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Bioorganic Chemistry

Gülin Renda, Suat Sari, Burak Barut, Michal Šoral, Tibor Liptaj, Büşra Korkmaz, Arzu Özel, İshak Erik, Didem Şöhretoğlu
Some Geranium species have been used to treat diabetes. To evaluate the scientific basis of this ethnopharmacological use, we aimed to isolate potent α-glucosidase inhibitory metabolites of Geranium asphodeloides Burm. through in vitro bioactivity-guided fractionation. All the tested extracts showed high α-glucosidase inhibitory effect compared to acarbose. Among the tested extracts, the ethyl acetate subextract showed the highest activity with an IC50 value of 0.85 ± 0.01 µM. A hydrolysable tannin, 1,2,4-tri-O-galloyl-β-d-glucopyranose (1), and five flavonoid glycosides, kaempferol-3-O-α-rhamnopyranoside (2), kaempferol-3-O-α-arabinofuranoside (3), quercetin-3-O-β-glucopyranoside (4), quercetin-3-O-α-rhamnopyranoside (5), and quercetin-3-O-α-rhamnofuranoside (6), were isolated from the ethyl acetate subextract...
September 12, 2018: Bioorganic Chemistry
Hong Chen, Feihong Chen, Nannan Liu, Xinyi Wang, Shaohua Gou
As a ubiquitous, highly pleiotropic and constitutively active serine/threonine protein kinase, casein kinase 2 (CK2) is closely associated with tumorigenesis by its overexpression in cancer cells. Here we report several proteolysis targeting chimeras (PROTACs) via "click reaction" to connect a CK2 inhibitor (CX-4945) and pomalidomide for degradation of CK2 protein. Among them, compound 2 degraded CK2 in a dose and time-dependent manner, and kept CK2 at a low basal level by recruiting ubiquitin-proteasome system...
September 12, 2018: Bioorganic Chemistry
Somaia S Abd El-Karim, Manal M Anwar, Yasmin M Syam, Manal A Nael, Hanan F Ali, Mohamed A Motaleb
Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC50 with 20-40 folds selectivity over DPP-8 and DPP-9...
September 12, 2018: Bioorganic Chemistry
P Thangarasu, S Thamarai Selvi, A Manikandan
In the present study, novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl) quinolines (4a-l) were recognized and evaluated as G-Protein Coupled Receptor (GPCR) ligands through molecular evaluations. Thrombin mediates adhesion of mast cell, a type of cell abundantly found in connective tissue and releasing histamine and other substances during inflammatory and allergic reactions, through phosphoinositol 3-kinase pathway. With this background, as preliminary, 4a-l are resolute to be potential leads, designated from their effective phosphoinositol 3-kinase (PI3-Kinase) inhibition potentials, best-docked scores, comparative ligand efficiency, and significant structural attributes evaluated by ab initio simulations...
September 12, 2018: Bioorganic Chemistry
Qi He, Jing Liu, Jin-Shuai Lan, Jiaoli Ding, Yongbing Sun, Yuanying Fang, Neng Jiang, Zunhua Yang, Liyuan Sun, Yi Jin, Sai-Sai Xie
A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0...
September 11, 2018: Bioorganic Chemistry
Wei-Chih Chao, Tzu-Hsuan Chiang, Prakash D Chaudhari, Li-Ju Lin, Jyh-Feng Lu, Bor-Cherng Hong, Jinn-Shyan Wang, Ta-Chun Lin, Jiun-Yi Shen, Pi-Tai Chou
The nuclear factor-κB (NF-κB) plays an important role in inflammatory and immune responses. Aberrant NF-κB signaling is implicated in multiple disorders, including cancer. Targeting the regulatory scaffold subunit IκB kinase γ (IKKγ/NEMO) as therapeutic interventions could be promising due to its specific involvement in canonical NF-κB activation without interfering with non-canonical signaling. In this study, the use of unnatural amino acid substituted IKKβ with unique photophysical activity to sense water environment changes upon interaction with NEMO provides a powerful in vitro screening platform that would greatly facilitate the identification of compounds having the potential to disrupt IKKβ-NEMO interaction, and thus specifically modulate the canonical NF-κB pathway...
September 11, 2018: Bioorganic Chemistry
K M Huttunen
Alkyl ester prodrugs are well known to be bioconverted by carboxylesterases, particularly in rodents' by first-pass metabolism in the systemic circulation and liver. However, the bioconversion of structurally more complex esters with polar functional groups is less well understood, especially in humans. Therefore, it is not clear if ester prodrugs can be utilized for targeted drug delivery. In the present study a brain-targeted ester prodrug (1) of ketoprofen, utilizing the l-type amino acid transporter 1 (LAT1) was prepared and the enzymes involved in its metabolism in human plasma and liver S9 subcellular fraction as well as rat brain S9 fraction were identified...
September 11, 2018: Bioorganic Chemistry
Nanwei Wan, Jiawei Tian, Huihui Wang, Meiting Tian, Qing He, Ran Ma, Baodong Cui, Wenyong Han, Yongzheng Chen
Halohydrin dehalogenases are remarkable enzymes which possess promiscuous catalytic activity and serve as potential biocatalysts for the synthesis of chiral halohydrins, epoxides and β-substituted alcohols. The enzyme HheC exhibits a highly R enantioselectivity in the processes of dehalogenation of vicinal halohydrins and ring-opening of epoxides, which attracts more attentions in organic synthesis. Recently dozens of novel potential halohydrin dehalogenases have been identified by gene mining, however, most of the characterized enzymes showed low stereoselectivity...
September 8, 2018: Bioorganic Chemistry
Mehtap Tugrak, Halise Inci Gul, Hiroshi Sakagami, Ilhami Gulcin, Claudiu T Supuran
New azafluorenones, 2-aryl-4-(4-hydroxyphenyl)-5H-indeno[1,2-b]pyridin-5-ones, were prepared to evaluate their cytotoxic/anticancer properties, also their inhibitory effects on hCA I and II isoenzymes. Aryl part was changed as [phenyl (H1), 4-methylphenyl (H2), 4-methoxyphenyl (H3), 4-fluorophenyl (H4), 4-bromophenyl (H5), 4-chlorophenyl (H6), 3-hydroxyphenyl (H7), and 4-hydroxyphenyl (H8)]. The structure of the synthesized compounds was characterized by 1 H NMR, 13 C NMR and HRMS spectra. Cytotoxicity results of the series pointed out that the compounds H6 (PSE: 28...
September 8, 2018: Bioorganic Chemistry
Wagdy M Eldehna, Alessio Nocentini, Sara T Al-Rashood, Ghada S Hassan, Hamad M Alkahtani, Abdulrahman A Almehizia, Ahmed M Reda, Hatem A Abdel-Aziz, Claudiu T Supuran
Three series of indolinone-based sulfonamides (3a-f, 6a-f and 9a-f) were in vitro evaluated as inhibitors of the tumor-associated carbonic anhydrase (CA, EC isoforms hCA IX and XII, using a stopped-flow CO2 hydrase assay. All the investigated sulfonamides displayed single- or double-digit nanomolar inhibitory activities towards both hCA IX (KI s: 6.2-64.8 nM) and XII (KI s: 7.1-55.6 nM) isoforms. All sulfonamides (3a-f, 6a-f and 9a-f) were in vitro examined for their potential anticancer activity against colorectal cancer HCT-116 and breast cancer MCF-7 cell lines...
September 7, 2018: Bioorganic Chemistry
Tao Wu, Jianjun Pei, Lin Ge, Zhenzhong Wang, Gang Ding, Wei Xiao, Linguo Zhao
In this study, a α-l-rhamnosidase gene from Bacteroides thetaiotaomicron VPI-5482 was cloned and expressed in Escherichia coli. The specific activity of rhamnosidase was 0.57 U/mg in LB medium with 0.1 mM Isopropyl β-d-Thiogalactoside (IPTG) induction at 28 °C for 8 h. The protein was purified by Ni-NTA affinity, which molecular weight approximately 83.3 kDa. The characterization of BtRha was determined. The optimal activity was at 55 °C and pH 6.5. The enzyme was stable in the pH range 5.0-8...
September 6, 2018: Bioorganic Chemistry
Lingnan Li, Miaomiao Zhou, Guimin Xue, Wenli Wang, Xuwei Zhou, Xiaobing Wang, Lingyi Kong, Jianguang Luo
Five previously undescribed 4,5-seco-abietane rearrange diterpenoids (1-5, Prionidipene A-E) were isolated from the aerial parts of Salvia prionitis, along with thirteen known seco-abietane diterpenoids (6-18). The structures of 1-5 were elucidated mainly based on analysis of NMR and MS data. The absolute configurations of 1-3 were determined by evaluation of experimental and calculated electronic circular dichroism (ECD) spectra. Putative biosynthetic pathways toward the formation of 1 and 2 are proposed. The nitric oxide (NO) production inhibitory effects of all isolates in lipopolysaccharide (LPS)-induced in RAW 264...
September 6, 2018: Bioorganic Chemistry
Si-Bei Wang, Dong-Rong Zhu, Biao Nie, Jing Li, Ying-Jun Zhang, Ling-Yi Kong, Jian-Guang Luo
Ten new withanolides (1-10) and three artificial withanolides (11-13) were isolated from the aerial parts of Tubocapsicum anomalum, together with five known analogues (14-18). Their structures were determined on the basis of extensive spectroscopic and chemical methods. They include seven acnistin-type (1-4, 11, 14 and 15), three withajardin-type (5-7), and eight normal-type (8-10, 12, 13 and 16-18) withanolides. Of normal-type withanolides, a chemical conversion from the 16α,17α-epoxywithanolide (16) to Δ13,14 -16α-hydroxywithanolide (18) was achieved by Wagner-Meerwein rearrangement...
September 4, 2018: Bioorganic Chemistry
Guo-Dong Yao, Jie Wang, Xiao-Yu Song, Le Zhou, Li-Li Lou, Wen-Yu Zhao, Bin Lin, Xiao-Xiao Huang, Shao-Jiang Song
Two 8-O-4'-type neolignan epimers erythro-guaiacylglycerol-β-coniferyl aldehyde ether (1) and threo-guaiacylglycerol-β-coniferyl aldehyde ether (2) were isolated from the stems of Picrasma quassioides. Further chiral separation gave two pairs of enantiomers 1a/1b and 2a/2b. The cytotoxicity assay against hepatocellular carcinoma Hep3B and HepG2 cells was evaluated by MTT assay. The results showed that 1b (IC50  = 45.56 μM) and 2b (IC50  = 39.02 μM) had more cytotoxic effect than its enantiomers 1a (IC50  = 82...
September 4, 2018: Bioorganic Chemistry
Jialing Han, Chengyu Chu, Guoxiu Cao, Wuxiang Mao, Sen Wang, Zhou Zhao, Mingqi Gao, Hui Ye, Xiaowei Xu
An approach of high sensitivity and selectivity for hydrogen peroxide (H2 O2 ) detection is highly demanded due to its important roles in regulating diverse biological process. In this work, we introduced an easily synthesized fluorescent "turn off" probe, BNBD. It is designed based on the core structure of 4-chloro-7-nitrobenzofurazan as a fluorophore and incorporated with a specific H2 O2 -reactive group, aryl boronate, for sensitive and selective detection of H2 O2 . We demonstrated its selectivity by incubating the probe with other types of ROS, and measured the limit of detection of BNBD as 1...
September 4, 2018: Bioorganic Chemistry
Sebastian Jäger, Lourdes Gude, María-Selma Arias-Pérez
A series of novel N1 -(4,5-diazafluoren-9-yliden)-N2 -glycopyranosyl hydrazines was prepared in synthetically useful yields by treatment of 9H-4,5-diazafluoren-9-hydrazone with different unprotected monosaccharides. The reactions with the monosaccharides tested afforded stereoselectively, and exclusively, cyclic derivatives, whose structures correspond to N-β-glycopyranosyl hydrazones except for the d-arabinose derivative that agrees with the α-anomer. Several copper(II) complexes having a 2:1 ligand to metal mole ratio were also prepared...
September 1, 2018: Bioorganic Chemistry
Chen Li, M B Sridhara, K P Rakesh, H K Vivek, H M Manukumar, C S Shantharam, Hua-Li Qin
Hydrazone compounds were considered as a useful moiety in drug design development. Therefore, these studies were aimed at the synthesis of new dihydrazones and were screened for their in vitro H+ /K+ -ATPase and anti-inflammatory activities. The results revealed that compounds 9 (22 ± 0.62 µg/mL), 10 (26 ± 0.91 µg/mL), 15 (24 ± 0.44 µg/mL), 16 (28 ± 0.63 µg/mL), 17 (12 ± 0.38 µg/mL), 18 (14 ± 0.47 µg/mL), 19 (26 ± 0.54 µg/mL), 20 (16 ± 0.41 µg/mL), 25 (06 ± 0...
September 1, 2018: Bioorganic Chemistry
Jinlei Bian, Jie Ren, Yongren Li, Jubo Wang, Xi Xu, Yifan Feng, Hui Tang, Yajing Wang, Zhiyu Li
Wogonin is a natural product isolated from the Scutellaria baicalensis and has been proved to be a potent and selective inhibitor of CDK9. Using this scaffold, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) targeting CDK9 by recruiting ubiquitin E3 ligase cereblon (CRBN). For constructing diverse Wogonin-based PROTACs, a "click chemistry" approach was employed for the synthesis of CDK9-targeting PROTACs. The results of western blotting assays showed that compounds containing triazole group in the linker could selectively downregulate the intracellular CDK9 level...
August 30, 2018: Bioorganic Chemistry
Phuong Chi Nguyen, Vincent Delorme, Anaïs Bénarouche, Alexandre Guy, Valérie Landry, Stéphane Audebert, Matthieu Pophillat, Luc Camoin, Céline Crauste, Jean-Marie Galano, Thierry Durand, Priscille Brodin, Stéphane Canaan, Jean-François Cavalier
A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc2 6230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M...
August 29, 2018: Bioorganic Chemistry
Shrinivas D Joshi, Sheshagiri R Dixit, Jeelan Basha, V H Kulkarni, Tejraj M Aminabhavi, Mallikarjuna N Nadagouda, Christian Lherbet
In an effort to produce new lead antimycobacterial compounds, herein we have reported the synthesis of a sequence of new pyrrolyl benzamide derivatives. The new chemical entities were screened to target enoyl-ACP reductase enzyme, which is one of the key enzymes of M. tuberculosis that are involved in type II fatty acid biosynthetic pathway. Compound 3q exhibited H-bonding interactions with Tyr158, Thr196 and co-factor NAD+ that binds the active site of InhA. All the pyrrolyl benzamide compounds were evaluated as inhibitors of M...
August 28, 2018: Bioorganic Chemistry
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