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Identification and Dereplication of Bioactive Secondary metabolites of Penicillium aurantiacobrunneum, a Fungal Associate of the Lichen Niebla homalea

Tan, Choon Yong
http://orcid.org/0000-0002-5091-1369
http://rave.ohiolink.edu/etdc/view?acc_num=osu1586533114478772

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Lichens are composite organisms consisting of multiple species of photobionts (cyanobacteria and microalgae) and mycobionts (fungi) living in symbiosis and have been found to survive under harsh conditions such as extreme temperatures or harmful UV rays. The secondary metabolites produced by these tenacious organisms have shown a wide array of biological activities, such as antimicrobial, cytotoxic, antioxidant and antiviral activities and its production has been mainly attributed to the mycobiont, or its microbial associates. In our systematic search for novel antiproliferative compounds, a fungal associate of the lichen, Niebla homalea, endemic to the U.S. has been isolated and identified as Penicillium aurantiacobrunneum. This relatively underexplored species belongs to a genus that has produced many important drugs for treatment of hyperlipidemia and infections, and has shown to exhibit cytotoxic activities against human breast (MCF-7) and human ovarian (A2780) cancer cell lines with IC50 values of 1.8 and 2.2 μg/mL respectively. From various fermentations of P. aurantiacobrunneum, one new α-pyrone polyene, 4-epi-citreoviridin (103), three new sterols, (20R)-7,8-dihydroxypaxisterol (105), auransterol (106) and (7S)-5-en-auransterol (107) and two new tetramic acids, 14-norepicoccarine A (109) and 14-norepicoccarine B (123) have been isolated alongside three known compounds, paxisterol (104), (15R*,20S*)-dihydroxyepisterol (108) and a pyridone alkaloid, PF1140 (124). Three of these isolated compounds (103, 105 and 106) were evaluated for their cytotoxic activities and compound 103 was the only compound found to be moderately active against both the cancer cell lines. (MCF-7 IC50 4.2 μg/mL and A2780 IC50 5.7 μg/mL). Of all the fermentations of this fungal strain, the extract from a brown rice culture afforded a total of six compounds (103, 105 – 109). This set of compounds served as an internal database for the development of a dereplication method by an NMR technique, selective 1D total correlation spectroscopy (1D TOCSY). Using this method, the new tetramic acid, 14-norepicoccarine B (123), was identified from a crude extract in Minimum Essential Medium, based on the previously isolated 14-norepicoccarine A (109). The method also demonstrated its advantage over LC-MS dereplication method for its ability to discern compounds of the same exact mass, as in the case of PF1140 (124) and its structural isomer, 8-methyl-pyridoxatin (125). Even with the signal overlaps between multiple compounds, selective irradiation of a signal can still differentiate spin coupling networks of two compounds, exemplified by PF1140 (124) and paxisterol (104). Throughout the rest of the dissertation, this method has also successfully dereplicated some of the isolated compounds in other extracts of P. aurantiacobrunneum and will continue to pave the way for identification of other secondary metabolites produced by this strain and extracts made from other natural sources.
Liva Rakotondraibe (Advisor)
Esperanza Carcache de Blanco (Committee Member)
James Fuchs (Committee Member)
319 p.
Pharmacy Sciences
Natural products; dereplication; selective 1D TOCSY; Penicillium aurantiacobrunneum; lichen; Niebla homalea; secondary metabolites; bioassay guided; anticancer; fungus

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Citations

  • Tan, C. Y. (2020). Identification and Dereplication of Bioactive Secondary metabolites of Penicillium aurantiacobrunneum, a Fungal Associate of the Lichen Niebla homalea [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1586533114478772

    APA Style (7th edition)

  • Tan, Choon Yong. Identification and Dereplication of Bioactive Secondary metabolites of Penicillium aurantiacobrunneum, a Fungal Associate of the Lichen Niebla homalea. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1586533114478772.

    MLA Style (8th edition)

  • Tan, Choon Yong. "Identification and Dereplication of Bioactive Secondary metabolites of Penicillium aurantiacobrunneum, a Fungal Associate of the Lichen Niebla homalea." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1586533114478772

    Chicago Manual of Style (17th edition)

osu1586533114478772
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