Structurally novel classes of natural products serve as leads for this program in that it combines total synthesis, reaction development, drug design, and structural biology. The lead structures for both components of this program are small, uncharged, rigid molecules with few hydrogen bonds and few rotatable bonds. Therefore both should provide attractive scaffolds for libraries of compounds that fulfill the criteria of Veber and Lipinski for solubility and permeability. SNF 4435C and D are natural products that demonstrate both immunosuppressive and multidrug resistance (mdr) reversal activity. SNF4435C is also active in vivo, enhancing the efficacy of vincristine treatment in mice that carry vincristine-resistant P388 leukemia. Our group has completed an asymmetric total synthesis of SNF 4435C and D. We have also prepared simple analogs that have mdr reversal activity in cells that overexpress the multidrug transporter P-glycoprotein. Efforts now will focus on the preparation of more potent mdr reversal agents that lack immunosuppressant activity and more potent immunosuppressants that do not inhibit multidrug transporters. Both molecular modeling and structure-activity approaches will be pursued. Biological activities will be monitored by mdr reversal assays, by drug efflux assays, and by flow cytometric analysis of immunosuppression. We will attempt to identify the mechanism of immunosuppression. Selected synthetic compounds will be examined for their ability to stabilize crystals of P- glycoprotein for x-ray crystallographic studies. The bisabosquals are inhibitors of yeast squalene synthase and have potential as leads for the development of antihypercholesteremics. Completion of the total synthesis will provide ground rules for the preparation of related structures. Molecular modeling will allow the design of candidates for more active drugs. Candidates will be evaluated in the squalene synthase assay. Collaborations for the medicinal chemistry components of the project have been arranged.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM074776-04
Application #
7650272
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2006-05-01
Project End
2011-10-31
Budget Start
2009-05-01
Budget End
2011-10-31
Support Year
4
Fiscal Year
2009
Total Cost
$286,046
Indirect Cost
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Elliott, Daniel C; Beutler, John A; Parker, Kathlyn A (2017) Importance of a 4-Alkyl Substituent for Activity in the Englerin Series. ACS Med Chem Lett 8:746-750
Parker, Kathlyn A; Sampson, Nicole S (2016) Precision Synthesis of Alternating Copolymers via Ring-Opening Polymerization of 1-Substituted Cyclobutenes. Acc Chem Res 49:408-17
Lim, Hee Nam; Parker, Kathlyn A (2014) Intermolecular radical cation Diels-Alder (RCDA) reaction of bicyclooctadienes: biomimetic formal total synthesis of kingianin A and total syntheses of kingianins D, F, H, and J. J Org Chem 79:919-26
am Ende, Christopher W; Zhou, Zhou; Parker, Kathlyn A (2013) Total synthesis of (ýý)-bisabosqual A. J Am Chem Soc 135:582-5
Lim, Hee Nam; Parker, Kathlyn A (2013) Total synthesis of kingianin A. Org Lett 15:398-401
Lee, Jungyong; Parker, Kathlyn A (2012) A formal synthesis of (-)-englerin A by relay ring closing metathesis and transannular etherification. Org Lett 14:2682-5
Kim, Keunsoo; Lauher, Joseph W; Parker, Kathlyn A (2012) Asymmetric induction in 8ýý electrocyclizations. Design of a removable chiral auxiliary. Org Lett 14:138-41
Song, Airong; Walker, Stephen G; Parker, Kathlyn A et al. (2011) Antibacterial studies of cationic polymers with alternating, random, and uniform backbones. ACS Chem Biol 6:590-9
Lim, Hee Nam; Parker, Kathlyn A (2011) Total synthesis of the potent androgen receptor antagonist (-)-arabilin: a strategic, biomimetic [1,7]-hydrogen shift. J Am Chem Soc 133:20149-51
Parker, Kathlyn A; Mindt, Thomas L (2011) Convergent Synthesis of 2H-Chromenes - a Formal [3+3] Cycloaddition by a One-pot, Three-Step Cascade. Tetrahedron 67:9779-9786

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