[Design and synthesis of inhibitors of biologically relevent enzymes]

Author

Sam F. Victory

Date of Award

8-1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Chemistry

Major Professor

David C. Baker

Committee Members

Elizabeth E. Howell

Abstract

This dissertation describes two different studies having the goal of the design and synthesis of inhibitors of biologically relevant enzymes. In the first study, the synthesis of a heavy-atom-containing analogue of the potent adenosine deaminase inhibitor 2'- deoxycoformycin was accomplished as a potential probe to further define the catalytic mechanism by which adenosine deaminase catalyzes the deamination of adenosine, as well as to further understand the interactions between adenosine deaminase and the coformycin series of enzyme inhibitors.

The second study describes the development of a recently isolated natural product, (+)-calanolide A, as well as its analogues as non-nucleoside inhibitors of the reverse transcriptase enzyme of the human immunodeficiency virus type-1 (HIV-1). (+)-Calanolide A is a dipyranocoumarin recently isolated from the extracts of the leaves and twigs of the Malaysian rainforest tree Calophyllum lanigerum. It was found to be a potent and specific inhibitor of the HIV-1 reverse transcriptase enzyme. More significantly, it was identified to be an excellent inhibitor of the pyridinone-resistant A17 strain of HIV, which is cross resistant to most other non-nucleoside inhibitors.

This study first investigated the design and synthesis of structurally simplified analogues of (+)-calanolide A in their racemic form as possible compounds for drug development. Next, the racemic syntheses of compounds possessing the full dipyranocoumarin ring system of the calanolides were carried out. This was followed by attempts to separate (±)-calanolide A into its separate enantiomers using several strategies in an effort to obtain (+)-calanolide A in its optically pure form. Finally, molecular modeling studies of the calanolides and their analogues were carried out in an effort to develop a pharmacophore model of the calanolides. Development of this model was useful for designing further analogues of the calanolides.

Recommended Citation

Victory, Sam F., "[Design and synthesis of inhibitors of biologically relevent enzymes]. " PhD diss., University of Tennessee, 1998.
https://trace.tennessee.edu/utk_graddiss/9394