Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 2Citation - Scopus: 2Gas Phase Fragmentation Behavior of Proline in Macrocyclic B7 Ions(American Chemical Society, 2023) Taşoğlu, Çağdaş; Arslanoğlu, Alper; Yalçın, TalatThefragmentation characteristics of b (7) ionsproduced from proline-containing heptapeptides have been studiedin detail. The study has utilized the following C-terminally amidatedmodel peptides: PA(6), APA(5), A(2)PA(4), A(3)PA(3), A(4)PA(2), A(5)PA, A(6)P, PYAGFLV, PAGFLVY, PGFLVYA, PFLVYAG,PLVYAGF, PVYAGFL, YPAGFLV, YAPGFLV, YAGPFLV, YAGFPLV, YAGFLPV, YAGFLVP,PYAFLVG, PVLFYAG, A(2)PXA(3), and A(2)XPA(3) (where X = C, D, F, G, L, V, and Y, respectively). The resultshave shown that b (7) ions undergo head-to-tailcyclization and form a macrocyclic structure. Under the collision-induceddissociation (CID) condition, it generates nondirect sequence ionsregardless of the position of the proline and the neighboring aminoacid residues. This study highlights the unusual and unique fragmentationbehavior of proline-containing heptapeptides. Following the head-to-tailcyclization, the ring opens up and places the proline residue in theN-terminal position while forming a regular oxazolone form of b (2) ions for all peptide series. Then, the fragmentationreaction pathway is followed by the elimination of proline with itsC-terminal neighbor residue as an oxazolone (e.g., PXoxa) for all proline-containing peptide series.Article Citation - WoS: 4Citation - Scopus: 5Development of Ab3-Type Novel Phthalocyanine and Porphyrin Photosensitizers Conjugated With Triphenylphosphonium for Higher Photodynamic Efficacy(American Chemical Society, 2022) Albakour, Mohamad; Önal, Emel; Tüncel, Özge; Erdoğan, İpek; Gümüşgöz Çelik, Gizem; Küçük, Tuǧba; Akgül, Bünyamin; Gürek, Ayşe Gül; Özçelik, SerdarThere are a number of lipophilic cations that can be chosen; the triphenylphosphonium (TPP) ion is particularly unique for mitochondrion targeting, mainly due to its simplicity in structure and ease to be linked to the target molecules. In this work, mitochondrion-targeted AB3-type novel phthalocyanine and porphyrin photosensitizers (PSs) were synthesized and their photophysical photochemical properties were defined. Fluorescence quantum yields (φF) are 0.009, 0.14, 0.13, and 0.13, and the singlet-oxygen quantum yields (φΔ) are 0.27, 0.75, 0.57, and 0.58 for LuPcPox(OAc), AB3TPP-Pc, AB3TPP-Por-C4, and AB3TPP-Por-C6, respectively. To evaluate the photodynamic efficacy of the TPP-conjugated PS cell viabilities of A549 and BEAS-2B lung cells were comparatively measured and IC-50 values were determined. AB3TPP-Por-C4, AB3TPP-Por-C6, and AB3TPP-Pc compounds compared to the reference molecules ZnPc and H2TPP were found to be highly cytotoxic (sub-micromolar concentration) under the light. LuPcPox(OAc) is the most effective molecule regarding cell killing (the activity). The cell killing of the TPP-conjugated porphyrin derivatives exhibits a similar response compared to LuPcPox(OAc) when the light absorbing factor of the PS is normalized at 660 nm: TPP-conjugated porphyrins absorb less light (lower extinction coefficient) but produce more radical species (higher singlet-oxygen quantum yield) and therefore effectively kill the cells. The singlet oxygen-producing capacity of AB3TPP-Pc is almost 3 times higher compared to LuPcPox(OAc) and 50% more efficient with respect to ZnPc, suggesting that TPP-conjugated phthalocyanine may serve as a good photosensitizer for photodynamic therapy (PDT). The high singlet oxygen generation capacity of these novel TPP-conjugated porphyrin and phthalocyanine PS suggests that they might be useful for PDT requiring lower photosensitizer concentration and reduced energy deposited through less light exposure.Article Gas-Phase Fragmentation Reactions of A7 Ions Containing a Glutamine Residue(Wiley-Blackwell, 2021) Atik, Ahmet; Arslanoğlu, Alper; Yalçın, Talat; Atik, Ahmet; Arslanoğlu, Alper; Yalçın, TalatThe gas-phase fragmentation reactions of the a7 ions derived from glutamine (Q) containing model heptapeptides have been studied in detail with low-energy collision-induced dissociation (CID) tandem mass spectrometry (MS/MS). Specifically, the positional effect of the Q residue has been investigated on the fragmentation reactions of a7 ions. The study involves two sets of permuted isomers of the Q containing model heptapeptides. The first set contains the QAAAAAA sequence, and the second set involves of QYAGFLV sequence, where the position of the Q residue is changed from N- to C-terminal gradually for both peptide series. An intense loss of ammonia from the a7 ions followed by internal amino acid eliminations strongly supports forming the imine-amides structure via cyclization/rearrangement reaction for all studied a7 ions. This is in agreement with the pioneering study reported by Bythell et al. (2010, 10.1021/ja101556g). A novel rearrangement reaction is detected upon fragmentation of imine-amide structure, which yields a protonated C-terminal amidated hexapeptide excluding the Q residue. A possible fragmentation mechanism was proposed to form the protonated C-terminal amidated hexapeptide, assisted via nucleophilic attack of the side chain amide nitrogen of the Q residue on its N-protonated imine carbon atom of the rearranged imine-amide structure. Highlights: The gas-phase fragmentation reactions of a7 ions obtained from protonated model peptides containing glutamine residue were studied by ESI-MS/MS. A rearranged imine-amide structure is the predominant even for a7 ions. Novel rearrangement reaction is observed which forms a protonated C-terminal amidated hexapeptide excluding Q residue upon fragmentation of the imine-amide structure.Article Citation - WoS: 2Citation - Scopus: 2Novel 2 '-alkoxymethyl Substituted Klavuzon Derivatives as Inhibitors of Topo I and Crm1(Academic Press, 2020) Çetinkaya, Hakkı; Yıldız, Mehmet Salih; Kutluer, Meltem; Alkan, Aylin; Otaş, Hasan Ozan; Çağır, AliIn this work, 2'-alkoxymethyl substituted klavuzon derivatives were prepared starting from 2-methyl-1-naphthoic acid in eight steps. Anticancer potencies of the synthesized compounds were evaluated by performing MTT cell viability test over cancerous and healthy pancreatic cell lines, along with CRM1 inhibitory properties in HeLa cells by immunostaining and Topo I inhibition properties by supercoiled DNA relaxation assay. Their cytotoxic activities were also presented in hepatocellular carcinoma cells (HuH-7) derived 3D spheroids. Among the tested klavuzon derivatives, isobutoxymethyl substituted klavuzon showed the highest selectivity of cytotoxic activity against pancreatic cancer cell line. They showed potent Topo I inhibition while their CRM1 inhibitory properties somehow diminished compared to 4'-alkylsubstituted klavuzons. The most cytotoxic 2'-methoxymethyl derivative inhibited the growth of the spheroids derived from HuH-7 cell lines and PI staining exhibited time and concentration dependent cell death in 3D spheroids.Article Citation - WoS: 10Citation - Scopus: 11A New Drug Testing Platform Based on 3d Tri-Culture in Lab-On Devices(Elsevier, 2020) Gökçe, Begüm; Akçok, İsmail; Çağır, Ali; Pesen Okvur, DevrimDrug discovery has a 90% rate of failure because preclinical platforms for drug testing do not mimic the in vivo conditions. Doxorubicin (DOX) is a commonly used drug to treat breast cancer patients even though it has side effects. Lab-on-a-chip (LOC) devices provide spatial control at the micrometer scale and can thus emulate the cancer microenvironment. Here, using a multidisciplinary approach, a new drug testing platform based on 3D tri-culture in LOC devices was developed. Breast cancer cells alone or with normal mammary epithelial cells and macrophages were cultured in matrigel in LOC devices. The platform was used to test DOX and (R)-4'-methylklavuzon (KLA), which is a new anti-cancer drug candidate. Results showed that DOX and KLA were equally effective on breast cancer cells in 3D monoculture. KLA produced 26% less death for breast cancer cells than DOX in 3D tri-culture. More importantly, DOX was not selective between breast cancer cells and normal mammary epithelial cells in 3D tri- culture whereas KLA caused 56% less cell death than DOX for normal mammary epithelial cells. Results strongly recommend that 3D tri-culture in LOC devices be used for assessment of drug toxicity at the preclinical stage.