Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7148
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Article Citation - WoS: 1Citation - Scopus: 1Optimization of Biotransformation Processes of <i>camarosporium Laburnicola</I> To Improve Production Yields of Potent Telomerase Activators(Bmc, 2024) Kuecueksolak, Melis; Coban, Hasan Bugra; Bedir, ErdalBackground Telomerase activators are promising agents for the healthy aging process and the treatment/prevention of short telomere-related and age-related diseases. The discovery of new telomerase activators and later optimizing their activities through chemical and biological transformations are crucial for the pharmaceutical sector. In our previous studies, several potent telomerase activators were discovered via fungal biotransformation, which in turn necessitated optimization of their production. It is practical to improve the production processes by implementing the design of experiment (DoE) strategy, leading to increased yield and productivity. In this study, we focused on optimizing biotransformation conditions utilizing Camarosporium laburnicola, a recently discovered filamentous fungus, to afford the target telomerase activators (E-CG-01, E-AG-01, and E-AG-02). Results DoE approaches were used to optimize the microbial biotransformation processes of C. laburnicola. Nine parameters were screened by Plackett-Burman Design, and three significant parameters (biotransformation time, temperature, shaking speed) were optimized using Central Composite Design. After conducting validation experiments, we were able to further enhance the production yield of target metabolites through scale-up studies in shake flasks (55.3-fold for E-AG-01, 13-fold for E-AG-02, and 1.96-fold for E-CG-01). Conclusion Following a process optimization study using C. laburnicola, a significant increase was achieved in the production yields. Thus, the present study demonstrates a promising methodology to increase the production yield of potent telomerase activators. Furthermore, C. laburnicola is identified as a potential biocatalyst for further industrial utilization.Article Anthraquinones and Macrocyclic Lactones From Endophytic Fungus Penicillium Roseopurpureum and Their Bioactivities(ACG Publications, 2024) Dizmen,B.; Üner,G.; Küçüksolak,M.; Gören,A.C.; Kırmızıbayrak,P.B.; Bedir,E.Endophytic fungi colonize the internal and distinct tissues of the host plants. In recent years, there has been growing interest in endophytic fungi as valuable sources for drug discovery based on their rich metabolic profiles consisting of novel and bioactive compounds. Accordingly, our preliminary study demonstrated that an endophyte, namely Penicillium roseopurpureum isolated from Astragalus angustifolius, had high chemical diversity with an antiproliferative effect. Herein, fermentation of P. roseopurpureum resulted in the production of five new anthraquinone-type compounds (2, 4, 6, 7, 8) together with several known compounds [11-methoxycurvularin (1: epimeric mixture of 1a and 1b), carviolin (3), 11-hydroxycurvularin (5: diastereoisomeric mixture of 5a and 5b) and 1-O-methylemodin (9)]. The structures of the new compounds were established by NMR spectroscopy and HR-MS analysis. Cytotoxicity studies demonstrated that none of the compounds except for 1 and 5 had antiproliferative activity against prostate cancer cell lines. Interestingly, 1 was found as cytotoxic, whereas 5 exhibited cytostatic properties. Also, 7-AAD/Annexin V staining supported these results by showing that 1 caused cellular death, while 5 did not show any increase in dead cell content in comparison to the control. Lastly, cell cycle analysis showed that compounds had distinctive cell cycle arrest patterns. © 2024 ACG Publications.Article Citation - WoS: 7Citation - Scopus: 7Potent Telomerase Activators From a Novel Sapogenin Via Biotransformation Utilizing Camarosporium Laburnicola, an Endophytic Fungus(BioMed Central Ltd., 2023) Küçüksolak, Melis; Yılmaz, Sinem; Ballar Kırmızıbayrak, Petek; Bedir, ErdalBACKGROUND: Cycloartane-type triterpenoids possess important biological activities, including immunostimulant, wound healing, and telomerase activation. Biotransformation is one of the derivatization strategies of natural products to improve their bioactivities. Endophytic fungi have attracted attention in biotransformation studies because of their ability to perform modifications in complex structures with a high degree of stereospecificity. RESULTS: This study focuses on biotransformation studies on cyclocephagenol (1), a novel cycloartane-type sapogenin from Astragalus species, and its 12-hydroxy derivatives (2 and 3) to obtain new telomerase activators. Since the hTERT protein levels of cyclocephagenol (1) and its 12-hydroxy derivatives (2 and 3) on HEKn cells were found to be notable, biotransformation studies were carried out on cyclocephagenol and its 12-hydroxy derivatives using Camarosporium laburnicola, an endophytic fungus isolated from Astragalus angustifolius. Later, immunoblotting and PCR-based ELISA assay were used to screen starting compounds and biotransformation products for their effects on hTERT protein levels and telomerase activation. All compounds showed improved telomerase activation compared to the control group. CONCLUSIONS: As a result of biotransformation studies, seven new metabolites were obtained and characterized, verifying the potential of C. laburnicola as a biocatalyst. Additionally, the bioactivity results showed that this endophytic biocatalyst is unique in transforming the metabolites of its host to afford potent telomerase activators. © 2023. The Author(s).Article Citation - WoS: 19Citation - Scopus: 21Telomerase Activators From 20(27)-Octanor Via Biotransformation by the Fungal Endophytes(Academic Press, 2021) Duman, Seda; Ekiz, Güner; Yılmaz, Sinem; Yusufoğlu, Hasan; Ballar Kırmızıbayrak, Petek; Bedir, ErdalCycloastragenol [20(R),24(S)-epoxy-3 beta,6 alpha,16 beta,25-tetrahydroxycycloartane] (CA), the principle sapogenol of many cycloartane-type glycosides found in Astragalus genus, is currently the only natural product in the anti-aging market as telomerase activator. Here, we report biotransformation of 20(27)-octanor-cycloastragenol (1), a thermal degradation product of CA, using Astragalus species originated endophytic fungi, viz. Penicillium roseopurpureum, Alternaria eureka, Neosartorya hiratsukae and Camarosporium laburnicola. Fifteen new biotransformation products (2-16) were isolated, and their structures were established by NMR and HRESIMS. Endophytic fungi were found to be capable of performing hydroxylation, oxidation, ring cleavage-methyl migration, dehydrogenation and Baeyer-Villiger type oxidation reactions on the starting compound (1), which would be difficult to achieve by conventional synthetic methods. In addition, the ability of the metabolites to increase telomerase activation in Hekn cells was evaluated, which showed from 1.08 to 12.4-fold activation compared to the control cells treated with DMSO. Among the compounds tested, 10, 11 and 12 were found to be the most potent in terms of telomerase activation with 12.40-, 7.89- and 5.43-fold increase, respectively (at 0.1, 2 and 10 nM concentrations, respectively).Article Citation - WoS: 5Citation - Scopus: 7Five New Cardenolides Transformed From Oleandrin and Nerigoside by Alternaria Eureka 1e1bl1 and Phaeosphaeriasp. 1e4cs-1 and Their Cytotoxic Activities(Elsevier Ltd., 2021) Karakoyun, Çiğdem; Küçüksolak, Melis; Bilgi, Eyüp; Doğan, Gamze; Çömlekçi, Yiğit Ege; Bedir, ErdalBiotransformation of oleandrin (1) and nerigoside (2) by endophytic fungi; Alternaria eureka 1E1BL1 and Phaeospheria sp. 1E4CS-1, has led to the isolation of five new metabolites (3, 5, 6, 7 and 8) together with a known compound (4). The structures of the biotransformation products were elucidated by 1D-, 2D NMR and HR-MS. Phaeospheria sp. mainly provided monooxygenation reactions on the A and B rings, whereas A. eureka afforded both monooxygenated and desacetylated derivatives of the substrates. Cytotoxic activity of the compounds was tested against a non-cancerous (HEK-293) and four cancer (PANC-1, MIA PaCa-2, DU 145 and A549) cell lines by MTT cell viability assay. All compounds were less cytotoxic than oleandrin, which had IC50 values ranging between 2.7 and 41.9 nM. Two of the monohydroxylated metabolites, viz. 7(?)-hydroxy oleandrin (3) and 1(?)-hydroxy oleandrin (7), were also potent with IC50 values from 18.45 to 39.0 nM, while desacetylated + monohydroxylated, or dihydroxylated products had much lower cytotoxicity. Additionally, the lesser activity of 2 and its metabolite (6) possessing diginose as sugar residue inferred that oleandrose moiety is important for the toxicity of oleandrin as well as hydrophobicity of the steroid core. © 2020 Phytochemical Society of Europe