An overview of carbohydrate-based carbonic anhydrase inhibitors

Carbonic anhydrases (CAs) are metalloenzymes responsible for the reversible hydration of carbon dioxide to bicarbonate, a fundamental reaction involved in various physiological and pathological processes. In the last decades, CAs have been considered as important drug targets for different pathologies such as glaucoma, epilepsy and cancer. The design of potent and selective inhibitors has been an outstanding goal leading to the discovery of new drugs. Among the different strategies developed to date, the design of carbohydrate-based CA inhibitors (CAIs) has emerged as a versatile tool in order to selectively target CAs. The insertion of a glycosyl moiety as a hydrophilic tail in sulfonamide, sulfenamide, sulfamate or coumarin scaffolds allowed the discovery of many different series of sugar-based CAIs, with relevant inhibitory results. This review will focus on carbohydrate-based CAIs developed so far, classifying them in glycosidic and glycoconjugated inhibitors based on the conjugation chemistry adopted

Developments in carbohydrate-based metzincin inhibitors

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models

Commissioning of a Novel Test Apparatus for the Identification of the Dynamic Coefficients of Large Tilting Pad Journal Bearings

This paper describes the commissioning of a novel test bench for the static and dynamic characterization of large tilting pad journal bearings, realized within a collaboration of the Department of Civil and Industrial Engineering of the University of Pisa, BHGE and AM Testing. The adopted test bench configuration has the test article (TA) floating at the mid-span of a rotor supported by two rolling bearings. The TA is statically loaded vertically upwards by a hydraulic actuator and excited dynamically by two orthogonal hydraulic actuators with multiple frequency sinusoidal forces. The test rig is capable of testing bearings with a diameter from 150 to 300 mm. It includes very complex mechanical, hydraulic, electrical and electronic components, and needs, for the whole plant, about 1 MW of electric power. The commissioning of the testing system involved several aspects and presented various issues. This work focuses on measuring systems and data acquisition of high-frequency data (forces, accelerations and relative displacements) and on data processing for the identification of the bearing dynamic coefficients. The identification procedure is based on the linearity assumption and the principle of superposition, operating in the frequency domain with the fast Fourier transforms of the applied forces and displacement signals. First results, referred to a 4-pad bearing, are in satisfactory agreement with theoretical ones

Risk adjustment for inter-hospital comparison of caesarean delivery rates in low-risk deliveries

BACKGROUND: Caesarean delivery (CD) rates have been frequently used as quality measures for maternity service comparisons. More recently, primary CD rates (CD in women without previous CD) or CD rates within selected categories such as nulliparous, term, cephalic singleton deliveries (NTCS) have been used. The objective of this study is to determine the extent to which risk adjustment for clinical and socio-demographic variables is needed for inter-hospital comparisons of CD rates in women without previous CD and in NTCS deliveries. METHODS: Hospital discharge records of women who delivered in Emilia-Romagna Region (Italy) from January, 2007 to June 2009 and in Tuscany Region for year 2009 were linked with birth certificates. Adjusted RRs of CD in women without a previous Caesarean and NTCS were estimated using Poisson regression. Percentage differences in RR before and after adjustment were calculated and hospital rankings, based on crude and adjusted RRs, were examined. RESULTS: Adjusted RR differed substantially from crude RR in women without a previous Caesarean and only marginally in NTCS group. Hospital ranking was markedly affected by adjustment in women without a previous CD, but less in NTCS. CONCLUSION: Risk adjustment is warranted for inter-hospital comparisons of primary CD rates but not for NTCS CD rates. Crude NTCS CD rates are a reliable estimate of adjusted NTCS CD

Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with KAs spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators

Seismic analysis of Fujian Hakka Tulous

The overall earthquake response of Hakka Tulous, traditional earth constructions of the Fujian Province (China) and listed among the UNESCO World Heritage buildings, is investigated. Non-linear static analysis (pushover) with the equivalent frame approach is used. Although some rough approximations are assumed, this approach is well suited to model complex masonry structures, like Tulous. In fact, nonlinear analysis implemented by finite elements or by discrete elements would involve complex models hard to converge and needing long computational time. After carrying out seismic analysis of a Tulou prototype, its failure modes and overall seismic response were evaluated. The Tulou has shown to have good earthquake resistance with respect to the maximum seismic action that can be expected in the Fujian Province

Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis

Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-β, playing a protective role in Alzheimer's disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal