Synthesis and Biological Evaluation of Open-Chain Epothilones
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University of Toledo Health Science Campus / OhioLINK
2012
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=mco1342626312 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-mco13426263122021-08-03T05:38:54Z Synthesis and Biological Evaluation of Open-Chain Epothilones Fedorka, Sara R. Organic Chemistry Pharmacy Sciences Epothilones non-small cell lung cancer microtubule-stabilizing agents Steglich esterification <p>Epothilones are naturally occurring anticancer agents that inhibit the growth of cancer cells through the stabilization of microtubules, which leads to the arrest of cell division in the G2/M phase. They have captured the attention of the scientific community due to the similarity of their mechanism of action to the blockbuster drug paclitaxel. Many macrocyclic epothilone analogues have been synthesized and tested for anticancer activity against a variety of cell lines including breast, ovarian, and prostate cancers. </p><p>We have successfully synthesized several open-chain epothilones analogues where the C9-C14 sector of cyclic epothilones has been deleted and the molecule rigidified with a cyclopentene molecular scaffold. The methyl group at C20 was replaced with different 2-substituted thiazole moieties of varying degrees of size and electronic properties. Steglich esterification reaction conditions were utilized to couple the acyl and alcohol precursors that were synthesized separately. The cytotoxicity of these open-chain epothilones was screened in the National Cancer Institute’s 60 cell line assay. An acetylene substituted open-chain epothilone analogue showed selective activity predominately against lung cancer cell NCI-H522 and to a lesser extent on melanoma cancer cell line LOX IMVI, ovarian cancer cell line IGROV1, and renal cancer cell line UO-31.</p><p>We also synthesized precursors to an open-chain epothilone with hydrophobic substitutions at C10 and C14. Preliminary solution molecular dynamic simulations have shown that these hydrophobic functionalities impose further conformational constraint in aqueous media due to hydrophobic collapse; which we hypothesize may lead to a biological conformation similar to macrocyclic epothilones. The acyl moiety with a phenyl substitution at C10 is synthesized by diastereoselective Aldol reaction, while substituents at C14 are incorporated through enolate alkylation of previously synthesized 2-substituted cyclopentenones.</p> 2012-09-04 English text University of Toledo Health Science Campus / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=mco1342626312 http://rave.ohiolink.edu/etdc/view?acc_num=mco1342626312 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Organic Chemistry Pharmacy Sciences Epothilones non-small cell lung cancer microtubule-stabilizing agents Steglich esterification |
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Organic Chemistry Pharmacy Sciences Epothilones non-small cell lung cancer microtubule-stabilizing agents Steglich esterification Fedorka, Sara R. Synthesis and Biological Evaluation of Open-Chain Epothilones |
| author |
Fedorka, Sara R. |
| author_facet |
Fedorka, Sara R. |
| author_sort |
Fedorka, Sara R. |
| title |
Synthesis and Biological Evaluation of Open-Chain Epothilones |
| title_short |
Synthesis and Biological Evaluation of Open-Chain Epothilones |
| title_full |
Synthesis and Biological Evaluation of Open-Chain Epothilones |
| title_fullStr |
Synthesis and Biological Evaluation of Open-Chain Epothilones |
| title_full_unstemmed |
Synthesis and Biological Evaluation of Open-Chain Epothilones |
| title_sort |
synthesis and biological evaluation of open-chain epothilones |
| publisher |
University of Toledo Health Science Campus / OhioLINK |
| publishDate |
2012 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=mco1342626312 |
| work_keys_str_mv |
AT fedorkasarar synthesisandbiologicalevaluationofopenchainepothilones |
| _version_ |
1719423015506149376 |