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Identification and Isolation of Secondary Metabolites from Podocarpus neriifolius Using Bioactivity-Guided and 1D-NMR-Based Dereplication Approaches
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Identification and Isolation of Secondary Metabolites from Podocarpus neriifolius Using Bioactivity-Guided and 1D-NMR-Based Dereplication Approaches. |
| 개인저자 | Benatrehina, Paule Annecie. |
| 단체저자명 | The Ohio State University. Pharmaceutical Sciences. |
| 발행사항 | [S.l.]: The Ohio State University., 2018. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2018. |
| 형태사항 | 314 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-05B. Dissertation Abstract International |
| ISBN | 9781687948694 |
| 학위논문주기 | Thesis (Ph.D.)--The Ohio State University, 2018. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-05, Section: B.
Advisor: Kinghorn, A. Douglas. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | In a continued effort aimed at the discovery of potential new anticancer leads of natural origin, a root sample of Podocarpus neriifolius D. Don, collected in the Vietnam rainforest, was selected as a candidate species for phytochemical and biological investigation of its bioactive secondary metabolites. An initial small-scale bioactivity-guided isolation of this plant sample was conducted, and yielded one new (83) and four known podolactones (77-79, and 84) together with three totarane-type diterpenes (80-82), with a structural revision carried out on 79. A larger scale extraction of the remaining sample was performed to isolate a greater amount of 83 for its complete structural characterization, as well as to investigate additional secondary metabolites from this plant. A 1D-NMR spectroscopy-guided fractionation method using both 1H and selective 1D-TOCSY NMR spectroscopy was developed as a dereplication procedure in the screening of the extracts and their fractions. This method led to the detection and isolation of further known compounds (85-92) from the hexanes, EtOAc, and aqueous extracts of P. neriifolius root sample, in addition to that of the targeted compound (83). Moreover, the 1H NMR profile of the aqueous extract revealed the presence of a major compound (89), corresponding to the glucoside derivative of the cytotoxic 78, and this compound by means of its extract of origin, was subjected to fungal-assisted biotransformation procedures using two Penicillium strains, namely, P. concentricum and P. expansum. A previously reported hydrolysis of compound 89 under harsh chemical conditions led to the A-ring epoxide unit opening of this compound, resulting in an inactive product. The fungal biotransformation proved to be a useful method for the successful hydrolysis of 89 to form 78, and the present study is the first report of a podolactone chemical modification in fungal fermentation cultures. The progress of the biotransformation reaction was monitored periodically using the newly developed 1D-NMR spectroscopic dereplication method, from which both the starting material (89) and product (78) were identified. The obtained isolates were evaluated for their antiproliferative activities against four human cancer cell lines, namely, HT-29 (colon), MDA-MB-231 (breast), MDA-MB-435 (melanoma), and OVCAR3 (ovarian). In addition, the bioactive and highly abundant inumakilactone A (78) was further evaluated in vivo in a murine xenograft model through a hollow fiber assay. Only compounds 78 and 79 were active against the cell lines used, while 78 did not show significant activity in vivo. Both 78 and 89 were tested in an insect anti-feedant assay, but neither were active.This dissertation study has opened new avenues for the dereplication in natural product discovery, as well as an additional method for the derivatization of the podolactones, using the 1D-NMR spectroscopic and fungal biotransformation experiments mentioned above, respectively. Finally, although the major compound, 78, did not exhibit in vivo activity against the human cancer subtypes tested, this information constitutes a new contribution to the published literature regarding the podolactone class of compounds. |
| 일반주제명 | Chemistry. Pharmacology. |
| 언어 | 영어 |
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