Abstract

This project is designed to: a. Obtain new synthetic congeners of vinblastine and vincristine, with a better therapeutic index as antileukemic agents and particularly with decreased neurotoxicity. These compounds are obtained by a new, highly effective and stereoselective synthetic reaction sequence. b. Explore tumor specific cytotoxicity, obtained by monoclonal antibody delivery of synthetic VLB congeners which are not cytotoxic but which have full VLB activity at the biochemical level of inhibition of microtubule formation and microtubule disassembly. c. Develop site activation chemotherapy based on thermal activation of atropisomeric VLB-type pro-drugs. d. Synthesized anti-multi-drug resistant agents based on observation of such activity with non-cytotoxic VLB congeners. e. Synthesized vindolinine congeners for screening as anti-AIDS agents. f. Synthesize the anti-leukemic marine indole alkaloid manzamine A and analogues for anticancer evaluation. g. Provide syntheses of compounds in the strychnine, akuammicine and tubotaiwin classes of alkaloids for anti-cancer and HIV evaluation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA012010-30
Application #
3163595
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1975-03-01
Project End
1995-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
30
Fiscal Year
1992
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; 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; 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; 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; Li, Y L; Wei, C Q (2000) Biogenetic syntheses of kopsijasminilam and deoxykopsijasminilam. J Org Chem 65:6434-40

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