Chemical synthesis of natural products inspired by their biogenesis is appealing due to the possibility to formulate biosynthetic hypotheses and invent the appropriate synthetic methodology to access synthetic targets. The proposed chemical synthesis studies should lead to the identification of novel, bioactive molecules and pharmacological tools. The overall goal of the project is to develop and refine biomimetic syntheses using copper-mediated enantioselective oxidation processes (Project 1), photochemical cycloaddition employing excited state intramolecular proton transfer (ESIPT) (Project 2), and asymmetric reactions of acylphloroglucinols (Project 3). Professor Porco and colleagues will apply these methodologies to the chemical synthesis of complex natural products including bisorbicillinol, sorbicillactone A, aglaiastatin, ponapensin, and myrtucommulones A and B. A collaboration in place with Professor Linda Doerrer (Boston University) will continue mechanistic investigations to understand the copper-mediated enantioselective oxygenase and oxidase processes. Likewise, a continuing collaboration with Professor Eric N. Jacobsen and coworkers (Harvard University) will seek to identify chiral thiourea photocatalysts for asymmetric photocycloadditions. Collaborations are also in place with biological collaborators including Dr. John A. Beutler (National Cancer Institute) and Professor Jerry Pelletier (McGill University) to evaluate compounds as anticancer agents and protein translation inhibitors.
The aims of the proposed project are to: 1) Synthesize the telomerase inhibitor (-) diazaphilonic acid, achieve the enantioselective syntheses of bisorbicillinol and bisvertilone using asymmetric oxidative dearomatization, achieve the enantioselective synthesis of the antileukemic agent sorbicillactone A, undertake mechanistic studies for copper-mediated oxidations using UV and Raman spectroscopy, and develop asymmetric oxidative dimerization of hydroxystyrene monomers to access 2,3-dihydrobenzofuran natural products. 2) Develop catalytic asymmetric photocycloaddition approaches to rocaglamide and related natural products employing chiral thioureas, achieve the syntheses of the aglain natural products ponapensin and foveoglin A and the rocaglates aglaiastatin and aglaroxin, and evaluate rocaglate and aglain compounds as protein translation inhibitors. 3) Develop asymmetric syntheses of the acylphloroglucinol natural products myrtucommulones A and B using chiral phase transfer catalysis and synthesize the natural product bullataketal A.

Public Health Relevance

This competing renewal application reflects the continuing interest of the Principal Investigator, John A. Porco, Jr., and colleagues in new chemical reaction development and synthesis of biorelevant molecules using approaches inspired by the biogenesis of complex natural products. The planned syntheses of complex natural products and derivatives are highly relevant to public health by facilitating identification of novel, bioactive molecules. The products of the proposed research ultimately should be useful as novel pharmacological tools and cytotoxic agents for treatment of various prevalent human malignancies, including human cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073855-07
Application #
8231446
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2006-02-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
7
Fiscal Year
2012
Total Cost
$323,994
Indirect Cost
$125,994
Name
Boston University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
049435266
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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