Dinucleosides with Non‐Natural Backbones: A New Class of Ribonuclease A and Angiogenin Inhibitors

Ribonuclease A (RNase A) serves as a convenient model enzyme in the identification and development of inhibitors of proteins that are members of the ribonuclease superfamily. This is principally because the biological activity of these proteins, such as angiogenin, is linked to their catalytic ribonucleolytic activity. In an attempt to inhibit the biological activity of angiogenin, which involves new blood vessel formation, we employed different dinucleosides with varied non‐natural backbones. These compounds were synthesized by coupling aminonucleosides with dicarboxylic acids and amino‐ and carboxynucleosides with an amino acid. These molecules show competitive inhibition with inhibition constant (K_i) values of (59±3) and (155±5) μM for RNase A. The compounds were also found to inhibit angiogenin in a competitive fashion with corresponding K_i values in the micromolar range. The presence of an additional polar group attached to the backbone of dinucleosides was found to be responsible for the tight binding with both proteins. The specificity of different ribonucleolytic subsites were found to be altered because of the incorporation of a non‐natural backbone in between the two nucleosidic moieties. In spite of the replacement of the phosphate group by non‐natural linkers, these molecules were found to selectively interact with the ribonucleolytic site residues of angiogenin, whereas the cell binding site and nuclear translocation site residues remain unperturbed. Docked conformations of the synthesized compounds with RNase A and angiogenin suggest a binding preference for the thymine–adenine pair over the thymine–thymine pair.     

Design,synthesis and biological evaluation of pyridyl substituted benzoxazepinones as potent and selective inhibitors of aldosterone synthase

Exorbitant aldosterone is closely associated with various severe diseases, including congestive heart failure and chronic kidney disease. As aldosterone synthase is the pivotal enzyme in aldosterone biosynthesis, its inhibition constitutes a promising treatment for these diseases. Via a structure-based approach, a series of pyridyl substituted 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ones were designed as inhibitors of aldosterone synthase. Six compounds (5j, 5l, 5m 5w, 5x and 5y) distinguished themselves with potent inhibition (IC₅₀ <100 nmol/L) and high selectivity over homogenous 11β-hydroxylase. As the most promising compound, 5x exhibited an IC₅₀ of 12 nmol/L and an excellent selectivity factor (SF) of 157, which are both superior to those of the reference fadrazole (IC₅₀ = 21 nmol/L, SF = 7). Importantly, 5x showed no inhibition against steroidogenic CYP17, CYP19 and a panel of hepatic CYP enzymes indicating an outstanding safety profile. As it manifested satisfactory pharmacokinetic properties in rats, compound 5x was considered as a drug candidate for further development.     

Synthesis and Assessment of Two Malonyl Dihydrazide Derivatives as Corrosion Inhibitors for Carbon Steel in Acidic Media: Experimental and Theoretical Studies

Despite the extensive use of carbon steel in all industrial sectors, particularly in the petroleum industry, its low corrosion resistance is an ongoing problem for these industries. In the current work, two malonyl dihydrazide derivatives, namely 2,2’-malonylbis (N-phenylhydrazine-1-carbothiamide (MBC) and N’1, N’3-bis(-2-hydroxybenzylidene) malonohydrazide (HBM), were examined as inhibitors for the carbon steel corrosion in 1.0 M HCl. Both MBC and HBM were characterised using thin-layer chromatography, elemental analysis, infrared spectroscopy, and nuclear magnetic resonance techniques. The corrosion tests were performed using mass loss measurements, polarisation curves, and electrochemical impedance spectroscopy. It is obtained from the mass loss studies that the optimal concentration for both inhibitors is 2.0 × 10⁻⁵ mol/L, and the inhibition efficiencies reached up to 90.7% and 84.5% for MBC and HBM, respectively. Electrochemical impedance spectroscopy (EIS) and potentiodynamic polarisation (PDP) indicate an increased impedance in the presence of both MBC and HBM and mixed-type inhibitors, respectively. Both inhibitors can mitigate corrosion in the range of 298–328 K. Values of free energy changes obtained from the Langmuir model suggest that the inhibitors suppress the corrosion process principally by chemisorption. The computational investigations were conducted to identify the factors connected with the anti-corrosive properties of the examined inhibitors.     

靶向抑制拓扑异构酶和端粒酶的钌配合物研究进展

金属配合物抗肿瘤研究,尤其是铂类药物,已取得了相对令人瞩目的成功,但同时也面临着包括耐药性和毒副作用等诸多问题。近年来钌配合物作为新的抗癌药物引起了人们的注意。在非铂系药物中,金钌配合物;拓扑异构酶;G-四链体;端粒酶属钌配合物是最有前途的抗癌药物之一,国际上普遍认为钌和钌的配合物属于低毒性,容易吸收并在体内很快排泄。本文将着重介绍钌配合物与DNA结合后进一步引发的细胞内核酶活性抑制研究,从新的角度来诠释钌配合物的抗肿瘤研究最新进展。     

Stabilization of zeylenone in rat plasma by the presence of esterase inhibitors and its LC‐MS/MS assay for pharmacokinetic study

Six esterase inhibitors, namely EDTA·2Na⁺, NaF, phenylmethanesulfonyl fluoride, dichlorvos, bis‐nitrophenyl phosphate (BNPP) and thenoyltrifluoroacetone, and the mixture of NaF and BNPP, were evaluated for the stabilization of labile benzoate containing zeylenone in rat plasma. The mixture appeared to exhibit the most effectively stabilizing effect with the degraded content of zeylenone decreasing from >60% (in the absence of inhibitors) to <6%. Following the stabilization by the addition of NaF (5 mm ) and BNPP (5 mm ), the analytes in rat plasma were acidified by formic acid and extracted into ethyl acetate at 0°C. After chromatographic separation, the detection of zeylenone was performed on a 3200 Q‐Trap with positive ion electrospray mode, monitoring the ion transition m/z 383.2 → 105.0. The method was validated over the range from 2.68 to 1340 ng/mL with inter‐ and intra‐run precision for the quality control samples being less than 6.8%. The assay accuracy was within 100 ± 7.0%. The validated method was successfully applied to a pharmacokinetic study in rats after the intratracheal administration of zeylenone in free drug or polymeric micellar solutions. The results showed that the pulmonary absorption of zeylenone loaded in micelles was significantly retarded compared with that of free drug solutions. Copyright © 2012 John Wiley & Sons, Ltd.     

The computer program LUDI: A new method for the de novo design of enzyme inhibitors

Summary A new computer program is described, which positions small molecules into clefts of protein structures (e.g. an active site of an enzyme) in such a way that hydrogen bonds can be formed with the enzyme and hydrophobic pockets are filled with hydrophobic groups. The program works in three steps. First it calculates interaction sites, which are discrete positions in space suitable to form hydrogen bonds or to fill a hydrophobic pocket. The interaction sites are derived from distributions of nonbonded contacts generated by a search through the Cambridge Structural Database. An alternative route to generate the interaction sites is the use of rules. The second step is the fit of molecular fragments onto the interaction sites. Currently we use a library of 600 fragments for the fitting. The final step in the present program is the connection of some or all of the fitted fragments to a single molecule. This is done by bridge fragments. Applications are presented for the crystal packing of benzoic acid and the enzymes dihydrofolate reductase and trypsin.