A concise synthesis of a β-lactamase inhibitor

MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N-H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.     

Practical asymmetric synthesis of a novel γ-secretase inhibitor

An efficient route to γ-secretase inhibitor hydroxyl thiophene sulfonamide 1 is described. The approach contains nine steps with an overall yield of 8%. The synthesis highlights a diastereoselective methylation using Evans' oxazolidinone method and a chiral Strecker reaction via Davis' sulfonimine protocol.     

5-epi-Deoxyrhamnojirimycin is a potent inhibitor of an α-l-rhamnosidase: 5-epi-deoxymannojirimycin is not a potent inhibitor of an α-d-mannosidase

Whereas deoxyrhamnojirimycin (LRJ) 1 shows no significant inhibition of naringinase (an α-l-rhamnosidase), its C-5 epimer 2 is a potent and specific inhibitor of the enzyme and demonstrates the value of unambiguous chemical synthesis of such materials in the evaluation of their biological properties. In contrast, moderately weak inhibition towards an α-d-mannosidase is shown by both deoxymannojirimycin (DMJ) 5 and its C-5 epimer 6. Mimics of l-rhamnose which are recognised by enzymes that synthesise or process l-rhamnose may inhibit either the biosynthesis of the sugar or its incorporation into mycobacterial cell walls, providing new strategies for the treatment of diseases such as tuberculosis and leprosy. Molecular modelling studies provide a rationale for the surprisingly potent activity of the C-5 epimer 2 compared with LRJ 1 and support a general hypothesis that potent piperidine glycosidase inhibitors mimic the ⁴H₃ conformation of the relevant glycopyranosyl cation intermediate.     

Preparation of conjugates of α-amylase with a protease inhibitor and their stability

A method for obtaining conjugates of -amylase with a trypsin inhibitor and separating them into fractions has been developed. Two fractions have been obtained—thermostable and thermolabile. The thermostable fraction retained about 80% of its amylase activity after incubation at 50°C for 2 h, with activation of the enzyme during the first 30 min. In the presence of trypsin the conjugated enzyme, retained 91% of its initial activity after incubation for 1 h, although the activity of the native enzyme fell to 35% under the same conditions.Mirzo Ulugbek [Ulugh-Beg] Tashkent State University. Translated from Khimiya Prirodnykh Soedimenii, No. 2, pp. 201–204, Marhc–April, 1998.     

Discovery of a small-molecule inhibitor of Dvl–CXXC5 interaction by computational approaches

The Wnt/β-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl–CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD). Based on the structural analysis of binding modes of MD-simulated Dvl PDZ domain with CXXC5 peptide and crystal Dvl PDZ domain with synthetic peptide–ligands, we generated two different pharmacophore models and applied pharmacophore-based virtual screening to discover potent inhibitors of the Dvl–CXXC5 interaction for the anabolic therapy of osteoporosis. Analysis of 16 compounds selected by means of a virtual screening protocol yielded four compounds that effectively disrupted the Dvl–CXXC5 interaction in the fluorescence polarization assay. Potential compounds were validated by fluorescence spectroscopy and nuclear magnetic resonance. We successfully identified a highly potent inhibitor, BMD4722, which directly binds to the Dvl PDZ domain and disrupts the Dvl–CXXC5 interaction. Overall, CXXC5–Dvl PDZ domain complex based pharmacophore combined with various traditional and simple computational methods is a promising approach for the development of modulators targeting the Dvl–CXXC5 interaction, and the potent inhibitor BMD4722 could serve as a starting point to discover or design more potent and specific the Dvl–CXXC5 interaction disruptors.     

Synthesis of bicyclic β-lactamase inhibitor relabactam derivatives from a relabactam intermediate

We have developed highly efficient chemistry to prepare two key intermediates from a Relabactam intermediate available from the process chemistry. The new intermediates enabled us to quickly synthesize other Ralebactam derivatives such as compound 1.     

Stereoselective synthesis of C-6 hydroxy tricyclic sulfone as a γ-secretase inhibitor

The synthesis of a C-6 hydroxy tricyclic sulfone was described with two key reactions: the Suzuki coupling and the regioselective and stereoselective cis ring opening of the epoxide. Overall, the 14-step synthesis was achieved in 2.1% yield.     

The first total synthesis of lamellarin α 20-sulfate, a selective inhibitor of HIV-1 integrase

The first total synthesis of lamellarin α 20-sulfate (1), a selective inhibitor of HIV-1 integrase, has been completed. The lamellarin α core in which 13-OH and 20-OH were differentially protected by isopropyl and benzyl groups, respectively, was constructed by using Hinsberg-type pyrrole synthesis and Suzuki-Miyaura coupling as the key reactions. The 20-sulfate was prepared by a sequence including debenzylation of 20-OBn, 2,2,2-trichloroethylsulfation of the resulting 20-OH, deprotection of 13-Oi-Pr, and final reductive cleavage of the 2,2,2-trichloroethyl ester.     

Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones

Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the proteasome. Compounds 13 and 15 are β5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent β1 selective compound active in living cells reported to date.     

NMR-restrained docking of a peptidic inhibitor to the N-terminal domain of the phosphoenolpyruvate:sugar phosphotransferase enzyme I

Starting from the NMR structure of the binary complex between the N-terminal domain of the unphosphorylated enzyme I (EIN) of the phosphoenolpyruvate:sugar phosphotransferase (PTS) and the histidine-containing phosphocarrier protein (HPr), a molecular model of the phosphorylated transition state of the related complex was established using constrained simulated annealing. The coordinates of the phosphorylated EIN enzyme were then used in a second step for flexible docking of a decapeptide inhibitor of EIN whose enzyme-bound conformation itself was determined by NMR using transferred nuclear Overhauser effects. Two phosphorylation models of the peptide inhibitor were investigated and shown to be both functional. Interestingly, one model is very similar to that of the complex between EIN and its natural substrate HPr. The present study demonstrates that NMR-guided flexible docking constitutes an interesting tool for docking highly flexible peptide ligands and facilitates the upcoming protein-based design of nonpeptide EIN inhibitors for discovering new antibiotics.     

Synthesis of uronic-noeurostegine--a potent bacterial β-glucuronidase inhibitor

Inhibition of β-glucuronidases has recently been shown to be useful in alleviating drug toxicity for common colon cancer chemotherapeutic CPT-11 (also called Irinotecan). We have prepared a new compound of the nortropane-type, uronic-Noeurostegine, and demonstrated that this is a competitive and potent E. coli β-glucuronidase inhibitor, while inhibition of the mammalian β-glucuronidase from bovine liver was found to be less significant. Although not intended, two other compounds having N-ethyl and N-(4-hydroxybutyl) substituents were also prepared in this study due to the sluggish debenzylation in the final step. The N-substituents are believed to come from reaction with the solvents used being ethanol and THF, respectively. These compounds also inhibited the two β-glucuronidases albeit to a lesser extent compared to the parent compound. Noeurostegine and the three uronic-noeurostegines were additionally evaluated as inhibitors against a wide panel of glycosidases with the former showing potent inhibition of rat intestinal lactase and trehalase, whereas the latter was found to be inactive.     

Dopamine-polyethyleneimine co-deposition of a capillary for α-glucosidase immobilization and its application in enzyme inhibitor screening

An online method based on CE was established to screen α-glucosidase inhibitors from traditional Tibetan medicine extracts. First, the inner wall at the inlet of capillary column was simply and effectively functionalized by dopamine-polyethyleneimine co-deposition method, which combines the adhesion property of dopamine and easy cationization of polyethyleneimine. Then α-glucosidase was rapidly immobilized on the inner wall of the capillary column by electrostatic adsorption. The inter- and intraday repeatability of the peak area of the enzymatic reaction product (p-nitrophenol) in a capillary was evaluated, and RSD% (n = 3) was 0.94% and 1.09%, respectively. Good batch-to-batch reproducibility of the peak area between different capillaries (RSD = 2.1%, n = 5) shows that the preparation method has good reproducibility. The Michaelis–Menten constant of the immobilized α-glucosidase was measured to be 1.18 mM, and the capillary column enzyme reactor retained 85.9% of initial activity after 30 cycles. Finally, it was applied to the screening of enzyme inhibitors in 20 traditional Tibetan medicine extracts. Sixteen medicines with inhibitory activity were screened out, and Rheum australe had the strongest inhibitory effect with an inhibitory rate of 83.3 ± 0.4%. These results showed that this method is effective to find potential enzyme inhibitors.     

Pycnalin, a new α-glucosidase inhibitor from Acer pycnanthum

A new compound, pycnalin (1), together with four known compounds, ginnalins A (2), B (3), C (4), and 3,6-di-O-galloyl-1,5-anhydro-D-glucitol (3,6-di-GAG) (5), were isolated from Acer pycnanthum. The structure of 1 was determined on the basis of 2D-NMR spectral data and synthesis of 1. Pycnalin (1) is the first 1,5-anhydro-D-mannitol linked to a gallic acid, while compounds 2-5 were 1,5-anhydro-D-glucitol linked to gallic acids. All compounds were tested in vitro for α-glucosidase inhibitory and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities. Pycnalin (1) exhibited moderate α-glucosidase inhibitory activity as well as free radical scavenging activity. Ginnalin A (2) and 3,6-di-GAG (5), which have two galloyl groups, exhibited potent α-glucosidase inhibition, compared to those of other compounds 1, 3, and 4 containing a galloyl group. These results suggest that α-glucosidase inhibition is influenced by the number of galloyl groups.     

Preparation of trehalase inhibitor validoxylamine A by biocatalyzed hydrolysis of validemycin a with honeybee (Apis cerana fabr.) β-glucosidase

Validoxylamine A is structurally similar to trehalose and acts a potent competivive inhibitor of trehalase. It has recently been receiving increased attention as a potential material for the development of new insecticides or drugs. In this study, β-glucosidase extracted from honeybees (Apis cerana Fabr.) was used as a catalyst to produce validoxylamine A through enzymatic hydrolysis of validamycin A. β-Glucosidase was separated and purified from honeybees, and its characteristics were examined. The results showed that β-glucosidase was stable across a range of temperatures from 30 to 40°C and across a relatively wide range of pH values from 5.0 to 7.5. Investigation of the biocatalyzed hydrolysis process from validamycin A to validoxylamine A with β-glucosidase revealed that both the substrate (validamycin A) and the product (validoxylamine A) inhibited β-glucosidase activity. The inhibition constant of the substrate K value was 5.01 mM, and that of the product K _ip value was 1.32 mM. This product inhibition was competitive.     

A synthesis of the γ-secretase inhibitor BMS-708163

A concise, convergent racemic synthesis of BMS-708163 is reported. Two fragments consisting of N-4-chlorophenylsulfonyl-3,3,3-trifluorpropylglycine and a 1,2,4-oxadiazole derivative of 2-fluorobenzyl alcohol were prepared in separate pots and then coupled together via a Mitsunobu reaction. Since a convenient chiral synthesis of optically pure (d)-3,3,3-trifluoropropyl glycine methyl ester was developed using Schöllkopf reagent alkylation, this methodology can also be adopted for the enantioselective synthesis of BMS-708163.     

Commiphora pedunculata gum as a green inhibitor for the corrosion of aluminium alloy in 0.1 M HCl

The effect of Commiphora pedunculata (CP) gum on the inhibition of the corrosion of aluminum alloy AA 3001) in solutions of HCl was investigated using gravimetric and thermometric methods of monitoring corrosion. The results obtained indicated that CP gum is a good adsorption inhibitor for the corrosion of aluminum in solutions of HCl. The inhibition efficiency of CP gum was found to increase with an increase in concentration but to decrease with increasing temperature. The adsorption of CP gum on the surface of aluminum was found to be endothermic, spontaneous and to support the mechanism of physical adsorption. The Langmuir adsorption model has been used to describe the adsorption characteristics of CP gum on aluminum surface.     

Investigation of formation of dimeric G-quadruplex of HIV-1 integrase inhibitor by nuclear magnetic resonance

In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.     

Total synthesis of the bacterial RNA polymerase inhibitor ripostatin b

A modular and highly stereoselective synthesis of the title compound was developed. Key steps in the assembly of the carbon framework of ripostatin?B (1; see scheme) were a stereoselective Paterson aldol reaction and a high-yielding ring-closing metathesis mediated by Grubbs first generation catalyst. The C15 hydroxy group was established through Tishchenko-Evans reduction in excellent yield and selectivity.