- Remarkable Reactivity Differences between Glucosides with Identical Leaving Groups
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Two isomeric aryl 2-deoxy-2-fluoro-β-glucosides react with a β-glucosidase at rates differing by 106-fold, despite the fact that they release the same aromatic aglycone. In contrast, the equivalent glucoside substrates react with essentially identical rate constants. Insight into the source of these surprising rate differences was obtained through a comprehensive study of the nonenzymatic (spontaneous) hydrolysis of these same substrates, wherein an approximate 105-fold difference in rates was measured, clarifying that the differences were inherent rather than being due to specific interactions with the enzyme. The possibility that an alternate nucleophilic aryl substitution mechanism was responsible for the rapid reaction of the faster substrate was excluded through 18O-labeling studies. Further exploration of the origins of these rate differences involved analysis of X-ray crystal structures as well as quantum chemical calculations, which surprisingly revealed that ground state destabilization and transition state stabilizing effects contribute almost equally to the observed reactivity differences. These studies highlight the dangers of using simple reference equilibria such as pKa values as measures of leaving group ability.
- Duo, Tianmeng,Robinson, Kyle,Greig, Ian R.,Chen, Hong-Ming,Patrick, Brian O.,Withers, Stephen G.
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- Synthesis and biological testing of novel glucosylated epigallocatechin gallate (EGCG) derivatives
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Epigallocatechin gallate (EGCG) is the most abundant component of green tea catechins and has strong physiological activities. In this study, two novel EGCG glycosides (EGCG-G1 and EGCG-G2) were chemoselectively synthesized by a chemical modification stra
- Zhang, Xin,Wang, Jing,Hu, Jiang-Miao,Huang, Ye-Wei,Wu, Xiao-Yun,Zi, Cheng-Ting,Wang, Xuan-Jun,Sheng, Jun
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- Novel perbutyrylated glucose derivatives of (–)-epigallocatechin-3-gallate inhibit cancer cells proliferation by decreasing phosphorylation of the egfr: Synthesis, cytotoxicity, and molecular docking
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Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7–12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property–activity relationship of EGCG derivatives. Compounds 11 and 12 showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC50 values in the range of 22.90–37.87 μM. Compounds 11 and 12 decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds 11 and 12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.
- Niu, Yun,Shen, Xiao-Jing,Sheng, Jun,Su, Fa-Wu,Wang, Li-Xia,Wang, Xuan-Jun,Wang, Ya,Wu, Yi-Long,Xie, Yin-Rong,Zhang, Dong-Ying,Zhang, Ning,Zi, Cheng-Ting
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- Synthesis of thioglycosides by tetrathiomolybdate-mediated michael additions of masked thiolates
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An efficient one-pot methodology for the synthesis of thioglycosides in excellent yields under neutral conditions through the use of benzyltriethylammonium tetrathiomolybdate [(BnNEt3) 2MoS4; 1] as a sulfur-transfer reagent has been developed. The reagent 1 reacts with sugar halides to give sugar disulfides, which then undergo reductive cleavage in situ to provide the corresponding thiolates, followed by Michael addition to give the corresponding thioglycosides. Further, the utility of this one-pot reaction in aqueous medium has been exemplified through the use of ammonium tetrathiomolybdate [(NH4)2 MoS4; 2]. The application of this methodology has been extended to the synthesis of a variety of thiosugar analogues with excellent diastereoselectivity through inter- and intramolecular reactions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Sridhar, Perali Ramu,Prabhu, Kandikere Ramaiah,Chandrasekaran, Srinivasan
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- Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression
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Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC50 values of 396.5 and 383.0 μM agitating on MT1 and MT2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs.
- Yang, Tong-Hua,Ma, Yun-Bao,Geng, Chang-An,Yan, De-Xiu,Huang, Xiao-Yan,Li, Tian-Ze,Zhang, Xue-Mei,Chen, Ji-Jun
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- Structures of Nostocyclophanes A-D
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Nostocyclophanes A-D are the cytotoxins associated with the blue-green alga Nostoc linckia (Roth) Bornet ex Bornet Flahault (UTEX B1932).The gross structures of these paracyclophanes have been elucidated by mass and NMR spectral analyses and the relative and absolute stereochemistry of nostocyclophane D determined by X-ray crystallography.Since the CD spectra of the four compounds are essentially identical, nostocyclophanes A-D are proposed to have the same stereochemistry.The sugar unit in nostocyclophanes A and B has been shown to be D-glucose by semisynthesis of nostocyclophane B 9-O-(2,3,4,6-tetra-O-acetyl)-β-D-glucopyranoside from nostocyclophanes B and D.
- Chen, Jian Lu,Moore, Richard E.,Patterson, Gregory M. L.
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- Challenges in the Conversion of Manual Processes to Machine-Assisted Syntheses: Activation of Thioglycoside Donors with Aryl(trifluoroethyl)iodonium Triflimide
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The steps needed to adapt a stable iodonium promoter for use in automated fluorous-assisted solution-phase oligosaccharide synthesis are described. Direct adaptation of the originally reported batch procedure resulted in the formation of an orthoester or
- Saliba, Regis C.,Wooke, Zachary J.,Nieves, Gabriel A.,Chu, An-Hsiang Adam,Bennett, Clay S.,Pohl, Nicola L. B.
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- Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity
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Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 μM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 μM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.
- Ahmed, Ajaz,Bhagat, Kavita,Choudhary, Sushil,Kaur Gulati, Harmandeep,Kumar, Ajay,Kumar, Nitish,Mukherjee, Debaraj,Singh Bedi, Preet Mohinder,Singh, Atamjit,Singh, Harbinder,Vir Singh, Jatinder
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- Synthesis and biological evaluation of 3β-O-neoglycosides of caudatin and its analogues as potential anticancer agents
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In order to study the structure–activity relationship (SAR) of C21-steroidal glycosides toward human cancer cell lines and explore more potential anticancer agents, a series of 3β-O-neoglycosides of caudatin and its analogues were synthesized. The results revealed that most of peracetylated 3β-O-monoglycosides demonstrated moderate to significant antiproliferative activities against four human cancer cell lines (MCF-7, HCT-116, HeLa, and HepG2). Among them, 3β-O-(2,3,4-tri-O-acetyl-β-L-glucopyranosyl)-caudatin (2k) exhibited the highest antiproliferative activity aganist HepG2 cells with an IC50 value of 3.11 μM. Mechanical studies showed that compound 2k induced both apoptosis and cell cycle arrest at S phase in a dose dependent manner. Overall, these present findings suggested that glycosylation is a promising scaffold to improve anticancer activity for naturally occurring C21-steroidal aglycones, and compound 2k represents a potential anticancer agent deserved further investigation.
- Li, Xiao-San,Chen, Tang-Ji,Xu, Zhi-Peng,Long, Juan,He, Miao-Ying,Zhan, He-Hui,Zhuang, Hai-Cai,Wang, Qi-Lin,Liu, Li,Yang, Xue-Mei,Tang, Jin-Shan
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- Synthesis of malformin-A1, C, a glycan, and an aglycon analog: Potential scaffolds for targeted cancer therapy
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Improvement in therapeutic efficacy while reducing chemotherapeutic side effects remains a vital objective in synthetic design for cancer treatment. In keeping with the ethos of therapeutic development and inspired by the Warburg effect for augmenting biological activities of the malformin family of cyclic-peptide natural products, specifically anti-tumor activity, a β-glucoside of malformin C has been designed and synthesized utilizing precise glycosylation and solution phase peptide synthesis. We optimized several glycosylation procedures utilizing different donors and acceptors. The overarching goal of this study was to ensure a targeted delivery of a glyco-malformin C analog through the coupling of D-glucose moiety; selective transport via glucose transporters (GLUTs) into tumor cells, followed by hydrolysis in the tumor microenvironment releasing the active malformin C a glycon analog. Furthermore, total synthesis of malformin C was carried out with overall improved strategies avoiding unwanted side reactions thus increasing easier purification. We also report on an improved solid phase peptide synthesis protocol for malformin A1.
- Andreana, Peter R.,Hossain, Farzana,Nishat, Sharmeen
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- Excited-State Palladium-Catalyzed Radical Migratory Mizoroki-Heck Reaction Enables C2-Alkenylation of Carbohydrates
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Excited-state palladium catalysis has emerged as a promising strategy for developing novel and valuable reactions. Herein, we report the first excited-state Pd-catalyzed 1,2-radical migratory Mizoroki-Heck reaction that enables C2-alkenylation of carbohydrates using readily available 1-bromosugars and alkenes. The reaction tolerates a wide variety of functional groups and complex molecular architectures, including derivatives of natural products and marketed drugs. Preliminary mechanistic studies and DFT calculations suggest the involvement of visible-light-induced photoexcitation of Pd species, 1,2-spin-centered-shift (SCS) process, and Heck-type cross-coupling reaction. The reaction expands the reactivity profile of excited-state Pd catalysis and provides a streamlined protocol for the preparation of a wide variety of C2-alkenylated carbohydrate mimetics to aid the discovery and development of new therapeutics, agrochemicals, and materials.
- Liu, Peng,Mukherjee, Upasana,Ngai, Ming-Yu,Wu, Yue,Yao, Wang,Zhao, Gaoyuan,Zhou, Lin
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supporting information
p. 3353 - 3359
(2022/03/08)
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- Synthesis and antifungal and antibacterial evaluation of novel pyrimidine derivatives with glycoside scaffolds
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In order to discover new leading compounds with high antifungal and antibacterial activities, in this study, fifteen novel pyrimidine derivatives with glycoside scaffolds were synthesized using d-glucose as a starting material by five-step reactions. All of the newly synthesized compounds were screened for their in vitro antifungal activities against Phytophthora infestans, Gibberella zeae, Botryosphaeria dothidea, Phompsis sp., Thanatephorus cucumeris, and antibacterial activities against Xanthomonas oryzae pv. oryzae and Xanthomonas citri subsp. citri. Bioassay results indicated that compounds 4l, 4m, and 4o showed better in vitro antifungal activity against P. infestans, with the EC50 values of 3.42, 3.99, and 2.73?μg/mL, respectively, than that of dimethomorph (4.49?μg/mL).
- Chen, Meihang,Zhang, Xun,Luo, Hairong,Zhou, Zengyan,Chen, Meiyun,Wu, Wenneng,Lu, Daowang
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p. 1321 - 1328
(2021/10/29)
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- Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase
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We applied dynamic combinatorial chemistry (DCC) to find novel ligands of the bacterial virulence factor glucosyltransferase (GTF) 180. GTFs are the major producers of extracellular polysaccharides, which are important factors in the initiation and development of cariogenic dental biofilms. Following a structure-based strategy, we designed a series of 36 glucose- and maltose-based acylhydrazones as substrate mimics. Synthesis of the required mono- and disaccharide-based aldehydes set the stage for DCC experiments. Analysis of the dynamic combinatorial libraries (DCLs) by UPLC-MS revealed major amplification of four compounds in the presence of GTF180. Moreover, we found that derivatives of the glucose-acceptor maltose at the C1-hydroxy group act as glucose-donors and are cleaved by GTF180. The synthesized hits display medium to low binding affinity (KD values of 0.4–10.0 mm) according to surface plasmon resonance. In addition, they were investigated for inhibitory activity in GTF-activity assays. The early-stage DCC study reveals that careful design of DCLs opens up easy access to a broad class of novel compounds that can be developed further as potential inhibitors.
- Hartman, Alwin M.,Jumde, Varsha R.,Elgaher, Walid A. M.,Te Poele, Evelien M.,Dijkhuizen, Lubbert,Hirsch, Anna K. H.
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p. 113 - 123
(2020/07/13)
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- Synthesis and antitumor activity of novel pyridoxine-based structural analogs of saccharumoside-B
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A series of 11 new pyridoxine-based structural analogs of saccharumoside-B were obtained using original synthetic approach. Antitumor activity of these compounds against nine human tumor cell lines (MCF-7, MDA-MB-231, A-498, SNB-19, M-14, NCI-H322M, HCT-115, HCT-116, and PC-3) was studied, and cytotoxic activity to three normal (HEK-293, Chang Liver, and MSC) cell lines was evaluated. Among the synthesized compounds, 12d, 12e, 13b, 13d, 13e, and 14 exhibited the highest antitumor activity, comparable to that of camptothecin and doxorubicin, but with significantly increased selectivity toward tumor cells. [Figure not available: see fulltext.]
- Pugachev, Mikhail V.,Agafonova, Maria N.,Bastrikova, Oksana A.,Gnezdilov, Oleg I.,Nikishova, Tatyana V.,Balakin, Konstantin V.,Shtyrlin, Yurii G.
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p. 1139 - 1150
(2021/03/31)
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- Synthesis of podophyllotoxin-glycosyl triazoles via click protocol mediated by silver (I)-N-heterocyclic carbenes and their anticancer evaluation as topoisomerase-II inhibitors
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Herein we report the regioselective synthesis of podophyllotoxin-Glycosyl triazole hybrids catalysed by Ag(I)-N-heterocyclic carbene (Ag(I)-NHC) in a short reaction time (～30 min) at ambient conditions. In principle, it is the first report of Click alkyne-azide cycloaddition catalysed by Ag(I)-NHC catalyst and moreover, this new methodology yielded good results when compared with traditional CuAAC in terms of reaction time and selectivity. The synthesised compounds were further explored for in vitro anticancer activity against four human cancer cell lines Du145, HeLa, A-549, and MCF-7 and found that these synthesised compounds possess significant anticancer activity. Further, the compounds 5a and 5e were identified as promising leads due to their better activity across all cell lines than that of the standard drug etoposide. Molecular docking studies of 5a & 5e with DNA Topoisomerase-II were revealed that the free energy calculations of active compounds were in good agreement with observed IC50 values.
- Nerella, Srinivas,Kankala, Shravankumar,Gavaji, Brahmeshwari
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supporting information
p. 9 - 16
(2019/06/27)
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- GLYCOSIDE COMPOUND AND PREPARATION METHOD THEREFOR, COMPOSITION, APPLICATION, AND INTERMEDIATE
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The present invention discloses a glycoside compound represented by Formula III, and a preparation method, a composition, use and an intermediate thereof. The glycoside compound provided in the present invention has simple preparation method, can significantly increase the expression of VEGF-A mRNA, and is effective in promoting the angiogenesis. This provides a reliable guarantee for the development of drugs with pro-angiogenic activity for treating cerebral infarction cerebral stroke, myocardial infarction, and ischemic microcirculatory disturbance of lower limbs.
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- Visible-light-promoted 3,5-dimethoxyphenyl glycoside activation and glycosylation
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A new glycosylation method promoted by visible light with 3,5-dimethoxyphenyl glycoside as the donor was developed. This protocol delivers bothO-glycosides andN-glycosides in moderate to excellent yields using a wide range ofO-nucleophiles and nucleobases as the glycosyl acceptors.
- Cao, Yafei,Li, Qin,Liu, Da-Ke,Liu, Jianhui,Mao, Run-Ze,Xia, Feng,Xiong, De-Cai,Ye, Xin-Shan,Zhou, Minmin,Zou, You
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supporting information
p. 10899 - 10902
(2021/10/25)
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- Synthesis and biological activities of novel S-β-D-glucopyranoside derivatives of 1,2,4-triazole
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In this study, 14 novel S-β-D-glucopyranosides of 1,2,4-triazole derivatives were synthesized and characterized by 1H NMR, 13C NMR, and HRMS. Then their antifungal activities against Gibberella zeae (G. zeae), Botryosphaeria dothidea (B. dothidea), Phompsis sp., Phytophthora infestans (P. infestans), Thanatephorus cucumeris (T. cucumeris) and antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas citri subsp. citri (Xcc) were evaluated. Bioassay results indicated that most of the title compounds exhibited good antifungal activities. Among them, compounds 4g, 4k, 4m, and 4n showed better antifungal activities against P. infestans with EC50 values of 4.98, 4.09, 3.85, and 4.90 μg/mL, respectively compared with Dimethomorph (6.06 μg/mL).
- Chen, Meihang,Lu, Daowang,Zhang, Xun,Chen, Meiyun,Dong, Changjun,Wang, Xian,Wu, Wenneng,Zhang, Guoping,Luo, Hairong
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supporting information
p. 679 - 684
(2021/03/24)
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- Synthesis of arylfuran derivatives as potential antibacterial agents
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Bacterial infections represent a serious health care problem mainly due to the misuse and overuse of antibiotics, with consequent emergence of multidrug resistant bacterial strains. Then, because the urgent need to find novel and alternative antibacterial agents, the present work focuses on the synthesis of arylfuran derivatives with potential antimicrobial activity. Eighteen arylfuran derivatives were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Among them, seven compounds containing an amino group in their structure showed activity, with compound 24 being the most effective against both Gram-negative (E. coli, MIC = 49 μM) and Gram-positive (S. aureus, MIC = 98 μM) bacteria, besides having exhibited a modest activity against P. aeruginosa (MIC = 770 μM). In addition, based on in silico studies, this is a druglike compound since it does not violate any rules for predicting oral bioavailability. In this context, the significant antibacterial potential and the low similarity with known antibiotics indicate the innovative aspect of compound 24.
- Andrade, Marina M. S.,Protti, ícaro F.,Maltarollo, Vinícius G.,da Costa, Ygor F. G.,de Moraes, Wesley G.,Moreira, Nicole F.,Garcia, Giovana G.,Caran, Gabriel F.,Ottoni, Flaviano M.,Alves, Ricardo J.,Moreira, Carolina P. S.,Martins, Helen R.,Alves, Maria Silvana,de Oliveira, Renata B.
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p. 1074 - 1086
(2021/02/26)
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- Discovery of degradable niclosamide derivatives able to specially inhibit small cell lung cancer (SCLC)
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Small cell lung cancer (SCLC) is exceedingly tough to treat and easy to develop resistance upon long use of the first-line drug carboplatin or radiotherapy. Novel medicines effective and specific against SCLC are greatly needed. Herein, we focused on the discovery of such a medicine by exploring a drug niclosamide with repurposing strategy. Initial screening efforts revealed that niclosamide, an anthelmintic drug, possessed the in vitro anticancer activity and an obvious sensitivity towards SCLC. This observation inspired the evaluation for two different kinds of niclosamide derivatives. 2 with a degradable ester as a linker exhibited the comparable activity but slightly inferior selectivity to SCLC, by contrast, the cytotoxicities of 4 and 5 with non-degradable ether linkages completely disappeared, clearly validating the importance of 2-free hydroxyl group or 2-hydroxyl group released in the antitumor activity. Mechanism study unfolded that, similar to niclosamide, 2 inhibited growth of cancer cells via p 53 activation and subsequent underwent cytochrome c dependent apoptosis. Further structural modification to afford phosphate sodium 8 with significantly enhanced aqueous solubility (22.1 mg/mL) and a good selectivity towards SCLC demonstrated more promising druggability profiles. Accordingly, niclosamide as an attractive lead hold a huge potential for developing targeted anti-SCLC drugs.
- He, XingGang,Li, MaoLin,Ye, WenChong,Zhou, Wen
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- A Sweet H2S/H2O2Dual Release System and Specific Protein S-Persulfidation Mediated by Thioglucose/Glucose Oxidase
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H2S and H2O2 are two redox regulating molecules that play important roles in many physiological and pathological processes. While each of them has distinct biosynthetic pathways and signaling mechanisms, the crosstalk between these two species is also known to cause critical biological responses such as protein S-persulfidation. So far, many chemical tools for the studies of H2S and H2O2 have been developed, such as the donors and sensors for H2S and H2O2. However, these tools are normally targeting single species (e.g., only H2S or only H2O2). As such, the crosstalk and synergetic effects between H2S and H2O2 have hardly been studied with those tools. In this work, we report a unique H2S/H2O2 dual donor system by employing 1-thio-β-d-glucose and glucose oxidase (GOx) as the substrates. This enzymatic system can simultaneously produce H2S and H2O2 in a slow and controllable fashion, without generating any bio-unfriendly byproducts. This system was demonstrated to cause efficient S-persulfidation on proteins. In addition, we expanded the system to thiolactose and thioglucose-disulfide; therefore, additional factors (β-galactosidase and cellular reductants) could be introduced to further control the release of H2S/H2O2. This dual release system should be useful for future research on H2S and H2O2.
- Ni, Xiang,Li, Xiaolu,Shen, Tun-Li,Qian, Wei-Jun,Xian, Ming
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supporting information
p. 13325 - 13332
(2021/09/03)
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- Excited-State Palladium-Catalyzed 1,2-Spin-Center Shift Enables Selective C-2 Reduction, Deuteration, and Iodination of Carbohydrates
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Excited-state catalysis, a process that involves one or more excited catalytic species, has emerged as a powerful tool in organic synthesis because it allows access to the excited-state reaction landscape for the discovery of novel chemical reactivity. Herein, we report the first excited-state palladium-catalyzed 1,2-spin-center shift reaction that enables site-selective functionalization of carbohydrates. The strategy features mild reaction conditions with high levels of regio- and stereoselectivity that tolerate a wide range of functional groups and complex molecular architectures. Mechanistic studies suggest a radical mechanism involving the formation of hybrid palladium species that undergoes a 1,2-spin-center shift followed by the reduction, deuteration, and iodination to afford functionalized 2-deoxy sugars. The new reactivity will provide a general approach for the rapid generation of natural and unnatural carbohydrates.
- Zhao, Gaoyuan,Yao, Wang,Mauro, Jaclyn N.,Ngai, Ming-Yu
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supporting information
p. 1728 - 1734
(2021/02/06)
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- Nickel-Catalyzed Radical Migratory Coupling Enables C-2 Arylation of Carbohydrates
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Nickel catalysis offers exciting opportunities to address unmet challenges in organic synthesis. Herein we report the first nickel-catalyzed radical migratory cross-coupling reaction for the direct preparation of 2-Aryl-2-deoxyglycosides from readily available 1-bromosugars and arylboronic acids. The reaction features a broad substrate scope and tolerates a wide range of functional groups and complex molecular architectures. Preliminary experimental and computational studies suggest a concerted 1,2-Acyloxy rearrangement via a cyclic five-membered-ring transition state followed by nickel-catalyzed carbon-carbon bond formation. The novel reactivity provides an efficient route to valuable C-2-Arylated carbohydrate mimics and building blocks, allows for new strategic bond disconnections, and expands the reactivity profile of nickel catalysis.
- Zhao, Gaoyuan,Yao, Wang,Kevlishvili, Ilia,Mauro, Jaclyn N.,Liu, Peng,Ngai, Ming-Yu
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supporting information
p. 8590 - 8596
(2021/06/28)
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- First total syntheses of two natural glycosides
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Isosyringinoside (1) and 3-(O-β-D-glucopyranosyl)-α-(O-β-D-glucopyranosyl)-4-hydroxy phenylethanol (2), the natural bioactive compounds contained unique structures, were first totally synthesized using easily available materials in short convenient routes with overall yields of 20.2% and 27.0%, respectively. An efficient total synthesis of 1 was developed in six steps, which contained two key steps of highly regioselective glycosylation without any selective protection steps. The seven-step synthesis of 2 involved two steps of regioselective glycosylations using BF3–O(C2H5)2 and TMSOTf as catalysts, respectively.
- Dong, Hongbo,Du, Weihong,Yao, Zhongquan,Wu, Min,Luo, Hongbing,He, Yujiao,Cao, Shenghua
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supporting information
(2020/12/02)
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- First total syntheses of four natural bioactive glucosides
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The efficient total syntheses of four biologically interesting natural glucosides Ethylconiferin, Butylconiferin, 2’-Butoxyethylconiferin and Balajaponin B, have been achieved for the first time starting from commercially available Vanilline via concise reaction sequence of 8–10 steps with the overall yield of 26–41%. This work definitely laid the foundation for the further pharmacological study of this kind of natural compounds. Meanwhile, currently developed approach could be used as a general synthetic strategy for the syntheses of other monolignol glucosides and their derivatives, and provides an opportunity for further study of the structure-activity relationship of this kind of glucosides.
- Xu, Guangya,Wu, Min,Yao, Zhongquan,Lou, Hongbin,Du, Weihong,Song, Mingwei,He, Yujiao,Dong, Hongbo
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supporting information
p. 1266 - 1271
(2021/02/06)
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- Chemical Synthesis and Biological Evaluations of Adiponectin Collagenous Domain Glycoforms
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The homogeneously glycosylated 76-amino acid adiponectin collagenous domains (ACDs) with all of the possible 15 glycoforms have been chemically and individually synthesized using stereoselective glycan synthesis and chemical peptide ligation. The following biological and pharmacological studies enabled correlating glycan pattern to function in the inhibition of cancer cell growth as well as the regulation of systemic energy metabolism. In particular, hAdn-WM6877 was tested in detail with different mouse models and it exhibited promising in vivo antitumor, insulin sensitizing, and hepatoprotective activities. Our studies demonstrated the possibility of using synthetic glycopeptides as the adiponectin downsized mimetic for the development of novel therapeutics to treat diseases associated with deficient adiponectin.
- Wu, Hongxiang,Zhang, Yiwei,Li, Yuanxin,Xu, Jianchao,Wang, Yu,Li, Xuechen
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supporting information
p. 7808 - 7818
(2021/05/26)
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- Paclitaxel cyanoside compound and preparation method and application of compound
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The invention discloses a paclitaxel cyanoside compound and a preparation method and application of the compound. The paclitaxel cyanoside compound is a compound as shown in the following formula I and pharmaceutically acceptable salt or hydrate of the compound. The paclitaxel cyanoside compound of the invention can be applied to preparing drugs for preventing and treating thrombotic diseases, andhas good drug effect and small toxic and side effects, and the invention further provides a method for extracting the paclitaxel cyanoside compound from sorghum roots and a preparation method of derivatives of the paclitaxel cyanoside compound. According to the present invention, the paclitaxel cyanoside compound extracted from the sorghum root is extracted and separated from the sorghum root forthe first time. A new choice is provided for the medicine for thrombotic diseases, and the application of the sorghum roots is broadened.
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Paragraph 0041; 0059-0060; 0062
(2021/01/25)
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- Synthesis and structural characterization of new benzylidene glycosides, cytotoxicity against cancer cell lines and molecular modeling studies
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This work describes the synthesis, structural characterization (by combined Fourier Transform Infrared - FTIR, 1H and 13C Nuclear Magnetic Resonance - NMR spectroscopy and High Resolution Mass Spectrometry - HRMS) and biological evaluation of a new series of glycosides designed from a benzylidene glucoside derived from eugenol (23) active against Candida glabrata. The mass accuracy between the calculated and found values observed in HRMS analyses were lower than 5 ppm, which are acceptable for proposing a molecular formula using this technique. We decided to keep the benzylidene group of 23, while changing either the saccharide unit (glucose or galactose) or the natural aglycone (eugenol, isoeugenol, dihydroeugenol or guaiacol) to check their influence in antifungal activity. Since the chemical modifications performed did not contribute to enhance the antifungal activity, the synthesized compounds (23–30) were further screened against four cancer cell lines (HeLa: cervix carcinoma; MDA-MB-231: breast carcinoma; T-24: urinary bladder carcinoma; and TOV-21G: ovarian carcinoma). The glucoside 27 showed promising activities (IC50 10.08–59.91 μM) against all the assayed cancer cell lines and higher values of selectivity index than doxorubicin, the control drug. The galactoside 28 demonstrated interesting results against HeLa, MDA-MB-231 and T-24 cells. This compound was active at 17.41 μM with a selectivity index greater than 13.7 against the HeLa cells, while doxorubicin was active at 10.01 μM with a selectivity index close to 1.5 considering this cell line. Further, we performed docking studies of these compounds with type II topoisomerase-DNA complex (TOP2) in order to try to explain their mechanism of action.
- Péret, Vinícius Augusto Campos,Reis, Adriana Cotta Cardoso,Silva, Naiara Chaves,Dias, Amanda Latercia Tranches,Carvalho, Diogo Teixeira,Dias, Danielle Ferreira,Braga, Saulo Fehelberg Pinto,Brand?o, Geraldo Célio,de Souza, Thiago Belarmino
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- Glucosyl-1,2,3-triazoles derived from eugenol and analogues: Synthesis, anti-Candida activity, and molecular modeling studies in CYP-51
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This work describes the synthesis, anti-Candida, and molecular modeling studies of eighteen new glucosyl-1,2,3-triazoles derived from eugenol and correlated phenols. The new compounds were characterized by combined Fourier Transform Infrared, 1H and 13C nuclear magnetic resonance and spectroscopy of high-resolution mass spectrometry. The synthesized compounds did not show significant cytotoxicity against healthy fibroblast human cells (MCR-5) providing interesting selectivity indexes (SI) to active compounds. Considering the antifungal activity, nine compounds showed anti-Candida potential and the peracetylated triazoles 17 and 18 were the most promising ones. Eugenol derivative 17 was active against three species of Candida at 26.1–52.1?μM. This compound was four times more potent than fluconazole against Candida krusei and less toxic (SI?>?6.6) against the MCR-5 cells than fluconazole (SI?>?3.3) considering this strain. Dihydroeugenol derivative 18?showed similar activity to 17 and was four times more potent and less toxic than fluconazole against C.?krusei. The deacetylated glucosides and non-glucosylated corresponding derivatives did not show considerable antifungal action, suggesting that the acetyl groups are essential for their anti-Candida activity. Molecular docking coupled with molecular dynamics showed that 14α-lanosterol demethylase is a feasible molecular target, since 17 and 18 could bind to this enzyme once deacetylated in vivo, thereby acting as prodrugs. Also, these studies demonstrated the importance of hydrophobic substituents at the phenyl ring.
- Magalh?es, Lorena Severiano de,Reis, Adriana Cotta Cardoso,Nakao, Izadora Amaral,Péret, Vinícius Augusto Campos,Reis, Rúbia Castro Fernandes Melo,Silva, Naiara Chaves,Dias, Amanda Latércia Tranches,Carvalho, Diogo Teixeira,Dias, Danielle Ferreira,Brand?o, Geraldo Célio,Braga, Saulo Fehelberg Pinto,Souza, Thiago Belarmino de
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p. 903 - 913
(2021/09/15)
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- Novel hymexazol oxyglycoside conjugate as well as preparation and application thereof
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The invention discloses a preparation method and application of a novel hymexazol oxyglycoside conjugate bactericide. Galactose, mannose, glucose, mannosamine, galactosamine, glucosamine, N-acetyl-galactosamine, N-acetyl-mannosamine and acetylglucosamine are respectively conjugated with hymexazol to obtain a series of hymexazol oxyglycoside conjugates. The structural general formula of the compound is shown as I, R is hydroxyl, oxyacetyl, amino and acetamido, and R1 is hydrogen and acetyl. The conjugate disclosed by the invention is novel in structure, has good solubility and antifungal activity, and has the potential of becoming a novel green bactericide.
- -
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Paragraph 0038; 0040
(2021/08/19)
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- Diastereoselective Synthesis of Thioglycosides via Pd-Catalyzed Allylic Rearrangement
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Stereoselective glycosylation is challenging in carbohydrate chemistry. Herein, stereoselective thioglycosylation of glycals via palladium-catalyzed allylic rearrangement yields various substituents on α-isomer thioglycosides. Two comprehensive series of aryl and benzyl thioglycosides were obtained via a combination of thiosulfates with glycals derived from glucose, arabinose, galactose, and rhamnose. Furthermore, diosgenyl α-l-rhamnoside and isoquercitrin achieved selectivity via stereospecific [2,3]-sigma rearrangements of α-sulfoxide-rhamnoside and α-sulfoxide-glucoside, respectively.
- Jiang, Xuefeng,Li, Jiagen,Wang, Ming
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supporting information
p. 9053 - 9057
(2021/11/30)
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- Large-scale synthesis of thio-glucose-conjugated chlorin E6 for photodynamic therapy
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Chlorin e6 is a heterocycle exhibiting spectral absorption in the 600-700 nm wavelength range used for photodynamic therapy (PDT). Herein, a sugar-conjugated chlorin e6 derivative was synthesized on a large scale. An alkyl spacer was fabricated by controlling the alkoxylation conditions between the thio-sugar and chlorin e6 and thio-glucose-conjugated chlorin e6 was successfully synthesized.
- Hyakumura, Keisuke,Kataoka, Hiromi,Kodama, Shintaro,Masuda, Masato,Narumi, Atsushi,Nomoto, Akihiro,Ogawa, Akiya,Okamoto, Yoshiharu,Osaki, Tomohiro,Tanaka, Mamoru,Yamaguchi, Hiroaki,Yano, Shigenobu,Yoshimura, Tomokazu
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- Halogenation and anomerization of glycopyranoside by TESH/bromine and BHQ/bromine
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Treatment of peracetylated glycosides and β-isopropyl glycosides with halogen in the presence of TESH and BHQ has been found to result in the halogenation and the anomerization, respectively. Peracetylatedglycosides treaded with I2/TESH or Br2/TESH leading tothe formation of corresponding glycosyl halides, and b-isopropyl glycosidesreacted with Br2/BHQ resulting in the formation of a-glycosides. The anomerizationof glycosidic bond was considered to be catalyzed by in situ formation of hydrogenbromide from the mixing of Br2/BHQ.
- Xu, Lai,Luo, Chin-Hung,Chen, Chien-Sheng
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p. 315 - 321
(2020/07/13)
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- GLUCOSE TRIPTOLIDE CONJUGATES AND USES THEREOF
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A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, the present disclosure designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activity in vitro and in vivo. The glutriptolides disclosed herein possess improved stability in human serum, greater selectivity towards cancer over normal cells and increased potency against cancer cells. Importantly, the glutriptolides are more potent against cancer cells under hypoxic conditions in contrast to existing cytotoxic drugs. These glutriptolides also exhibit sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Together, these findings suggest a new strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.
- -
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Paragraph 00268
(2021/09/11)
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- Convenient synthesis of long alkyl-chain triazolylglycosides using ionic liquid as dual promoter-solvent: Readily access to non-ionic triazolylglycoside surfactants for evaluation of cytotoxic activity
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A convenient method for the one-pot synthesis of long alkyl-chain triazolylglycosides using ionic liquid as dual promoter and solvent is described via a sequential one-pot two-step glycosidation-CuAAc click reaction. The reaction was carried out using commercially available substrates, including glycosyl bromides, sodium azide and various long alkyl-chain alkynes to achieve the corresponding products in moderate to high yields. Furthermore, this approach was successfully applied for the preparation of non-ionic monocatenary triazolylglycoside surfactants in excellent yields through simple deacetylation. Subsequently, these surfactants were further evaluated for their cytotoxic activity.
- Ketsomboon, Nutthanicha,Saeeng, Rungnapha,Sirion, Uthaiwan,Srisook, Klaokwan
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- CuAAC mediated synthesis of cyclen cored glycodendrimers of high sugar tethers at low generation
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Glycodendrimers are receiving considerable attention to mimic a number of imperative features of cell surface glycoconjugate and acquired excellent relevance to a wide domain of investigations including medicine, pharmaceutics, catalysis, nanotechnology, carbohydrate-protein interaction, and moreover in drug delivery systems. Toward this end, an expeditious, modular, and regioselective triazole-forming CuAAC click approach along with double stage convergent synthetic method was chosen to develop a variety of novel chlorine-containing cyclen cored glycodendrimers of high sugar tethers at low generation of promising therapeutic potential. We developed a novel chlorine-containing hypercore unit with 12 alkynyl functionality originated from cyclen scaffold which was confirmed by its single crystal X-ray data analysis. Further, the modular CuAAC technique was utilized to produce a variety of novel 12–sugar coated (G0) glycodendrimers 12-15 adorn with β-Glc-, β-Man-, β-Gal-, β-Lac, along with 36-galactose coated (G1) glycodendrimer 18 in good-to-high yield. The structures of the developed glycodendrimer architectures have been well elucidated by extensive spectral analysis including NMR (1H & 13CNMR), HRMS, MALDI-TOF MS, UV–Vis, IR, and SEC (Size Exclusion Chromatogram) data.
- Agrahari, Anand K.,Jaiswal, Manoj K.,Yadav, Mangal S.,Tiwari, Vinod K.
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- CHARGE VARIANT LINKERS
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The present disclosure provides, inter alia, ADCs with charge variant chemical linkers useful in treating various diseases such as cancer and autoimmune disorders.
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Page/Page column 219
(2021/10/15)
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- Synthesis and antimicrobial studies of novel n-glycosyl hydrazino carbothioamide
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In view of applications of N-glycosylated compounds in medicinal chemistry and in many other ways, herein the synthesis of novel N-glycosyl hydrazino carbothioamides is reported. New N-glycosyl hydrazino carbothioamides were synthesized by the condensation of per-O-acetyl glycosyl isothiocyanate with different aromatic hydrazides. The newly synthesized compounds were characterized by using the IR, 1H NMR and mass spectral studies. Antimicrobial evaluation of the synthesized N-glycosyl hydrazino carbothioamide was also examined. Antimicrobial activities of the synthesized compound were evaluated against bacteria E. coli, P. aeruginosa, S. aureus, S. pyogenus and fungi C. albicans, A. niger and A. clavatus. All the N-glycosyl hydrazino carbothioamides exhibit promising antimicrobial activity.
- Nayak, Riddhi A.,Mangte, Anvita D.
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p. 127 - 131
(2021/01/06)
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- Allyl palladium complexes bearing carbohydrate-based N-heterocyclic carbenes: Anticancer agents for selective and potent in vitro cytotoxicity
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Novel allyl palladium compounds stabilized by carbohydrate-based N-heterocyclic carbenes (NHCs) were prepared and characterized by nuclear magnetic resonance, high-resolution mass spectrometry and elemental analysis. The antiproliferative activity of the compounds was tested on a panel of different tumor lines, especially ovarian cancer and MRC-5 human lung fibroblasts (nontumor cells). These experiments showed that both mixed NHC/PPh3 and NHC/PTA (PTA = 1,3,5-triaza-7-phosphaadamantane) allyl complexes have IC50 (half maximal inhibitory concentration) values comparable and sometimes even significantly lower than cisplatin. Moreover, the mixed NHC/PTA allyl complexes exhibit good activity toward the seven tumor lines tested with a substantial inactivity against normal cells, a necessary condition to avoid the general cytotoxicity of a metallo-drug. Furthermore, this subclass of compounds proved particularly active on the A549 lung cancer tumor line (up to 100-fold more cytotoxic than cisplatin) and exhibited satisfactory cytotoxicity against KURAMOCHI and OVCAR3 cell lines, which are currently considered the best in vitro models for serous ovarian cancer, the most lethal tumor for women worldwide.
- Scattolin, Thomas,Bortolamiol, Enrica,Rizzolio, Flavio,Demitri, Nicola,Visentin, Fabiano
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- Structure–Activity Relationship Study of a Potent α-Thrombin Binding Aptamer Incorporating Hexitol Nucleotides
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The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the hexitol backbone. Importantly, the NU172-TH9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 percent human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.
- De Fenza, Maria,Eremeeva, Elena,Troisi, Romualdo,Yang, Hui,Esposito, Anna,Sica, Filomena,Herdewijn, Piet,D'Alonzo, Daniele,Guaragna, Annalisa
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p. 9589 - 9597
(2020/07/13)
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- Applicability of aluminum amalgam to the reduction of arylnitro groups
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An array of arylnitro compounds with various functionality were treated with freshly-prepared aluminum amalgam in THF/water solution and resulted in the corresponding arylamines. The Al(Hg)-mediated reductions are relatively rapid with consumption of the amalgam and disappearance of starting material occurring over 20–30 min. The workup of the reductions involves only removal of the insoluble by-products by filtration followed by concentration. Only in some cases is chromatography required to secure the pure product. The desired arylamines are furnished in quantities of 25–100 mg, which in some cases, could be taken on to the next reaction without further purification. Reductions of 4-nitrobenzyl derivatives of carbohydrates or nucleosides were selective in affording the corresponding 4-aminobenzyl products. To show applicability in click chemistry, selected aminobenzyl products are directly azidated to yield products that were then used in click reactions to afford the corresponding 1,2,3-triazoles.
- Luzzio, Frederick A.,Monsen, Paige J.
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supporting information
(2020/11/02)
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- Synthesis of photolabile group protected anomeric acetals and its application in carbohydrate synthesis with the assistance of continuous flow photo-reactor
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Selective deprotection of photolabile anomeric 2-nitrobenzyl acetals was achieved using continuous flow photo-reactor (UV radiation at 355 nm) in methanol-water. Various protecting groups such as acetyl, benzyl, benzoyl, benzylidine, TBS, etc. were found to be highly stable during the photolysis.
- Tiwari, Varsha,Badavath, Vishnu Nayak,Singh, Adesh Kumar,Kandasamy, Jeyakumar
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p. 227 - 236
(2020/03/18)
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- Substituted pyrazole compound, preparation method, pharmaceutical composition and applications thereof
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The invention discloses a substituted pyrazole compound represented by a formula I, and a preparation method, a pharmaceutical composition and applications thereof, wherein the compound has characteristics of good stability, excellent solubility, low cytotoxicity and remarkable neuroprotective effect, can effectively prevent and treat nerve cell injury, and is an ideal medicinal compound for preventing or treating cerebral stroke, cerebral embolism, cerebral stroke sequelae, cerebral stroke dyskinesia, mitochondrial encephalomyopathy and amyotrophic lateral sclerosis of spinal cord.
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Paragraph 0299; 0304-0306
(2020/03/12)
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- Design, synthesis and biological evaluation of carbohydrate-based sulphonamide derivatives as topical antiglaucoma agents through selective inhibition of carbonic anhydrase II
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A series of new carbohydrate-based sulphonamide derivatives were designed, synthesised by employing the so-call ‘sugar-tail’ approach. The compounds were evaluated in vitro against a panel of CAs. Compared to their parent compound p-sulfamoylbenzoic acid, these compounds showed nearly 100-fold improvement in their binding affinities against hCA II in vitro. All of compounds showed great water solubility and the pH value of their water solutions of compounds is 7.0. Such properties are advantageous to make them much less irritating to the eye when applied topical glaucomatous drugs, compared to the relatively highly acidic dorzolamide preparations (pH 5.5). Notably, compounds 7d, 7 g, 7 h demonstrated to topically lower intraocular pressure (IOP) in glaucomatous animals better than brinzolamide when applied as a 1% solution directly into the eye. Low cytotoxicity on human cornea epithelial cell was observed in the tested concentrations by the MTT assay.
- Fan, Zhanfang,Guo, Chun,Hou, Zhuang,Li, Chuanchao,Lin, Bin,Liu, Yang,Liu, Yichuang,Wang, Yitong,Zhang, Miao
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p. 383 - 390
(2019/12/30)
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- An Efficient Strategy for the Chemo-Enzymatic Synthesis of Bufalin Glycosides with Improved Water Solubility and Inhibition against Na+, K+-ATPase
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In this study, bufalin was glycosylated by an efficient chemo-enzymatic strategy. Firstly, 2-chloro-4-nitrophenyl-1-O-β-D-glucoside (sugar donors) was obtained by chemical synthesis. Then, the glycosylation of the bufalin was achieved with the synthesized sugar donor under the catalysis of two glycosyltransferases (Loki and ASP). Finally, two glycosides, i. e., bufalin-3-O-β-D-glucopyranoside and bufalin-3-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside)], were obtained by preparative HPLC. Compared to our previously reported sole chemical (total yield 10 % in four steps) or enzymatic methods (30 %), our combined chemo-enzymatic strategy in this article greatly improves the yields of monoglycoside (68 %) and diglycoside (21 %) and decreased the experimental cost (90 %). Furthermore, we tested the water solubility of these glycosides and found that the water solubilities of the two glycosides were 13.1 and 53.7 times of bufalin, respectively. In addition, the inhibitory activity of these glycosides against Na+, K+-ATPase were evaluated. The mono-glycosylated compound showed more potent activity than bufalin, while the diglycosylated compound was less potent.
- Liu, Yan,Xu, Wei,Huang, Zhao-He,Guo, Jun,Jiang, Ren-Wang
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- Method for preparing halogenated sugar under mild conditions
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The invention discloses a method for preparing halogenated sugar under mild conditions. The method comprises the following steps that an easily-prepared thioglycoside donor and a halogen simple substance or halogen intercompound undergo a reaction at room temperature to obtain the halogenated sugar (chlorine, bromine and iodine). The halogen simple substance or the halogen intercompound is commercial easily available iodine elementary substance, iodine bromide and iodine chloride. The method is suitable for various pyranoses and furanoses. The method has no limitation on a protecting group ofthe thioglycoside donor, and the protecting group can be an electron withdrawing group such as acetyl, benzoyl and the like, and can also be an electron donating group such as benzyl, silicon base andthe like. Meanwhile, the reaction can occur in various organic solvents such as dichloromethane, acetonitrile and methylbenzene. The preparation method of the halogenated sugar is simple, reaction conditions are mild, raw materials are easy to obtain, the application range is wide, the halogenated sugar is compatible with acid-labile groups such as isopropylidene ketal and silicon groups, and a pure product can be obtained by removing a solvent from the halogenated sugar which is not stable in the separation process.
- -
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Paragraph 0022-0024
(2020/07/02)
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- Neuroprotective activity of different monosaccharide-modified gastrodin analogs
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Gastrodin is a very important and well-known bioactive glycoside compound in Chinese medicine. It is also known as a drug with neuroprotective function. Here, a practical diversified synthesis of a series of gastrodin analogs was reported, which involved four-step procedures consisting of bromination, oxidation, etherification, and reduction. Various gastrodin analogs were obtained in good yields. The compound 4c in this study has a good neuroprotective function: it can significantly downregulate tumor necrosis factor-α and inducible nitric oxide synthase protein levels. The results of this study can provide a research basis for the development of neuroprotective drugs.
- Xu, Kun-Lun,Yu, Lan
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p. 1263 - 1269
(2020/01/21)
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- Synthesis and biological screening of thiosemicarbazones of substituted 3-acetylcoumarins having D-glucose moiety
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Thiosemicarbazones 5a-j were synthesized with yields of 45–68% by condensation of 3-acetylcoumarins 3a-j and tetra-O-acetyl-β-D-thiosemicarbazide 4. All obtained thiosemicarbazones were screened for anti-microorganic activities against bacteria (B. subtilis, S. aureus, S. epidermidis, E. coli, P. aeruginosa, K. pneumoniae, S. typhimurium) and fungi (A. niger, C. albicans, S. cerevisiae, and A. flavus). Some compounds had significant inhibitory activity with MICs of 0.78–3.125 μM in comparison with 5a, including 5e,h,i for S. aureus, and 5c,f,i for S. epidermidis (Gram-(+) bacteria), 5c,f,g for E.coli, 5f for K. pneumoniae, 5b,c,g for P. aeruginosa, and 5i for S. typhimurium (Gram-(?) bacteria), 5d,h,i for A. niger, 5i for A. flavus, 5b,d,e,h for C. albicans, and 5i for S. cerevisiae. Compounds exhibited excellent activity against tested microorganism with MIC = 0.78 μM, including 5h,i (against S. aureus), 5h (against C. albicans), and 5i (against S. cerevisiae).
- Ngoc Toan, Vu,Dinh Thanh, Nguyen,Minh Tri, Nguyen,Thi Thu Huong, Nguyen
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supporting information
(2020/11/20)
-
- Lapachol acetylglycosylation enhances its cytotoxic and pro-apoptotic activities in HL60 cells
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Lapachol is a plant-derived naphthoquinone that kills several types of cancer cells. Derivatives of this molecule may therefore prove to be useful chemotherapeutic agents. In this study, we explored whether glycosylation increases the cytotoxic potency of lapachol towards HL-60 human leukemia cells. Two beta-glycosides were synthesized and characterized: LA4A (lapachol-β-glucoside) and LA4C (lapachol-N-acetylglucosamine-β-glucoside). The sugar moieties of both novel molecules were per-acetylated to facilitate cellular uptake. The IC50 values (in μM) for LA4A (5.7) and LA4C (5.3) were lower than those for lapachol (25). LA4A and LA4C triggered typical signs of apoptosis, such as the exposure of phosphatidylserine on the outside of cells, chromatin condensation, DNA fragmentation and a decrease of the mitochondrial transmembrane potential (ΔΨm) prior to cell lysis. Moreover, DNA fragmentation triggered by the lapachol-glycosides was reduced by pre-treatment with the caspase inhibitor, z-VAD-fmk. While LA4A and LA4C activated caspases-3, -8 and -9, lapachol failed to activate these apoptotic proteases, even when used at high concentrations. Finally, the toxicity of lapachol and its derivatives was also tested on non-tumor cells. We used human peripheral neurons (PeriTox test) to evaluate the side effect potential of these compounds. LA4C was clearly less toxic than LA4A. We conclude that LA4C had the most favorable profile as drug candidate (high tumor cell toxicity, reduced neurotoxicity). In general, this study shows that the cytotoxicity of lapachol towards HL-60 can be enhanced by glycosylation, and that the therapeutic ratio may be modified by the type of sugar added.
- Alves, Ricardo José,Holzer, Anna-Katharina,Kisitu, Jaffar,Leist, Marcel,Marques, Lucas Bonfim,Ottoni, Flaviano Melo,Pinto, Mauro Cunha Xavier,Ribeiro, Juliana Martins,Souza-Fagundes, Elaine Maria,Weinlich, Ricardo,de Sousa, Fernanda S.,de Victo, Nathalia Cruz
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- Synthesis of (-)-epigallocatechin-3-gallate derivative containing a triazole ring and combined with cisplatin/paclitaxel inhibits NSCLC cancer cells by decreasing phosphorylation of the EGFR
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Non-small-cell lung cancer is one of the principal causes of cancer-related death around the world. Chemotherapy is commonly used to treat wild type of epidermal growth factor receptor non-small-cell lung cancer. (-)-Epigallocatechin-3-gallate is the most abundant and active catechin. However, (-)-epigallocatechin-3-gallate has limited clinical application due to its poor stability and absorption. Herein, we report that a glycosylated azide undergoes a click reaction with the terminal alkyne of (-)-epigallocatechin-3-gallate to yield a triazole-linked glucose-(-)-epigallocatechin-3-gallate derivative and have evaluated its in vitro anticancer activity against human non-small-cell lung cancer cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The product inhibits human non-small-cell lung cancer cell lines with wild type of epidermal growth factor receptor and in combination with cisplatin/paclitaxel results in more pronounced proliferation inhibition than when used alone. Stability investigations indicates that the conjugated glucose residue can improve the stability of the (-)-epigallocatechin-3-gallate scaffold. Our studies suggest that the combination of the glucose-(-)-epigallocatechin-3-gallate derivative and chemotherapeutic drugs may provide a novel strategy for the treatment of non-small-cell lung cancer.
- Zi, Cheng-Ting,Sun, Pei-Yuan,Zhang, Ning,Tang, Han,Yang, Hao-Nang,Wang, Qi,Wang, Yu-Na,Wang, Jing,Wang, Xuan-Jun,Sheng, Jun
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p. 586 - 591
(2020/04/22)
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- Chemical glucosylation of pyridoxine
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The chemical synthesis of pyridoxine-5′-β-D-glucoside (5′-β-PNG) was investigated using various glucoside donors and promoters. Hereby, the combination of α4,3-O-isopropylidene pyridoxine, glucose vested with different leaving and protecting groups and the application of stoichiometric amounts of different promoters was examined with regards to the preparation of the twofold protected PNG. Best results were obtained with 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl fluoride and boron trifluoride etherate (2.0 eq.) as promoter at 0 °C (59%). The deprotection was accomplished stepwise with potassium/sodium hydroxide in acetonitrile/water followed by acid hydrolysis with formic acid resulting in the chemical synthesis of 5′-β-PNG.
- Bachmann, Thomas,Rychlik, Michael
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-
- Chemical synthesis of 5’-β-glycoconjugates of vitamin B6
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Various 5’-β-saccharides of pyridoxine, namely the mannoside, galactoside, arabinoside, maltoside, cellobioside and glucuronide, were synthesized chemically according to KOENIGS-KNORR conditions using α4,3-O-isopropylidene pyridoxine and the respective acetobromo glycosyl donors with AgOTf (3.0 eq.) and NIS (3.0 eq.) as promoters at 0 °C. Furthermore, 5’-β-[13C6]-labeled pyridoxine glucoside (PNG) was prepared starting from [13C6]-glucose and pyridoxine. Additionally, two strategies were examined for the synthesis of 5’-β-pyridoxal glucoside (PLG).
- Bachmann, Thomas,Schnurr, Christian,Zainer, Laura,Rychlik, Michael
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supporting information
(2020/02/15)
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- Photocatalyzed reductive fluoroalkylation of 2-acetoxyglycals towards the stereoselective synthesis of α-1-fluoroalkyl-: C -glycosyl derivatives
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A benign, efficient, regio- and stereoselective protocol for the syntheses of α-1-fluoroalkyl-C-glycosyl compounds bearing CF3, C4F9, and C6F13 substituents on the anomeric carbon has been developed by a new methodology starting from 2-acetoxyglycals for the first time. Remarkably, the reactions proceeded in only one step, through the visible light-photocatalyzed reductive fluoroalkylation of 2-acetoxyglycals by means of an Ir photocatalyst and employed commercially available fluoroalkyl iodides n-CnF2n+1-I (n = 1, 4, 6) as a source of fluoroalkyl radicals.
- Mora Flores, Erwin W.,Postigo, Al,Uhrig, María Laura
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supporting information
p. 8724 - 8734
(2020/11/17)
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- From Glucose to Polymers: A Continuous Chemoenzymatic Process
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Efforts to synthesize degradable polymers from renewable resources are deterred by technical and economic challenges; especially, the conversion of natural building blocks into polymerizable monomers is inefficient, requiring multistep synthesis and chromatographic purification. Herein we report a chemoenzymatic process to address these challenges. An enzymatic reaction system was designed that allows for regioselective functional group transformation, efficiently converting glucose into a polymerizable monomer in quantitative yield, thus removing the need for chromatographic purification. With this key success, we further designed a continuous, three-step process, which enabled the synthesis of a sugar polymer, sugar poly(orthoester), directly from glucose in high yield (73 % from glucose). This work may provide a proof-of-concept in developing technically and economically viable approaches to address the many issues associated with current petroleum-based polymers.
- Banahene, Nicholas,Bettinger, Reuben,Du, Wenjun,Esser-Kahn, Aaron P.,Liang, Zhijie,Maiti, Sampa,Manna, Saikat,Pham, Lucynda,Wang, Jun,Xu, Yi,Zientko, John
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supporting information
p. 18943 - 18947
(2020/08/25)
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- Synthesis of 2′-paclitaxel 2-deoxy-2-fluoro-glucopyranosyl carbonate for specific targeted delivery to cancer cells
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A novel 2-fluorodeoxyglucose conjugated derivative of paclitaxel was efficiently synthesized using a linker between 2′-OH of paclitaxel and C1-hydroxyl group of 2-fluorodeoxyglucose. In preparation of the prodrug, allyl carbonates were selected as the protective group and the efficient one-step removal of allyloxycarbonyl groups at the end of the synthesis using palladium chemistry gave the target molecule in good yield. The prodrug not only improved the pharmaceutical properties of paclitaxel, such as solubility and stability, but also demonstrated enhanced cytotoxicity and selectivity for cancer cells and less toxicity toward normal HUVEC cells.
- Li, Tingshen,Li, Xiao,Lian, Xujing,Meng, Xin,Ya, Qiang,Yang, Yang,Zhang, Yan,Zhang, Yongmin
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supporting information
(2020/06/01)
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- Synthesis method and application of gastrodin semihydrate
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The invention belongs to the technical field of bulk drug synthesis, and particularly relates to a synthesis method of gastrodin semihydrate. The synthesis method of the gastrodin semihydrate comprises a step of reacting 2-bromo-alpha-D-glucose tetraacetate with 4-hydroxymethylphenol in the presence of an alkali, a phase transfer catalyst, water and an organic solvent so as to obtain the gastrodinsemihydrate. The synthesis method is reasonable in reaction route, simple and feasible in operation process, high in the yield and purity of the gastrodin semihydrate, reasonable in cost and more beneficial for industrial production of the gastrodin semihydrate.
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Paragraph 0038-0065
(2020/05/01)
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