The overall objective of this research program involves the development of general, broadly applicable methods for the synthesis of novel heterocyclic systems. Emphasis is to be placed on the use of 1,3- dipolar cycloaddition chemistry for the construction of a variety of biologically interesting molecules. Among the reactions to be studied are dipolar cycloadditions of carbonyl ylides, azomethine ylides, thiocarbonyl ylides, and mesoionic dipoles. The project will focus on using the rhodium catalyzed reaction of alpha-diazo carbonyl compounds as a method for generating a variety of 1,3-dipoles. It is intended to use the dipolar cycloaddition reaction of a five ring cyclic carbonyl ylide dipole as the key step for the construction of the illudin/ ptaquilosin skeleton. This strategy is to provide for a rapid assembly of the basic core unit of the target molecules having most of the functionality in place. The principal investigator notes that because of their extreme toxicity and consequent low therapeutic index, it seems reasonable to him to modify the basic skeletons so as to reduce cytotoxicity without compromising antitumor activity. His intention is synthesize analogs of these compounds so as to evaluate their DNA cleaving abilities. It is noted that the synthetic analogs may be more stable and more easily available than the natural compounds. The tandem cyclization-cycloaddition chemistry to be developed will also be used for the synthesis of complex alkaloids and to provide quantities of material needed for detailed biological assay. It is reported that many alkaloids have been shown to be carcinogenic and mutagenic and their metabolites are known to react with DNA and other cellular nucleophiles. The principal investigator notes that it should be possible to construct analogs of alkaloids which may be selective enough in their administered form to reach the active sites of tumor cell growth and possess proper alkylating ability to interfere with DNA replication. It is the goal of this proposal to seek support for the preparation of such analogs, which are to be submitted to the NIH for determination of structure activity relationships in the treatment of various cancers. It is stated that the generation of biologically-active compounds by synthesis remains an important part of both health related and chemical research.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059384-23
Application #
6520026
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1999-05-01
Project End
2004-08-02
Budget Start
2002-05-01
Budget End
2004-08-02
Support Year
23
Fiscal Year
2002
Total Cost
$238,444
Indirect Cost
Name
Emory University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
England, Dylan B; Eagan, James M; Merey, Gokce et al. (2008) The Rhodium(II) Carbenoid Cyclization-Cycloaddition Cascade of alpha-Diazo Dihydroindolinones for the Synthesis of Novel Azapolycyclic Ring Systems. Tetrahedron 64:988-1001
England, Dylan B; Merey, Gokce; Padwa, Albert (2007) Substitution and cyclization reactions involving the quasi-antiaromatic 2H-indol-2-one ring system. Org Lett 9:3805-7
Rose, Mickea D; Cassidy, Michael P; Rashatasakhon, Paitoon et al. (2007) Acid-promoted cyclization reactions of tetrahydroindolinones. Model studies for possible application in a synthesis of selaginoidine. J Org Chem 72:538-49
England, Dylan B; Padwa, Albert (2007) Synthesis of (+/-)-3H-epivincamine via a Rh(II)-triggered cyclization/cycloaddition cascade. Org Lett 9:3249-52
Zhang, Hongjun; Boonsombat, Jutatip; Padwa, Albert (2007) Total synthesis of (+/-)-strychnine via a [4 + 2]-cycloaddition/rearrangement cascade. Org Lett 9:279-82
Padwa, Albert; Boonsombat, Jutatip; Rashatasakhon, Paitoon (2007) An Approach Toward Oxidopyrylium Ylides Using Rh(II)-Catalyzed Cyclization Chemistry. Tetrahedron Lett 48:5938-5941
Hong, Xuechuan; France, Stefan; Padwa, Albert (2007) A Dipolar Cycloaddition Approach Toward the Kopsifoline Alkaloid Framework. Tetrahedron 63:5962-5976
Padwa, Albert; Bur, Scott K (2007) The Domino Way to Heterocycles. Tetrahedron 63:5341-5378
Padwa, Albert; Zhang, Hongjun (2007) Synthesis of some members of the hydroxylated phenanthridone subclass of the Amaryllidaceae alkaloid family. J Org Chem 72:2570-82
Padwa, Albert; Crawford, Kenneth R; Straub, Christopher S et al. (2006) Halo substituent effects on intramolecular cycloadditions involving furanyl amides. J Org Chem 71:5432-9

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