The goals of the proposed MIRA (R35) research program are to continue chemical syntheses of bioactive molecules and expand our efforts and capabilities in translational science. The MIRA effort will allow flexibility and stability to enabe important new research directions that come up during the course of research. Our two NIGMS-funded RO1 grants (Biomimetic Synthesis of Complex Natural Products (GM-073855) and Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products) have been highly productive and have led to 41 publications from 2015 - 2010. These include 19 collaborative manuscripts with clinical and biological investigators. As part of our studies, we have taken opportunities to address key questions and contemporary needs in organic chemistry including asymmetric catalysis of photocycloadditions, enantioselective dearomatization, and atropselective synthesis. Key accomplishments in the past five years include asymmetric photocycloadditions of 3-hydroxyflavones to access rocaglate antitumor agents, synthesis of derivatives of the tubulin inhibitor chamaecypanone C using copper-mediated enantioselective oxidative dearomatization, synthesis of the anticancer agents and antibiotics kibdelones A and C using Pt(IV)-mediated arylations of quinone monoketals, and synthesis of the antibiotic rugulotrosin A employing vinylogous addition of siloxyfurans to chromones and atropselective dimerization. As part of the proposed MIRA project, the Principal Investigator Professor John Porco and colleagues will continue development of novel synthetic methodologies for concise entry to bioactive classes of natural products including oxaphenalenones, meroterpenoids, polyprenylated acylphloroglucinols, tetrahydroxanthones, and dimeric chromones. The project will continue major emphasis on collaborations to study biological properties and mode of action (MoA) of target molecules for ultimate use as pharmacological therapies for human cancers as well as viral and bacterial illnesses. It is anticipated that the MIRA effort will allow us to continue development of innovative syntheses of complex natural products and derivatives and continue work to highly interface these studies with applications of compounds in clinical and translational research.

Public Health Relevance

The goals of the proposed MIRA (R35) research program are to develop novel synthetic methods and expedient approaches to access important, unstudied classes of bioactive natural products 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 human cancers as well as viral and bacterial illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM118173-05
Application #
9920757
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Bond, Michelle Rueffer
Project Start
2016-05-01
Project End
2021-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Boston University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Wu, Xiaowei; Iwata, Takayuki; Scharf, Adam et al. (2018) Asymmetric Synthesis of Gonytolide A: Strategic Use of an Aryl Halide Blocking Group for Oxidative Coupling. J Am Chem Soc 140:5969-5975
Qi, Chao; Wang, Wenyu; Reichl, Kyle D et al. (2018) Total Synthesis of Aurofusarin: Studies on the Atropisomeric Stability of Bis-Naphthoquinones. Angew Chem Int Ed Engl 57:2101-2104
Langlais, David; Cencic, Regina; Moradin, Neda et al. (2018) Rocaglates as dual-targeting agents for experimental cerebral malaria. Proc Natl Acad Sci U S A 115:E2366-E2375
Smith, Michael J; Reichl, Kyle D; Escobar, Randolph A et al. (2018) Asymmetric Synthesis of Griffipavixanthone Employing a Chiral Phosphoric Acid-Catalyzed Cycloaddition. J Am Chem Soc :
Zhang, Wenhan; Liu, Shufeng; Maiga, Rayelle I et al. (2018) Chemical Synthesis Enables Structural Reengineering of Aglaroxin C Leading to Inhibition Bias for HCV Infection. J Am Chem Soc :
Qin, Xu-Jie; Feng, Mi-Yan; Liu, Hui et al. (2018) Eucalyptusdimers A-C, Dimeric Phloroglucinol-Phellandrene Meroterpenoids from Eucalyptus robusta. Org Lett 20:5066-5070
Wang, Wenyu; Clay, Anthony; Krishnan, Retheesh et al. (2017) Total Syntheses of the Isomeric Aglain Natural Products Foveoglin?A and Perviridisin?B: Selective Excited-State Intramolecular Proton-Transfer Photocycloaddition. Angew Chem Int Ed Engl 56:14479-14482
Manier, Salomon; Huynh, Daisy; Shen, Yu J et al. (2017) Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma. Sci Transl Med 9:
Yueh, Han; Gao, Qiwen; Porco Jr, John A et al. (2017) A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues. Bioorg Med Chem 25:6197-6202
Reichl, Kyle D; Smith, Michael J; Song, Min K et al. (2017) Biomimetic Total Synthesis of (±)-Griffipavixanthone via a Cationic Cycloaddition-Cyclization Cascade. J Am Chem Soc 139:14053-14056

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