Abstract

The development of synthetic methodology for formation of alkaloids and related compounds which have established or potential use in chemotherapy. Novel reaction steps and reaction sequences, diasteroselectivity, enantioselectivity and new reactive intermediates will be explored in order to provide practical syntheses of selected goal compounds. Structural variations on compounds with valuable biological activity are made to provide fundamental tools for structure-activity correlations and for generation of compounds with an improved therapeutic index. A new cancer chemotherapy principle, based on conformational inversions in the vinblastine class of agents, is proposed. Synthetic studies were designed to provide the required agents for this site activation chemotherapy (SAC).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA012010-25
Application #
3163591
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1975-03-01
Project End
1990-02-28
Budget Start
1987-03-01
Budget End
1988-02-29
Support Year
25
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of Vermont & St Agric College
Department
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; 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
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
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

Showing the most recent 10 out of 15 publications