Abstract

This proposal describes 8 projects in synthesis of congeners of indole alkaloids with established high biological activities. 1. Synthesis of non-cytotoxic pro-drugs, which are site selectively activated by atropisomeric (conformational) inversion to provide vinblastine-type anticancer compounds. 2. Synthesis of anticancer pro-drugs based upon high antimicrotubule activity but have the requirement of site selected activation for cell membrane penetration. 3. Synthesis of anti-multidrug resistance compounds derived from stereoisomers of vinblastine-type yohimbe-type and strychnos-type alkaloids. 4. Synthesis of vindolinine congeners as potential anti-AIDS agents. 5. Synthesis of the potent anticancer marine alkaloid manzamine-A. 6. Studies in new synthetic methodology that can be used in the above projects as well as in other syntheses of complex structures.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA012010-33
Application #
2086009
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1975-03-01
Project End
1999-02-28
Budget Start
1995-05-05
Budget End
1996-02-29
Support Year
33
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of Vermont & St Agric College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405

  Publications

Pace, Christopher J; Glick, Stanley D; Maisonneuve, Isabelle M et al. (2004) Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration. Eur J Pharmacol 492:159-67
Kuehne, Martin E; He, Liwen; Jokiel, Patrick A et al. (2003) Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents. J Med Chem 46:2716-30
Kuehne, Martin E; Bornmann, William G; Marko, Istvan et al. (2003) Syntheses and biological evaluation of vinblastine congeners. Org Biomol Chem 1:2120-36
Zhang, Wenjiang; Ramamoorthy, Yamini; Tyndale, Rachel F et al. (2003) Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro. Drug Metab Dispos 31:768-72
Zhang, Wenjiang; Ramamoorthy, Yamini; Tyndale, Rachel F et al. (2002) Metabolism of 18-methoxycoronaridine, an ibogaine analog, to 18-hydroxycoronaridine by genetically variable CYP2C19. Drug Metab Dispos 30:663-9
Gruol, Donald J; King, Miranda N; Kuehne, Martin E (2002) Evidence for the locations of distinct steroid and Vinca alkaloid interaction domains within the murine mdr1b P-glycoprotein. Mol Pharmacol 62:1238-48
Kuehne, M E; Dai, W; Li, Y L (2001) New ferrocenyl chiral auxiliary substituents for amines: applications to syntheses of mossambine and vinblastine. J Org Chem 66:1560-6
Kuehne, M E; Qin, Y; Huot, A E et al. (2001) The syntheses of 16a'-homo-leurosidine and 16a'-homo-vinblastine. Generation of atropisomers. J Org Chem 66:5317-28
Kuehne, M E; Cowen, S D; Xu, F et al. (2001) Syntheses of 5a'-homo-vinblastine and congeners designed to establish structural determinants for isolation of atropisomers. J Org Chem 66:5303-16
Kuehne, M E; Li, Y L; Wei, C Q (2000) Biogenetic syntheses of kopsijasminilam and deoxykopsijasminilam. J Org Chem 65:6434-40

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