Trihydroxy-2-thiaquinolizidine derivatives as a new class of bicyclic glycosidase inhibitors

Trihydroxy-2-thiaquinolizidines, a new class of bicyclic dideoxy-iminohexitol glycosidase inhibitor derivatives with nominally the d-gluco, l-ido, d-manno and l-gulo configurations were synthesized. X-ray analyses indicated that the preferred conformation for d-gluco and d-manno derivatives was a flat trans-fused system. Unlike deoxynojirimycin, the compound with d-gluco configuration was selective for α-glucosidases (yeast and rice) and showed no inhibitory activity towards β-glucosidase (almond), α-galactosidase (green coffee beans), α-galactosidase (E. coli) and α-mannosidase (jack bean), while the l-ido derivative was specific for β-glucosidase (almond).     

Piperidines: a new class of urease inhibitors

A variety of piperidines (2-12, 14-26) with variable substituents at N-atoms have been synthesized and evaluated as urease inhibitors. The synthesized compounds showed varying degree of urease inhibitory activity ranging from 31.97 to 254 microM. The size and electron-donating or -withdrawing effects of substituents influence the activity, which lead to the formation of urease inhibitors.     

Metal complexes of anthranilic acid derivatives: A new class of noncompetitive α-glucosidase inhibitors

Metal complexes of anthranilic acid derivatives that constitute a novel class of non-sugar-type aglucosidase inhibitors were synthesized and assessed in vitro for inhibitory activity. All of the Ag(I)complexes(9–16) inhibited a-glucosidase at the nanomolar scale, while 3,5-dichloroanthranilic acid silver(I)(9) was the most potent(IC_(50)= 3.21 nmol/L). Analysis of the kinetics of enzyme inhibition indicated that the mechanism of the newly prepared silver complexes was noncompetitive. The structure-activity relationships were also analyzed, and they are discussed in this report.     

Synthesis of a new class of uridine phosphorylase inhibitors

A new series of potent uridine phosphorylase inhibitors have been prepared from barbituric acid. Among them, 1-[(2-hydroxyethoxy)methyl]-5-)(m--benzyloxy)benzylbarbituric acid ( 37 , BBBA) is the most promising having a K_i value of 1.1 ± 0.2 nM with uridine phosphorylase from human liver. The new inhibitors are easily synthesized and are better inhibitors of human uridine phosphorylase than their uracil counterparts.     

Identification of a new class of nonpeptidic inhibitors of cruzain

Cruzain is the major cysteine protease of Trypanosoma cruzi, which is the causative agent of Chagas disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the substrate activity screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor 38 was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored beta-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group p K a, with 2,3,5,6-tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second-order inactivation constant of 147,000 s (-1) M (-1). This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemotherapeutics for Chagas disease.     

Platinum coordination compounds of thiosemicarbazide derivatives: a new class of platinum blues

Platinum(II) forms blue 1?:?2 coordination compounds with 1-phenylthiosemicarbazide [H(1-PTSC)], 4-phenylthiosemicarbazide [H(4-PTSC)], 1,4-diphenylthiosemicarbazide [H(1,4-DPTSC)] and 4-(2-pyridyl)-thiosemicarbazide [H(4-(2py)-TSC)]. Electronic spectra of these compounds have been studied in different solvents. In all compounds, a band is observed in the 650–750?nm region that appears to be a metal-to-ligand charge transfer band. Infrared and proton NMR studies have been carried out to determine possible coordination sites and the nature of the complexes. IR spectra indicate bonding through sulfur and nitrogen and proton NMR spectra indicate bonding through the N¹nitrogen.     

Triple-helical transition state analogues: a new class of selective matrix metalloproteinase inhibitors

Alterations in activities of one family of proteases, the matrix metalloproteinases (MMPs), have been implicated in primary and metastatic tumor growth, angiogenesis, and pathological degradation of extracellular matrix (ECM) components, such as collagen and laminin. Since hydrolysis of the collagen triple-helix is one of the committed steps in ECM turnover, we envisioned modulation of collagenolytic activity as a strategy for creating selective MMP inhibitors. In the present study, a phosphinate transition state analogue has been incorporated within a triple-helical peptide template. The template sequence was based on the alpha1(V)436-450 collagen region, which is hydrolyzed at the Gly(439)-Val(440) bond selectively by MMP-2 and MMP-9. The phosphinate acts as a tetrahedral transition state analogue, which mimics the water-bound peptide bond of a protein substrate during hydrolysis. The phosphinate replaced the amide bond between Gly-Val in the P1-P1' subsites of the triple-helical peptide. Inhibition studies revealed Ki values in the low nanomolar range for MMP-2 and MMP-9 and low to middle micromolar range for MMP-8 and MMP-13. MMP-1, MMP-3, and MT1-MMP/MMP-14 were not inhibited effectively. Melting of the triple-helix resulted in a decrease in inhibitor affinity for MMP-2. The phosphinate triple-helical transition state analogue has high affinity and selectivity for the gelatinases (MMP-2 and MMP-9) and represents a new class of protease inhibitors that maximizes potential selectivity via interactions with both prime and nonprime active site subsites as well as with secondary binding sites (exosites).     

5-membered cyclic acyl phosphates : A new class of extremely reactive phosphorylating agents

The reaction of phosgene with the oxyphosphorane made from biacetyl and trimethyl phosphite gives an α-(dimethylphosphato)-β-ketoacid chloride, which undergoes an intramolecular loss of methyl chloride under catalysis; by CuSO₄, and yields the first reported 5-membered cyclic acyl phosphate. The acyl phosphate is attacked exclusively at phosphorus by water, alcohols and phenols, at an extraordinarily rapid rate. In contrast, tertiary amines attack only the Me carbon of the exocyclic OMe group of the acyl phosphate to give quaternary ammonium salts of 5-membered cyclic acyl phosphates. These cyclic mixed anhydrides of phosphoric acid are the most powerful phosphorylating agents for oxygen-containing nucleophiles known at present. The end-products of the phosphorylations are phosphotriesters, phosphodiesters, and phosphomonoesters, containing the easily removable acetoinyl group, [(CH₃CO)(CH₃)CHO]P(O)(OR)(OR′).     

Silyl celluloses: A new class of soluble cellulose derivatives

Two general methods for the silylation of cellulose have been developed. Silyl amides undergo silyl—proton exchange reactions with cellulose in polar solvents leading to displacement of 80–90% of the hydroxyl protons by silyl groups. The same products are obtained by reaction of the corresponding chlorosilanes with cellulose in pyridine; however, di- and trifunctional impurities present in commercial chlorosilanes have to be removed by scavenging with a carbohydrate in order to avoid crosslinking. Cellulose derivatives with trimethylsilyl, dimethylphenylsilyl, methyldiphenylsilyl, and γ-cyanopropyldimethylsilyl substituents have been prepared by both methods. The properties of the new soluble polymers are largely dependent on the nature of the silyl substituents. The silyl celluloses exhibit a relatively high degree of hydrolytic stability; methyldiphenylsilyl cellulose is hydrolytically stable even under severe conditions.     

Synthesis of nicotinonitrile derivatives as a new class of NLO materials

4,6-Diaryl-2-(pyrrolidin-1-yl)-nicotinonitriles 2a-k and 3-amino-2,4-dicyano-5-aryl-biphenyls 3a-c were synthesized from 1,3-diaryl-prop-2-en-1-ones 1a-k and malononitrile by a convenient one-pot method. Likewise, the reaction of aromatic aldehydes with malononitrile afforded 6-amino-4-aryl-2-(pyrrolidin-1-yl)-pyridine-3,5-dicarbonitriles 6a-f. The reaction of mesityl oxide with malononitrile gave 5-amino-7-(pyrrolidin-1-yl)-2,4,4-trimethyl-1,4-dihydro-1,6-naphthyridine-8-carbonitrile 8. The NLO studies of the pyridinedinitrile derivatives 6a, b, f showed a high value while that of nicotinonitrile 2b was weak.     

Dithiocarbamates: a new class of carbonic anhydrase inhibitors. Crystallographic and kinetic investigations

The zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) is inhibited by several classes of zinc-binders (sulfonamides, sulfamates, and sulfamides) as well as by compounds which do not interact with the metal ion (phenols, polyamines and coumarins). Here we report a new class of potent CA inhibitors which bind the zinc ion: the dithiocarbamates (DTCs). They coordinate to the zinc ion from the enzyme active site in monodentate manner and establish many favorable interactions with amino acid residues nearby. Several low nanomolar CA I, II and IX inhibitors were detected.     

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.     

N-acyl-N-formylcarbamates. A new class of carbamate derivatives

N-Acyl-N-formylcarbamates III can be prepared in good yields by singlet oxygen oxidation of 5-unsubstituted 4-alkoxyoxazoles I. They are photo- and thermo-stable and sensitive to hydrolysis under very mild conditions. In contrast 4-unsubstituted 5-alkoxyoxazole V reacts with singlet oxygen to give oxamate VII via dioxazole VI.     

Formation of pyranoanthocyanins in red wines: a new and diverse class of anthocyanin derivatives

Pyranoanthocyanins constitute one of the most important classes of anthocyanin-derived pigments occurring naturally in red wine. Nonetheless, correct assignment of their structures and pathways of formation in red wine has been relatively recent—less than two decades. Study of these newly discovered pigments is progressively unfolding the chemical pathways that drive the evolution of red wine colour during ageing. The objective of this paper is to review current knowledge regarding the pathway of formation in red wine of a great variety of pyranoanthocyanin structures, namely carboxypyranoanthocyanins, methylpyranoanthocyanins, pyranoanthocyanin-flavanols, pyranoanthocyanin-phenols, portisins, oxovitisins, and pyranoanthocyanin dimers. The chromatic features of some of the compounds, for example their colour expression and acid–base equilibria in aqueous media, are also discussed.