Beard, Jacob P.
(2024)
Synthesis and Biological Evaluation of FR901464 Analogs.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
FR901464 is a cytotoxic natural product isolated from the soil bacteria, Burkholderia, and possesses low nanomolar antiproliferative activity against various cancer cell lines. FR901464 acts by binding splicing factor 3b subunit 1 (SF3B1) and PHD finger protein 5A (PHF5A), the components of the human spliceosome. Through structure-activity relationship (SAR) studies, the Koide group has developed a series of analogs, meayamycins. This dissertation outlines the continued synthetic investigation of FR901464 analogs and gives new insight into the compound binding and activity.
The first study investigates the three-dimensional conformation of meayamycin, centered around the conformation of the central tetrahydropyran ring. Four analogs were synthesized to determine that the amide-containing tetrahydropyran ring assumes only one of the two possible chair conformations. Additionally, the series of analogs bearing alkyl ethers were found to have long half-lives in mouse plasma and showed strong synergism in drug-resistant lung cancer cells.
The second study outlines the investigation of the enamide moiety in meayamycin. Analysis of the crystal structure places this motif in a narrow region of the binding pocket. Two new analogs were synthesized bearing a methyl substituent on the α or β position of the amide. With these analogs, discrete interactions within the narrow region of SF3B1 were investigated using a human/yeast chimeric SF3B1 protein, and the V1078 residue of SF3B1 was found to affect compound binding.
The third study follows insights from the close association of the V1078 residue in SF3B1. Analysis of the sequence alignment in many pathogenic fungal species revealed that the valine residue is replaced by asparagine. Four new analogs bearing substitutions at the C3' and C5' positions were synthesized to target this residue. Cell proliferation assays indicate these analogs are sterically constrained at both positions, with the C5' tolerant of less bulky substituents.
Finally, the last study investigates the scalable preparation of the central tetrahydropyran ring fragment. The protecting group for the amine was changed from Boc to tosyl, improving yields and the time economy. The revised synthetic scheme highlights the use of nontraditional Birch reduction conditions for N-detosylation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
27 August 2024 |
| Date Type: |
Publication |
| Defense Date: |
15 July 2024 |
| Approval Date: |
27 August 2024 |
| Submission Date: |
9 August 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
570 |
| 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 Aug 2024 13:05 |
| Last Modified: |
27 Aug 2024 13:05 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46907 |
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Synthesis and Biological Evaluation of FR901464 Analogs. (deposited 27 Aug 2024 13:05)
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