Tangirala, Raghuram Sundara
(2005)
CASCADE RADICAL CYCLIZATION: APPLICATION TO THE DEVELOPMENT OF NOVEL CAMPTOTHECIN ANALOGS AND A SHORT SYNTHESIS OF LUOTONIN A AND ITS ANALOGS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cascade radical cyclizations have been employed in the synthesis of several novel analogs of camptothecin and luotonin A. The mild conditions of the cyclization allowed for the synthesis of a wide variety of analogs with high functional group tolerance in a modular fashion.The asymmetric synthesis of a pyridone lactone, a key intermediate in Lavergne and Bigg¡¦s synthesis of (R)-hCPT, is described. The synthesis furnished the product in good enantiopurity (96% ee) in eleven synthetic steps starting from commercially available 2-methoxypyridine. The key reactions in this synthesis are Sharpless asymmetric epoxidation and Corey-Stille coupling. Attempts towards a more efficient synthesis of the DE-fragment of (R)-hCPT which were not successful, but led to the synthesis of novel non-lactone analogs of camptothecin are discussed. These non-lactone analogs contain either a cyclic ether or an ƒÑ,ƒÒ-unsaturated lactone in place of the ƒÑ-hydroxy-ƒÔ-lactone as the E-ring of camptothecin. Despite possessing interesting structural features, these analogs were shown to be biologically inactive in the topo I inhibition assays as well as cell growth inhibition studies.The semi-synthesis and biological evaluation of E-ring open form analogs of camptothecin was developed. This analog synthesis evolved from an interesting report by Stewart and coworkers of the X-ray crystal structure of topo I-DNA-topotecan ternary complex. Amongst the six open form analogs synthesized, the hydrazides showed activity comparable to that of camptothecin in the DNA cleavage assays. This activity may be due to the reclosure to camptothecin under the assay conditions. 20-Fluorocamptothecin was accidentally discovered upon fluorination of the tertiary alcohol of CPT with DAST at -78 ¢XC. This discovery led to the stereoselective total synthesis of racemic, 20R- and 20S-fluorocamptothecin. It was concluded from the biological data that the fluorination occurred with inversion of configuration.The total synthesis of luotonin A, a recently isolated topo I poison, and its analogs using the radical cascade cyclization strategy, was accomplished. A concise, modular approach was undertaken for the synthesis of all the analogs of luotonin A. This exercise would provide more insight into the structure-activity relationships of this new drug candidate.The development of camptothecin analogs with interesting biological properties and differing mainly in the D, E rings was the central theme of the research work described in this thesis. Knowledge acquired from this research can be used for future discovery and development of potential drug candidates.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Tangirala, Raghuram Sundara | raghu@pitt.edu | RAGHU | |
|
| ETD Committee: |
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| Date: |
6 June 2005 |
| Date Type: |
Completion |
| Defense Date: |
16 December 2004 |
| Approval Date: |
6 June 2005 |
| Submission Date: |
20 December 2004 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| 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: |
camptothecin; fluorocamptothecin; luotonin A; topoisomerase I; cascade radical cyclization; non-lactone analogs |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-12202004-155533/, etd-12202004-155533 |
| Date Deposited: |
10 Nov 2011 20:11 |
| Last Modified: |
15 Nov 2016 13:54 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10436 |
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