Smith, Sara E
(2014)
Metabolism In Vitro of the Microtubule Perturbagens: Ceratamines A and B.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Ceratamines A and B are heterocyclic alkaloids isolated from a Pseudoceratina sp. marine sponge. These natural products behave as antimitotic agents by targeting microtubules, specifically through a stabilization mechanism. Their identification led to the discovery of a novel class of structurally simple microtubule stabilizers, with implications in the treatment of cancer and perhaps tauopathies, including Alzheimer’s disease. To date, no pre-clinical studies of the ceratamines have been reported. Therefore, I determined the phase I metabolism of each compound in vitro. Ceratamine A is rapidly metabolized into nine phase I metabolites by rat liver microsomes, while ceratamine B only yielded five metabolites. The majority of these metabolites were formed as a result of N- and O-dealkylations. While the metabolites formed from both compounds were similar when incubated with human liver microsomes, the major metabolites were not the same as those from rat liver microsomes. The aminoimidazole is the most metabolically labile site in rat liver microsomes, however the dibrominated aromatic moiety is the preferred site for metabolism in human liver microsomes. A metabolic stability assay revealed that both compounds have a high estimated clearance in rat liver microsomes, but they appear to be more stable in human liver microsomes. Ceratamine B was estimated to have a moderate clearance, while ceratamine A was found to have a low clearance. Finally, isozyme mapping and small molecule inhibition studies revealed that the specific P450 isoforms responsible for the formation of two major metabolites of ceratamine B in human liver microsomes is CYP3A4/5.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
25 September 2014 |
| Date Type: |
Publication |
| Defense Date: |
30 July 2014 |
| Approval Date: |
25 September 2014 |
| Submission Date: |
8 August 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
117 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
analytical chemistry; drug discovery; mass spectrometry; structure elucidation; in vitro metabolism; anticancer agents |
| Date Deposited: |
25 Sep 2014 14:23 |
| Last Modified: |
15 Nov 2016 14:22 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/22634 |
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