Osman, Sami
(2012)
SYNTHETIC AND BIOLOGICAL STUDIES ON ANALOGUES OF FR901464 AND TMC-205.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
FR901464 is a natural product that elicits anticancer activity via inhibition of pre-mRNA splicing, a novel therapeutic approach. Through structure-activity relationship (SAR) studies on FR901464, the Koide group reported a potent stable synthetic analogue of FR901464, meayamycin B (GI50 4 – 211 pM).
An objective of this thesis was to probe electrophilic sites of meayamycin B through SAR anaylsis. This studies in this thesis provided insights into the effects of cis-C2´-C3´ enamide and epoxide moieties. A newly synthesized inhibitor, in which the epoxide was replaced with a ketone, exhibited elevated inhibition against cellular proliferation. Cell growth assays illustrated that this analogue inhibited the proliferation of cells in an irreversible manner.
Addtionally, an in vivo study led to the development of meayamycin C which, although less potent than meayamycin and meayamycin B, exhibited single digit nanomolar GI50 values and selectivity to inhibit the proliferation of certain human cancer cells.
Continuing with the design of pre-mRNA splicing inhibition tools, we also report the preparation and evaluation of two tetraethylene-linked derivatives of meayamycin. These two derivatives inhibited the proliferation of human cell lines and pre-mRNA splicing in cells. Structurally, one of the derivatives is far less complex than tetraethylene glycol-linked meayamycin, though still retained sufficient inhibitory activity towards cell proliferation and pre-mRNA splicing. These two compounds have the potential serve as starting points for conjugatable FR901464 analogues.
Furthermore, a new synthetic route for meayamycin is described. The new route consists of 8 steps to prepare the western fragment, followed by a final cross metathesis interchange strategy between the right half and FR901464 to yield meayamycin. This is the shortest synthetic approach to prepare meayamycin.
Finally, a study was begun on TMC-205, which was discovered in 2001 in a similar manner to FR901464. The work in this dissertation reports the first synthesis of TMC-205 and developed analogues, including alcohol 3.21, an eight-fold more potent analogue of TMC-205. Importantly, there is a range of TMC-205 and analogue 3.13 concentrations where the compounds activate an SV40-controlled gene without detectable antiproliferative activity.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
9 October 2012 |
| Date Type: |
Publication |
| Defense Date: |
16 August 2012 |
| Approval Date: |
9 October 2012 |
| Submission Date: |
24 August 2012 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
362 |
| 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: |
FR901464, TMC-205 |
| Date Deposited: |
09 Oct 2012 18:35 |
| Last Modified: |
09 Oct 2017 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13738 |
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