The overall goal of this research program is to develop new and broadly useful methods and strategies and to apply these to the concise and efficient syntheses of biologically-active, heterocyclic natural products and analogs thereof that will serve as potential leads for developing novel therapeutic agents. This goal will be achieved by meeting specific objectives that fall into the two main categories of methodological studies and total synthesis. In the arena of synthetic methodology, we will: (1) Establish the versatility and practicality of our unified strategy for C-aryl glycoside synthesis;(2) Develop new methods for the facile synthesis of angular xanthone and anthracene derivatives;(3) Expand the scope of enantioselective and tandem ring closing metathesis reactions;(4) Develop tandem Staudinger/aza-Wittig/Ugi multicomponent reactions for the rapid synthesis of highly substituted glycine derivatives;(5) Discover tactics to effect enantioselective 1,4-additions of aryl reagents to 2-alkyl cycloalkenones;and (6) Develop new methods for the enantioselective synthesis of 2,2,5,5-tetrasubstituted tetrahydrofurans. In the arena of target directed synthesis, we will: (1) Complete the first synthesis of 5-hydroxyaloin A, a biologically active C-aryl glycoside;(2) Complete the first synthesis of the anticancer antibiotic kidamycin;(3) Complete the first synthesis of the anticancer agent pluramycin A and selected derivatives thereof containing replacements of the epoxide side chain and the sugar residues;(4) Complete the first synthesis of the anticancer agent IB-00208 and selected derivatives thereof containing a lactam ring in place of the lactone ring and replacements of the sugar residue;(5) Complete the first synthesis of the anticancer agent lundurine B;(6) Complete the first synthesis of the anticancer agent cortistatin A and selected derivatives thereof that contain different aryl substituents and variations of the amino diol array;(7) Determine the DNA alkylating specificities and activities of pluramycin A analogs and the stability of complexes of pluramycin-modified DNA with TATA binding proteins;and (8) Submit selected compounds to Merck Research Laboratories for biological evaluation, especially for anticancer activity, and to develop SARs for pluramycin A, IB-00208, and cortistatin A analogs in cellular assays to identify new cancer and other potential drug leads.. Two aspects of the proposed research are critical to public health. Firstly, the new methods that enable the synthesis of diverse structures incorporating heterocyclic rings will be of immeasurable use to chemists in the pharmaceutical industry and will facilitate their efforts to identify and develop new drug candidates. Secondly, the targets we have identified have significant potential as leads for the development of novel anticancer agents having improved biological profiles.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031077-26
Application #
7849718
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Hagan, Ann A
Project Start
1990-12-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
26
Fiscal Year
2010
Total Cost
$315,886
Indirect Cost
Name
University of Texas Austin
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Martin, Stephen F (2017) Natural Products and Their Mimics as Targets of Opportunity for Discovery. J Org Chem 82:10757-10794
Yang, Jingyue; Knueppel, Daniel; Cheng, Bo et al. (2015) Approaches to polycyclic 1,4-dioxygenated xanthones. Application to total synthesis of the aglycone of IB-00208. Org Lett 17:114-7
Hethcox, J Caleb; Shanahan, Charles S; Martin, Stephen F (2015) Diastereoselective addition of monoorganocuprates to a chiral fumarate: reaction development and synthesis of (-)-dihydroprotolichesterinic acid. Tetrahedron 71:6361-6368
Knueppel, Daniel; Yang, Jingyue; Cheng, Bo et al. (2015) Total Synthesis of the Aglycone of IB-00208. Tetrahedron 71:5741-5757
Fang, Chao; Paull, Daniel H; Hethcox, J Caleb et al. (2013) Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst. Org Lett 15:972
Shanahan, Charles S; Fang, Chao; Paull, Daniel H et al. (2013) Asymmetric Formal Total Synthesis of the Stemofoline Alkaloids: The Evolution, Development and Application of a Catalytic Dipolar Cycloaddition Cascade. Tetrahedron 69:7592-7607
Fang, Chao; Shanahan, Charles S; Paull, Daniel H et al. (2012) Enantioselective formal total syntheses of didehydrostemofoline and isodidehydrostemofoline through a catalytic dipolar cycloaddition cascade. Angew Chem Int Ed Engl 51:10596-9
Fang, Chao; Paull, Daniel H; Hethcox, J Caleb et al. (2012) Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst. Org Lett 14:6290-3
Paull, Daniel H; Fang, Chao; Donald, James R et al. (2012) Bifunctional catalyst promotes highly enantioselective bromolactonizations to generate stereogenic C-Br bonds. J Am Chem Soc 134:11128-31
Nichols, Alexander L; Zhang, Patricia; Martin, Stephen F (2012) Concise Approach to 1,4-Dioxygenated Xanthones via Novel Application of the Moore Rearrangement. Tetrahedron 68:7591-7597

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