Bioengineering / Biyomühendislik
Permanent URI for this collectionhttps://hdl.handle.net/11147/4529
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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: 8Citation - Scopus: 9Neuroprotective Metabolites Via Fungal Biotransformation of a Novel Sapogenin, Cyclocephagenol(Nature Research, 2022) Küçüksolak, Melis; Üner, Göklem; Ballar Kırmızıbayrak, Petek; Bedir, ErdalCyclocephagenol (1), a novel cycloartane-type sapogenin with tetrahydropyran unit, is only encountered in Astragalus species. This rare sapogenin has never been a topic of biological activity or modification studies. The objectives of this study were; (i) to perform microbial transformation studies on cyclocephagenol (1) using Astragalus endophyte, Alternaria eureka 1E1BL1, followed by isolation and structural characterization of the metabolites; (ii) to investigate neuroprotective activities of the metabolites; (iii) to understand structure–activity relationships towards neuroprotection. The microbial transformation of cyclocephagenol (1) using Alternaria eureka resulted in the production of twenty-one (2–22) previously undescribed metabolites. Oxidation, monooxygenation, dehydration, methyl migration, epoxidation, and ring expansion reactions were observed on the triterpenoid skeleton. Structures of the compounds were established by 1D-, 2D-NMR, and HR-MS analyses. The neuroprotective activities of metabolites and parent compound (1) were evaluated against H2O2-induced cell injury. The structure–activity relationship (SAR) was established, and the results revealed that 1 and several other metabolites had potent neuroprotective activity. Further studies revealed that selected compounds reduced the amount of ROS and preserved the integrity of the mitochondrial membrane. This is the first report of microbial transformation of cyclocephagenol.Article Citation - WoS: 5Citation - Scopus: 6Undescribed Polyether Ionophores From Streptomyces Cacaoi and Their Antibacterial and Antiproliferative Activities(Elsevier, 2022) Gezer, Emre; Üner, Göklem; Küçüksolak, Melis; Kurt, Mustafa Ünver; Doğan, Gamze; Ballar Kırmızıbayrak, Petek; Bedir, ErdalPolyether ionophores represent a large group of naturally occurring compounds mainly produced by Streptomyces species. With previously proven varieties of bioactivity including antibacterial, antifungal, antiparasitic, antiviral and anti-tumor effects, the discovery of undescribed polyethers leading to development of efficient therapeutics has become important. As part of our research on polyether-rich Streptomyces cacaoi, we previously performed modification studies on fermentation conditions to induce synthesis of specialized metabolites. Here, we report four undescribed and nine known polyether compounds from S. cacaoi grown in optimized conditions. Antimicrobial activity assays revealed that four compounds, including the undescribed (6), showed strong inhibitory effects over both Bacillus subtilis and methicillin-resistant Staphylococcus aureus (MRSA) growth. Additionally, K41-A and its C15-demethoxy derivative exhibited significant cytotoxicity. These results signified that selectivity of C15-demethoxy K41-A towards cancer cells was higher than K41-A, which prompted us to conduct mechanistic experiments. These studies showed that this uninvestigated compound acts as a multitarget compound by inhibiting autophagic flux, inducing reactive oxygen species formation, abolishing proteasome activity, and stimulating ER stress. Consequently, the optimized fermentation conditions of S. cacaoi led to the isolation of undescribed and known polyethers displaying promising activities.Article Citation - WoS: 12Citation - Scopus: 12New Cardenolides From Biotransformation of Gitoxigenin by the Endophytic Fungus Alternaria Eureka 1e1bl1: Characterization and Cytotoxic Activities(MDPI, 2021) Bedir, Erdal; Karakoyun, Çiğdem; Doğan, Gamze; Kuru, Gülten; Küçüksolak, Melis; Yusufoğlu, HasanMicrobial biotransformation is an important tool in drug discovery and for metabolism studies. To expand our bioactive natural product library via modification and to identify possible mammalian metabolites, a cytotoxic cardenolide (gitoxigenin) was biotransformed using the endophytic fungus Alternaria eureka 1E1BL1. Initially, oleandrin was isolated from the dried leaves of Nerium oleander L. and subjected to an acid-catalysed hydrolysis to obtain the substrate gitoxigenin (yield; similar to 25%). After 21 days of incubation, five new cardenolides 1, 3, 4, 6, and 8 and three previously- identified compounds 2, 5 and 7 were isolated using chromatographic methods. Structural elucidations were accomplished through 1D/2D NMR, HR-ESI-MS and FT-IR analysis. A. eureka catalyzed oxygenation, oxidation, epimerization and dimethyl acetal formation reactions on the substrate. Cytotoxicity of the metabolites were evaluated using MTT cell viability method, whereas doxorubicin and oleandrin were used as positive controls. Biotransformation products displayed less cytotoxicity than the substrate. The new metabolite 8 exhibited the highest activity with IC50 values of 8.25, 1.95 and 3.4 mu M against A549, PANC-1 and MIA PaCa-2 cells, respectively, without causing toxicity on healthy cell lines (MRC-5 and HEK-293) up to concentration of 10 mu M. Our results suggest that A. eureka is an effective biocatalyst for modifying cardenolide-type secondary metabolites.Article Citation - WoS: 6Citation - Scopus: 6Benzodiazepine Derivatives From Marine-Derived Streptomyces Cacaoi 14cm034(ACG Publications, 2021) Çetinel Aksoy, Semiha; Küçüksolak, Melis; Uzel, Ataç; Bedir, Erdal7-methoxy-8-hydroxy cycloanthranilylproline (2), a new natural product with pyrrolobenzodiazepine (PBD) framework, was isolated from marine-derived actinobacterium Streptomyces cacaoi 14CM034, together with cycloanthranilylproline (1). Structural elucidation of the compounds was based on FTIR, 1D-(H-1 and C-13 NMR), 2D-NMR (COSY, HMBC and NOESY) and HR-MS analyses. Compounds 1 and 2 exhibited notable antimicrobial activity. The presence of PBD derivatives in S. cacaoi was first demonstrated with this study.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 EuropeArticle Citation - WoS: 7Citation - Scopus: 7Flavonol Glycosides From Reseda Lutea L(Elsevier Ltd., 2019) Kızıltaş, Hatice; Küçüksolak, Melis; Duman, Seda; Bedir, ErdalTwo new flavonol glycosides; kaempferol-3-O-[2-O-(beta-D-xylopyranosyl)-3-O-(beta-D-glucopyranosyl)]-alpha-L-rhamnopyranosyl-7-O-alpha-L-rhamnopyranoside (1) and kaempferol-3-O-[2-O-((6-O-trans-p-coumaryl)-beta-D-glucopyranosyl)-3-O-(beta-D-xylopyranosyl)]-alpha-L-rhamnopyranosyl-7-O-alpha-L-rhamnopyranoside (2) were isolated from the aerial parts of Reseda lutea L., together with five known flavonol glycosides. Structural elucidation of the compounds was based on both spectroscopic evidence and reference data comparison. The new compounds are the first tetrasaccharidic secondary metabolites isolated from Resedaceae family.