Bressin, Robert
(2019)
DEVELOPMENT OF ANTIDOTES FOR ORGANOPHOSPHORUS POISONING AND OF ANTICANCER SPLICING REGULATORS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Development of novel small molecules with application in medicine and chemical biology are described within. One of the two projects is the development of antidotes for organophosphorus poisoning. Current therapy for organophosphorus poisoning uses combination treatment that relies on a single FDA-approved molecule in its class. Poor permeability and lack of broad-spectrum efficiency make this treatment ineffective against most organophosphorus agents. The second project is the development of small molecules that regulate splicing. Defects in the splicing machinery and aberrant splicing are common hallmarks of many human diseases, including cancer. Small molecules that regulate splicing can correct or alter gene expression to treat diseases. There are currently no approved therapies that target the human spliceosome.
The design and synthesis of pyridinium oximes as antidotes to treat organophosphorus poisoning is presented. Several strategies are employed to mitigate or remove the positive charge to produce more blood-brain barrier permeable molecules including spirocyclization and resonance delocalization. The reactivation potential of these compounds against organophosphorus agent-inhibited acetylcholinesterase is measured in vitro against a panel of nerve agents. Initial results indicate a lead compound and subsequent structure-activity-relationship studies follow. Preliminary studies in mice are also described. The lead compound from this study has been demonstrated to have broad-spectrum efficiency against a panel of nerve agents, however the permeability was not improved.
Next, the synthesis of analogs of FR901464, a natural product splicing regulator, is discussed. Meayamycin B, the most potent analog, has been previously shown to have low picomolar potency against various cancer cell lines and regulate the alternative splicing of the myeloid cell leukemia 1 pre-mRNA. We describe the development of new analogs of meayamycin B designed to improve in vivo performance. Two structural motifs probed in this study are the 4’-carbamate and the 1’-amide. Growth inhibition against several cancer cell lines are measured. The new analog meayamycin D was shown to inhibit cancer cell growth with picomolar potency and is nearly as potent as meayamycin B.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
27 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
4 April 2019 |
| Approval Date: |
27 September 2019 |
| Submission Date: |
8 May 2019 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
451 |
| 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: |
synthetic chemistry, medicinal chemistry, structure-activity-relationship |
| Date Deposited: |
27 Sep 2020 05:00 |
| Last Modified: |
27 Sep 2020 05:00 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/36688 |
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