This proposal centers on the development of new tether methods to be championed in the context of complex synthetic challenges to aid in solving biologically relevant problems in order to advance current drug discovery efforts towards the ultimate goal of developing novel therapeutic agents and probes to treat human disease. While historical and traditional views toward the use of phosphates in organic synthesis were skeptical, the body of evidence provided in the last granting period has highlighted the versatilit of phosphates as synthetic tools. In tune with previous work, the development of additional tethered processes will establish these methods as practical and advantageous pathways to the total synthesis of natural products. The proposed method will serve as the cornerstone in the asymmetric synthesis of (1) IKD-8344, which has shown potent anthelmintic acvitivity, cytotoxicity and anti antifungal activity against different cell lines;(2) Reidispongiolide A, an actin-binding 26-membered macrolide that has potential in the treatment of multi- drug resistant tumors;(3) Dictyostatin, which has been shown to have antitumor/antimitotic activity against several cell lines;(4) Leustroducsin B (LSN-B), which has shown antitumor activity and has potential as a novel hematopoietic growth factor (HGF) with application to a number of hematopoietic diseases;and (5) Franklinolides A-C, which display cytotoxicity against several cancer cell lines. Taken collectively, the development of this approach represents an integrated platform for the emergence of new and powerful tether systems for use in small molecule synthesis that will aid in molecular design and chemical synthesis of analogs for biological investigations.

Public Health Relevance

This project entitled Methods for Bioactive Compound Synthesis focuses on the development of new tether-mediated synthetic methods for the construction of complex bioactive natural products. These methods will aid in the design and chemical synthesis of analogs for use in chemical biology investigations with collaborators. Ultimately, this study aims to advance current drug discovery efforts towards the goal of developing novel therapeutic agents and probes to treat human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM077309-05A1
Application #
8460397
Study Section
Special Emphasis Panel (ZRG1-BCMB-P (02))
Program Officer
Lees, Robert G
Project Start
2007-05-01
Project End
2016-11-30
Budget Start
2012-12-05
Budget End
2013-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$277,520
Indirect Cost
$87,520
Name
University of Kansas Lawrence
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Bodugam, Mahipal; Javed, Salim; Ganguly, Arghya et al. (2016) A Pot-Economical Approach to the Total Synthesis of Sch-725674. Org Lett 18:516-9
Markley, Jana L; Maitra, Soma; Hanson, Paul R (2016) Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of P-Stereogenic, Z-Configured Bicyclo[7.3.1]- and Bicyclo[8.3.1]phosphates. J Org Chem 81:899-911
Javed, Salim; Bodugam, Mahipal; Torres, Jessica et al. (2016) Modular Synthesis of Novel Macrocycles Bearing α,β-Unsaturated Chemotypes through a Series of One-Pot, Sequential Protocols. Chemistry 22:6755-8
Maitra, Soma; Bodugam, Mahipal; Javed, Salim et al. (2016) Synthesis of the C9-C25 Subunit of Spirastrellolide B. Org Lett 18:3094-7
Hanson, Paul R; Jayasinghe, Susanthi; Maitra, Soma et al. (2015) Phosphate tethers in natural product synthesis. Top Curr Chem 361:253-71
Maitra, Soma; Markley, Jana L; Chegondi, Rambabu et al. (2015) Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of Medium to Large, P-Stereogenic Bicyclo[n.3.1]phosphates. Tetrahedron 71:5734-5740
Chegondi, Rambabu; Hanson, Paul R (2015) Synthetic Studies to Lyngbouilloside: A Phosphate Tether-Mediated Synthesis of the Macrolactone Core. Tetrahedron Lett 56:3330-3333
Jayasinghe, Susanthi; Venukadasula, Phanindra K M; Hanson, Paul R (2014) An efficient, modular approach for the synthesis of (+)-strictifolione and a related natural product. Org Lett 16:122-5
Hanson, Paul R; Jayasinghe, Susanthi; Maitra, Soma et al. (2014) A modular phosphate tether-mediated divergent strategy to complex polyols. Beilstein J Org Chem 10:2332-7
Chegondi, Rambabu; Maitra, Soma; Markley, Jana L et al. (2013) Phosphate-tether-mediated ring-closing metathesis for the preparation of complex 1,3-anti-diol-containing subunits. Chemistry 19:8088-93

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