr, John A (2014) Rapid synthesis of polyprenylated acylphloroglucinol analogs via dearomative conjunctive allylic annulation. J Am Chem Soc 136:11799-804
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Robert, Francis; Roman, William; Bramoullé, Alexandre et al. (2014) Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma. Proc Natl Acad Sci U S A 111:13421-6
Zhu, Lijia; Qi, Ji; Chiao, Christine Ya-Chi et al. (2014) Identification of a novel polyprenylated acylphloroglucinol?derived SIRT1 inhibitor with cancer?specific anti-proliferative and invasion-suppressing activities. Int J Oncol 45:2128-36
Qi, Chao; Qin, Tian; Suzuki, Daisuke et al. (2014) Total synthesis and stereochemical assignment of (±)-sorbiterrin A. J Am Chem Soc 136:3374-7
Jin, C; Rajabi, H; Rodrigo, C M et al. (2013) Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein. Oncogene 32:2179-88
Nasr, Z; Robert, F; Porco Jr, J A et al. (2013) eIF4F suppression in breast cancer affects maintenance and progression. Oncogene 32:861-71
Sadlish, Heather; Galicia-Vazquez, Gabriela; Paris, C Gregory et al. (2013) Evidence for a functionally relevant rocaglamide binding site on the eIF4A-RNA complex. ACS Chem Biol 8:1519-27

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