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Development of Novel Naphthalimide Compounds and Estrogen Conjugates for Treatment in Breast Cancer
Başlık:
Development of Novel Naphthalimide Compounds and Estrogen Conjugates for Treatment in Breast Cancer
Yazar:
Skubic, Kristin Nicole, author.
ISBN:
9780355984927
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (114 pages)
Genel Not:
Source: Masters Abstracts International, Volume: 57-06M(E).
Advisors: Christopher K. Arnatt Committee members: Michael Lewis; Brent M. Znosko.
Özet:
Deoxyribonucleic acid (DNA) plays an important role in replication, transcription, and translation as the genetic material for living organisms. For this reason, DNA has been an ideal target for several anticancer therapies through different modes of binding. Intercalation, with naphthalimide compounds, is one particular mode that was investigated here. Within this work, naphthalimide derivatives were synthesized and experimentally tested in order to explore structure-activity-relationship (SAR) in breast cancer cell lines for an anticancer therapy. First, a series of novel monosubstituted compounds were synthesized as derivatives to original work completed by Brana and coworkers. Once synthesized, these compounds were tested for their anti-proliferative effects in several breast cancer cells lines and their relative DNA binding strength in a variety of oligonucleotide sequences. The data from both of these studies suggests that the compounds synthesized have activity as anti-proliferative agents in several breast cancer cell lines and show direct correlation in DNA binding strength depending upon the electronic properties of the substituent, the substituent position along the aryl ring, and the size of the terminal amine on the anhydride ring. Furthermore, these compound derivatives were tested in a cell cycle determination assay and topoisomerase II assay determining that these compounds arrest cells at the G2 phase and inhibit topoisomerase II as their mode of action. An imaging study was presented, illustrating the location of the naphthalimide compounds within the cell nucleus.
Additionally, a novel synthetic route was designed and optimized to introduce a new series of disubstituted naphthalimide compounds in order to study the differences in toxicological profiles compared to the monosubstituted naphthalimides. Several reactions including reduction reaction, protection of a primary aryl amine, ortho-lithiation reaction, deprotection of primary amine, and condensation reaction were all investigated for this project.
Due to the current extreme side effects of anticancer therapies, a synthetic route was proposed for monosubstituted naphthalimide conjugation to estrogen. This bivalent ligand containing both estrogen and a toxic monosubstituted naphthalimide linked together by a diamine and an anhydride is suspected to possess anti-proliferative effects on breast cancer cell lines. The side effects of this conjugated compound should be decreased in comparison to the unconjugated species as the breast cancer cells will uptake the estrogen at a much higher rate than the normal cells as there is an overexpression of estrogen receptors in breast cancer cell lines.
In all, intercalative species are known to exhibit cytotoxic behavior in cancer cell lines and even clinical trials. Presented novel monosubstituted naphthalimide compounds have been determined to possess anticancer properties for breast cancer through cell cycle arrest and topoisomerase II inhibition. Disubstituted naphthalimide compounds are a possibility and will provide a large series of compounds for additional biological testing. Further work needs to be explored in conjugating estrogen to monosubstituted naphthalimide compounds for avoiding unwanted side effects in cancer patients.
Notlar:
School code: 0193
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(693726.1) | 693726-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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