Ozli, Gulsen; Sakagami, Hiroshi; Polat, M. Fatih; Kazaz, Cavit; Kurosaki, Kota; Uesawa, Yoshihiro; Inden, Kaito; Gul, Halise Inci

Multidrug resistance and off-target toxicity remain major challenges in the treatment of oral squamous cell carcinoma (OSCC). In this study, sulfonamide-chalcone hybrids were designed by combining the chalcone scaffold with a benzenesulfonamide moiety to explore tumor-selective cytotoxicity and structure-activity relationships. Thirty-two N-(4-(3-(aryl)prop-2-enoyl)phenyl)benzenesulfonamide derivatives, including 17 previously unreported compounds, were synthesized via base-catalyzed Claisen-Schmidt condensation and characterized by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Cytotoxicity was evaluated against the human OSCC cell lines Ca9-22 and HSC-2 and non-malignant human gingival fibroblasts and human pulp cells. Compounds 5, 13, 21, 30, and 32 showed the most favorable activity/selectivity profiles, with 50% cytotoxic concentration values of 1.6–2.2 µM against Ca9-22 cells and tumor-selectivity index values of 14.6–21.1. Structure-activity relationship analysis indicated that meta- and para-substitution patterns generally favored tumor-selective cytotoxicity, whereas bulky ortho-substituents reduced activity. Descriptor-based quantitative structure-activity relationship analysis suggested associations between cytotoxicity and molecular shape, polarizability, electronic properties, polarity, and surface descriptors. In silico studies indicated variable gastrointestinal absorption among the selected lead compounds, while none were predicted to permeate the blood–brain barrier. The selected leads also complied with Lipinski’s Rule of Five. Overall, these findings suggest that sulfonamide–chalcone hybrids represent potentially useful tumor-selective cytotoxic scaffolds for further OSCC-focused optimization. (Figure presented.)

Ersan, Ronak Haj; Kuzu, Burak; Yetkin, Derya; Alagoz, Mehmet Abdullah; Dogen, Aylin; Burmaoglu, Serdar; Algul, Oztekin

The inability to meet the desired outcomes of anticancer treatment and decrease in treatment success of bacterial and fungal infections accelerated research in these areas. Our research group has conducted numerous studies, especially on benzimidazole ring systems’ antiproliferative and antimicrobial activities. In this study, the antiproliferative activity of benzimidazole compounds was tested against A549, A498, HeLa, A375, and HepG2 cancer cell lines by MTT assay. All compounds exhibited good to potent antiproliferative activity against all tested cancer cell lines. Compounds 6-chloro-2-(4-fluorobenzyl)-1H-benzo[d]imidazole (30) and 6-chloro-2-phenethyl-1H-benzo[d]imidazole (46) were especially active against HeLa and A375 cancer cell lines with IC50 values in the range of 0.02–0.04 µM. In contrast, compounds 6-chloro-2-((p-tolyloxy)methyl)-1H-benzo[d]imidazole (67) and 5(6)-chloro-2-((4-hydroxyphenoxy)methyl)-1H-benzimidazole (68) were active against A549 and A498 cancer cell lines with an IC50 value of 0.08 µM. These compounds (30, 46, 67, and 68) were less toxic to normal human cells than the positive control compound methotrexate, which was screened to determine its toxicity against normal cell lines (HEK293). In the second part of the study, all compounds were tested to demonstrate their antimicrobial properties. All compounds exhibited moderate activity against all tested bacteria and fungi. However, some phenoxy methyl derivatives 5-chloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d]imidazole (69) and 5,6-dichloro-2-((4-chlorophenoxy)methyl)-1H-benzo[d]imidazole and (74) were most active against Candida (<3.90 µg/mL). Molecular docking studies were carried out against certain proteins in order to identify potential targets of the antiproliferative effects of the synthesized compounds. The docking scores of the compounds were found to be significantly compatible with the antiproliferative activity results. [Figure not available: see fulltext.]

Dadou, Said; Altay, Ahmet; Koudad, Mohammed; Türkmenoğlu, Burçin; Yeniçeri, Esma; Çağlar, Sema; Allali, Mustapha; Oussaid, Adyl; Benchat, Noureddine; Karrouchi, Khalid

A new series of imidazo[2, 1-b]thiazole-based chalcone derivatives were designed, synthesized, and tested for their anticancer activities. Firstly, the cytotoxic ability of the compounds was tested on three different types of cancer cells, namely colorectal adenocarcinoma (HT-29), lung carcinoma (A-549), breast adenocarcinoma (MCF-7), and mouse fibroblast cells (3T3-L1) by XTT tests. Afterwards, further anticancer activity studies with the compound 3j having the lowest IC50 and highest SI values were performed on MCF-7 cells. XTT results revealed that all the test compounds exhibited much higher cytotoxic activity on the cancer cells than that of normal 3T3-L1 cells. Among the compounds, 3j especially stood out with its IC50 (9.76 µM) and SI (14.99) values on MCF-7 cells. Flow cytometry analysis proved that 3j-treated MCF-7 cells was resulted in the mitochondrial membrane depolarization, multicaspase activation, and ultimately apoptosis. Additionally, in silico molecular docking approaches were carried out to confirm the experimental observations and investigate the efficacy of the compound 3j. The interactions of 3j on DNA dodecamer and caspase-3 were investigated by molecular docking studies. Based on these interactions, the active amino acids in the binding site were determined and their free binding energies (ΔGBind) were calculated.

Merde, İrem B.; Önel, Gülce T.; Türkmenoğlu, Burçin; Gürsoy, Şule; Dilek, Esra

Alzheimer’s disease is a progressive and fatal neurodegenerative disease affecting the elderly population accompanied by a decrease in cholinergic transmission, impairing cognitive functions. Acetylcholine deficiency is important in the development of disease symptoms. Inhibition of acetylcholinesterase, an important enzyme in acetylcholine hydrolysis, is one of the important drug targets to increase acetylcholine levels. In this study, we aimed to develop acetylcholinesterase inhibitor compounds. For this, we synthesized compounds 6(a–e) bearing 3(2H)-pyridazinone and 1,2,4-triazole ring structures. We determined the IC50, Ki and inhibition types of N-substituted-(p-methoxyphenyl)pyridazin-3(2H)-one derivatives that we synthesized and elucidated their structures. The compound with the best AChE activity was compound 6b (Ki = 3.73 ± 0.9 nM) with the p-methylphenyl group it carried and showed competitive inhibition. Kinetic study was also performed for the compounds with the highest BChE 6a (Ki = 0.95 ± 0.16 nM) inhibitory activities. Molecular docking studies have shown that the p-methylphenyl group is indeed active in the hinge region of the AChE crystal structure as a result of experimental activity. In addition, the best free binding energy (ΔGBind), docking score and Glide score values were determined by examining the interactions with AChE crystal structure for compound 6b and with BChE crystal structure for 6a in silico approaches. [Figure not available: see fulltext.]

Adem, Sevki; Akkemik, Ebru; Aksit, Hüseyin; Guller, Pınar; Tüfekci, Ali Rıza; Demirtas, İbrahim; Ciftci, Mehmet

Carbonic anhydrases (CAs) play a significant function in diverse pathological and physiological processes. Their inhibitors and activators are suitable molecules to use as a drug in the treatment of different disease. In the present study, seven natural compounds, namely didymin, retusin isoquercitrin, silymarin, verbascoside, teucroside, and 3′-O-methylhypolaetin 7-O-[6′′′-O-acetyl-β-D-allopyranosyl-(1→2)]-6′′-O-acetyl-β-D-glucopyranoside were isolated from Mentha spicata, Sideritis libanotica linearis, Platanus orientalis, Teucrium chamaedrys subsp. chamaedrys, and Silybum marianum. The influences of compounds on the carbonic anhydrase I(hCAI) and II(hCAII) purified from human erythrocytes were tested. Five phenolic compounds acted as an inhibitor on the activity of hCAI, and IC50 values were computed between 18.16 and 172.5 μM. Isozyme hCAII is only inhibited by silymarin with an IC50 value of 43.12 μM. This isoenzyme was effectively activated by five natural compounds with AC50 values in the range of 2.98–18.53 μM. To understand the binding patterns of molecules that show activation effect against hCAII, molecular docking was done using Leadit 2.3.2 software, and calculated between −19.05 and −14.42 (kJ/mol) binding energies. Both in vitro and in silico results demonstrated that the best activators against hCAII were teucroside and isoquercitrin, with AC50 values of 2.98 and 3.17 μM, and binding energies −19.05 and −18.01 (kJ/mol), respectively. According to the ADME results, retusin demonstrated physicochemical and pharmacokinetic properties specific to the drug candidates.

Gul, Halise Inci; Yamali, Cem; Gunesacar, Gulsen; Sakagami, Hiroshi; Okudaira, Noriyuki; Uesawa, Yoshihiro; Kagaya, Hajime

In the present study, chalcones “(E)-1-(10H-phenothiazine-2-yl)-3-aryl-prop-2-en-1-ones, FS1-11” were successfully synthesized via base-catalyzed Claisen–Schmidt condensation. Chemical structures of the compounds were confirmed by 1H NMR, 13C NMR, and HRMS techniques. Aryl part of the chalcone was changed as mono, di, and trimethoxylated phenyls. Cytotoxicities of the phenothiazine derivatives were evaluated against four human oral squamous cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, and HSC-4) and three human normal oral cells (HGF, HPLF, and HPC) by MTT test. The CC50 values of the compounds were calculated in the range of 0.9–109.8 µM towards OSCC malign cell lines. Trimethoxylated compound FS6, (E)-1-(10H-phenothiazine-2-yl)-3-(2,4,5-trimethoxyphenyl)-prop-2-en-1-one, was found the most selective cytotoxic compound among the series with the highest selectivity index (SI) (SI = 76.5) and potency-selectivity expression (PSE) (PSE = >1285; > 1602) values. Western blot analysis demonstrated that FS6 (8–64 μM) induced the production of cleaved product of PARP and the activation of caspase-3 in HSC-2 cells, suggesting the induction of apoptosis by FS6. QSAR analysis suggested that the tumor specificity of the chalcones correlated with their molecular shape, volume, and electrostatic properties.

Cinar, Seda; Unaleroglu, Canan; Ak, Ayşe; Garipcan, Bora

New β-aryl-α-dimethoxyphosphoryl-γ-lactams 4a, b were designed and synthesized through the intra-molecular cyclization of 3a, b obtained from the addition reaction of methyl 2-(dimethoxyphosphoryl)acetate to (E)-2-(2-nitrovinyl)thiophene and (E)-2-(2-nitrovinyl)furan, respectively. The in vitro cytotoxicity of these compounds was evaluated against human breast cancer (MCF-7), rat glioblastoma (C6), prostate cancer (PC3), neuroblastoma (SHSY-5Y), and mouse fibroblast cell lines (L929). Dimethyl (4-(furan-2-yl)-2-oxopyrrolidin-3-yl)phosphonate (4b) was found to have cytotoxic activity towards MCF-7 and PC3 cell lines at the concentration values above 5 mM and 6 mM, respectively (IC50 values of MCF-7, 5.92 ± 1.86; PC3, 6.70 ± 2.10 mM). Dimethyl (2-oxo-4-(thiophen-2-yl)pyrrolidin-3-yl)phosphonate (4a) only decreased the viability of MCF-7 cells at 8 mM concentration (IC50 value of MCF-7 5.67 ± 1.70 in mM). In addition 4a, b had shown no significant cytotoxic effect on C6, SHSY-5Y and L929 cell lines.

Bozkurt, İlyas; Dilek, Esra; Erol, Hüseyin Serkan; Çakir, Ahmet; Hamzaoğlu, Ergin; Koç, Murat; Keleş, Osman Nuri; Halici, Mesut Bünyami

Previously, water extract of Maclura pomifera plant has been found effective on gastric damage. In this study, pomiferin product was purified from this plant by thin-layer chromatography method and its structure was elucidated by nuclear magnetic resonance methods. Its antiulcer effect was investigated on indomethacin-induced gastric damage in rats. For this study, a total of 36 Sprague Dawley female rats were divided into six groups such as healthy, control, reference, and three treatment groups (n = 6 each). Ranitidine (Ulcuran® 25 mg/ml vial) was used as reference. Biochemically, lipid peroxidation, and glutathione levels as well as superoxide dismutase, catalase, myeloperoxidase, and cyclooxygenase isoenzymes activities were measured in stomach tissues. Comparing with healthy group, ulcerative area was observed in control group (only administered to indomethacin group). However, Ulcerative area in stomach tissues of rats administered of all doses of pomiferin and ranitidine showed significant decrease (p < 0.05). Also, there were significant changes at the antioxidant levels (lipid peroxidation, glutathione, superoxide dismutase, and catalase) and some important enzyme activities (myeloperoxidase, cyclooxygenase isoenzymes). We found that pomiferin was effective on gastric damage induced by indomethacin. This effect was thought to be caused by positive changes in the antioxidant system.

Güvenalp, Zühal; Özbek, Hilal; Dursunoğlu, Benan; Yuca, Hafize; Gözcü, Sefa; Çil, Yeşim M.; Kazaz, Cavit; Kara, Kemalettin; Demirezer, Ömür L.

A new phenylpropanoid named 4-(1′,1′,2′,2′-tetramethylpropyl)-1,2-benzenediol (1) with a known phenylpropanoid: 3-(p-methoxyphenyl)-1,2-propanediol (2), a coumarin: herniarin (3), and a flavonol glycoside: rutin (4) were isolated from the aerial parts of Artemisia dracunculus L. Their structures were elucidated by detailed analyses of 1D and 2D nuclear magnetic resonance, IR, ESI–MS and HR–ESI–MS data. Methanol extract of aerial parts of the plant, different polarity fractions of methanol extract and the isolated compounds from these fractions were evaluated for their alpha amylase and alpha glucosidase inhibitory effects. Phenylpropanoids containing fraction had a significantly higher α-glucosidase inhibitory activity (90.4%) when compared with the standart compound acarbose (26.0%) at 1 mg/mL. However none of the tested extracts or compounds were found to be active on α-amylase inhibition.