The goal of this proposed program is to develop new and broadly useful synthetic methods and strategies and apply these to preparing biologically active alkaloids and other nitrogen containing compounds that serve as potential leads for developing novel therapeutic agents. The specific objectives fall into the categories of methodological studies and total synthesis. In the arena of synthetic methodology, we will develop: (1) new tactics to prepare y-ylidenetetronates, key subunits in biologically active compounds;(2) new procedures for generating and reacting azomethine, carbonyl and thiocarbonyl ylids as a novel entry to nitrogen, oxygen and sulfur heterocycles;(3) new protocols for enantioselective introduction of functionalized alkyl substituents onto electron rich heterocycles and aromatic rings;and (4) new means for effecting diastereoselective, oxidative rearrangements of indoles to oxindoles. In the arena of target directed synthesis, we will: (1) develop the first enantioselective route to didehydrostemofoline, a novel alkaloid having potent anticancer and anti-oxytocin activity;(2) complete the first synthesis of (-)-/V- methylwelwitindolinone C isothiocyanate, an unusual alkaloid that reverses multiple drug resistance in cancer cell lines;and (3) complete the first synthesis of (-)-citrinadin A, an unusual pentacyclic alkaloid that exhibits promising anticancer activity. The synthetic routes to each of the natural products has been uniquely designed so analogs may be easily prepared to conduct critical SAR studies that will establish some essential features for optimal biological activity. Derivatives of the natural products and selected synthetic intermediates will be submitted to Abbott Laboratories and Merck Research Laboratories for biological evaluation for anticancer activity. Two aspects of the proposed research are critical to public health. Firstly, the new methods for synthesizing heterocycles having diverse structures will be of great use to chemists in the pharmaceutical industry in their efforts to identify new drug candidates. Secondly, the synthetic targets we have identified have significant potential as leads for the development of novel anticancer agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM025439-27
Application #
7781375
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Hagan, Ann A
Project Start
1979-01-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
27
Fiscal Year
2010
Total Cost
$263,934
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
Cheng, Bo; Sunderhaus, James D; Martin, Stephen F (2015) Applications of Ring Closing Metathesis. Total Synthesis of (±)-Pseudotabersonine. Tetrahedron 71:7323-7331
Bian, Zhiguo; Marvin, Christopher C; Pettersson, Martin et al. (2014) Enantioselective total syntheses of citrinadins A and B. Stereochemical revision of their assigned structures. J Am Chem Soc 136:14184-92
Granger, Brett A; Jewett, Ivan T; Butler, Jeffrey D et al. (2014) Concise total synthesis of (±)-actinophyllic acid. Tetrahedron 70:4094-4104
Hethcox, J Caleb; Shanahan, Charles S; Martin, Stephen F (2013) Total synthesis of (-)-dihydroprotolichesterenic acid via diastereoselective conjugate addition to chiral fumarates. Tetrahedron Lett 54:2074-2076
Fu, Tsung-Hao; McElroy, William T; Shamszad, Mariam et al. (2013) Studies toward welwitindolinones: formal syntheses of N-methylwelwitindolinone C isothiocyanate and related natural products. Tetrahedron 69:5588-5603
Granger, Brett A; Jewett, Ivan T; Butler, Jeffrey D et al. (2013) Synthesis of (±)-actinophyllic acid and analogs: applications of cascade reactions and diverted total synthesis. J Am Chem Soc 135:12984-6
Bian, Zhiguo; Marvin, Christopher C; Martin, Stephen F (2013) Enantioselective total synthesis of (-)-citrinadin A and revision of its stereochemical structure. J Am Chem Soc 135:10886-9
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
Granger, Brett A; Wang, Zhiqian; Kaneda, Kyosuke et al. (2013) Multicomponent assembly processes for the synthesis of diverse yohimbine and corynanthe alkaloid analogues. ACS Comb Sci 15:379-86

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