Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design and Synthesis of 1,2-Deoxy-pyranose Derivatives of Spliceostatin A toward Prostate Cancer Treatment.

ABSTRACT: We designed and synthesized a novel 1,2-deoxy-pyranose and terminal epoxide methyl substituted derivatives of spliceostatin A using Julia-Kocienski olefination as a key step. With respect to the biological activity, the 1,2-deoxy-pyranose analogue of spliceostatin A suppressed AR-V7 expression at the nano level (IC₅₀ = 3.3 nM). In addition, the in vivo toxicity test showed that the 1,2-deoxy-pyranose analogue was able to avoid severe toxicity compared to spliceostatin A.

SUBMITTER: Yoshikawa Y

PROVIDER: S-EPMC7294732 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1.

Project description:Galectins are a family of galactoside-recognizing proteins involved in different galectin-subtype-specific inflammatory and tumor-promoting processes, which motivates the development of inhibitors that are more selective galectin inhibitors than natural ligand fragments. Here, we describe the synthesis and evaluation of 3-C-methyl-gulopyranoside derivatives and their evaluation as galectin inhibitors. Methyl 3-deoxy-3-C-(hydroxymethyl)-β-d-gulopyranoside showed 7-fold better affinity for galectin-1 than the natural monosaccharide fragment analog methyl β-d-galactopyranoside, as well as a high selectivity over galectin-2, 3, 4, 7, 8, and 9. Derivatization of the 3-C-hydroxymethyl into amides gave gulosides with improved selectivities and affinities; methyl 3-deoxy-3-C-(methyl-2,3,4,5,6-pentafluorobenzamide)-β-d-gulopyranoside had Kd 700 µM for galectin-1, while not binding any other galectin.

| S-EPMC6696278 | biostudies-literature

Synthesis and Antimicrobial Activity of 1,2-Benzothiazine Derivatives.

Project description:A number of 1,2-benzothiazines have been synthesized in a three-step process. Nine chalcones 1-9 bearing methyl, fluoro, chloro and bromo substituents were chlorosulfonated with chlorosulfonic acid to generate the chalcone sulfonyl chlorides 10-18. These were converted to the dibromo compounds 19-27 through reaction with bromine in glacial acetic acid. Compounds 19-27 were reacted with ammonia, methylamine, ethylamine, aniline and benzylamine to generate a library of 45 1,2-benzothiazines 28-72. Compounds 28-72 were evaluated for their antimicrobial activity using broth microdilution techniques against two Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) and two Gram-negative bacteria (Proteus vulgaris and Salmonella typhimurium). The results demonstrated that none of the compounds showed any activity against Gram-negative bacteria P. vulgaris and S. typhimurium; however, compounds 31, 33, 38, 43, 45, 50, 53, 55, 58, 60, 63 and 68 showed activity against Gram-positive bacteria Bacillus subtilis and Staphylococcous aureus. The range of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) was 25-600 µg/mL, though some of the MIC and MBC concentrations were high, indicating weak activity. Structure activity relationship studies revealed that the compounds with a hydrogen atom or an ethyl group on the nitrogen of the thiazine ring exerted antibacterial activity against Gram-positive bacteria. The results also showed that the compounds where the benzene ring of the benzoyl moiety contained a methyl group or a chlorine or bromine atom in the para position showed higher antimicrobial activity. Similar influences were identified where either a bromine or chlorine atom was in the meta position.

| S-EPMC6274075 | biostudies-literature

Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors.

Project description:A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC50 values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound 22e inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated cancer cells and model cells. Compound 22e significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different species has been proposed, and a major NADPH-dependent metabolite 33 was generated by liver microsomes. To block the metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaffold showed promising pharmacological inhibition of c-Met and warrants further investigation.

| S-EPMC4434476 | biostudies-literature

Enantioselective Synthesis of Spliceostatin G and Evaluation of Bioactivity of Spliceostatin G and Its Methyl Ester.

Project description:An enantioselective total synthesis of spliceostatin G has been accomplished. The synthesis involved a Suzuki cross-coupling reaction as a key step. The functionalized tetrahydropyran ring was constructed from commercially available optically active tri-O-acetyl-d-glucal. Other key reactions include a highly stereoselective Claisen rearrangement, a Cu(I)-mediated 1,4 addition of MeLi to install the C8 methyl group, and a reductive amination to incorporate the C10 amine functionality of spliceostatin G. Biological evaluation of synthetic spliceostatin G and its methyl ester revealed that it does not inhibit splicing in vitro.

| S-EPMC5972028 | biostudies-literature

Synthesis of 2-azido-2-deoxy- and 2-acetamido-2-deoxy-D-manno derivatives as versatile building blocks.

Project description:Reported herein is the synthesis of a number of building blocks of 2-amino-2-deoxy-d-mannose from common d-glucose precursors.

| S-EPMC7012756 | biostudies-literature

Design, synthesis, and pharmacological evaluations of pyrrolo[1,2-a]quinoxaline-based derivatives as potent and selective sirt6 activators.

Project description:Sirt6 activation has emerged as a promising drug target for the treatment of various human diseases, while only limited Sirt6 activators have been reported. Herein, a series of novel pyrrolo[1,2-a]quinoxaline-based derivatives have been identified as potent and selective Sirt6 activators with low cytotoxicity. Sirt6-knockdown findings have validated the on-target effects of this class of Sirt6 activators. Docking studies indicate the protonated nitrogen on the side chain of 38 forms π-cation interactions with Trp188, further stabilizing it into this extended binding pocket. New compounds 35, 36, 38, 46, 47, and 50 strongly repressed LPS-induced proinflammatory cytokine/chemokine production, while 38 also significantly suppressed SARS-CoV-2 infection with an EC50 value of 9.3 μM. Moreover, compound 36 significantly inhibited the colony formation of cancer cells. These new molecules may serve as useful pharmacological tools or potential therapeutics against cancer, inflammation, and infectious diseases.

| S-EPMC9805530 | biostudies-literature

Design and Synthesis of Imidazo/Benzimidazo[1,2-<i>c</i>]quinazoline Derivatives and Evaluation of Their Antimicrobial Activity.

Project description:A new class of fused quinazolines has been designed and synthesized via copper-catalyzed Ullmann type C-N coupling followed by intramolecular cross-dehydrogenative coupling reaction in moderate to good yields. The synthesized compounds were tested for in vitro antibacterial activity against three Gram negative (Escherichia coli, Pseudomonas putida, and Salmonella typhi) and two Gram positive (Bacillus subtilis, and Staphylococcus aureus) bacteria. Among all tested compounds, 8ga, 8gc, and 8gd exhibited promising minimum inhibitory concentration (MIC) values (4-8 μg/mL) for all bacterial strains tested as compared to the positive control ciprofloxacin. The synthesized compounds were also evaluated for their in vitro antifungal activity against Aspergillus niger and Candida albicans and compounds 8ga, 8gc, and 8gd having potential antibacterial activity also showed pronounced antifungal activity (MIC values 8-16 μg/mL) against both strains. The bactericidal assay by propidium iodide and live-dead bacterial cell screening using a mixture of acridine orange/ethidium bromide (AO/Et·Br) showed considerable changes in the bacterial cell membrane, which might be the cause or consequence of cell death. Moreover, the hemolytic activity for most potent compounds (8ga, 8gc, and 8gd) showed their safety profile toward human blood cells.

| S-EPMC6643530 | biostudies-literature

Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-?-?-arabinose.

Project description:The incorporation of basic substituents into the structurally conserved domains of cell wall lipopolysaccharides has been identified as a major mechanism contributing to antimicrobial resistance of Gram-negative pathogenic bacteria. Inhibition of the corresponding enzymatic steps, specifically the transfer of 4-amino-4-deoxy-?-arabinose, would thus restore the activity of cationic antimicrobial peptides and several antimicrobial drugs. C-glycosidically-linked phospholipid derivatives of 4-amino-4-deoxy-?-arabinose have been prepared as hydrolytically stable and chain-shortened analogues of the native undecaprenyl donor. The C-phosphonate unit was installed via a Wittig reaction of benzyl-protected 1,5-arabinonic acid lactone with the lithium salt of dimethyl methylphosphonate followed by an elimination step of the resulting hemiketal, leading to the corresponding exo- and endo-glycal derivatives. The ensuing selective monodemethylation and hydrogenolysis of the benzyl groups and reduction of the 4-azido group gave the ?-?-anomeric arabino- and ribo-configured methyl phosphonate esters. In addition, the monomethyl phosphonate glycal intermediates were converted into n-octyl derivatives followed by subsequent selective removal of the methyl phosphonate ester group and hydrogenation to give the octylphosphono derivatives. These intermediates will be of value for their future conversion into transition state analogues as well as for the introduction of various lipid extensions at the anomeric phosphonate moiety.

| S-EPMC6964659 | biostudies-literature

Diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside: synthesis, derivatives and antimicrobial activity.

Project description:The synthesis of diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside is presented for the first time. This synthetic saponin was transformed into its hydrochloride as well as N-acyl, 2-ureido, N-alkyl, and N,N-dialkyl derivatives. Antifungal and antibacterial studies show that some of the obtained compounds are active against Gram-positive bacteria and Candida type fungi.

| S-EPMC5687012 | biostudies-literature