Katzkolding3571

Most of title compounds showed potent in vitro antitumor activities against Bel7404 and SMMC7721 tumor cell lines. Compounds 5j and 6 exhibited more potent antitumor activity than positive controlSA and DOX.

Structural modification of SA could lead to the discovery of potent anti-HCV or antitumor agents. Compounds 5h, 5j and 6 werepromising lead compounds development of novel HCV entry inhibition or antitumor agents.

Structural modification of SA could lead to the discovery of potent anti-HCV or antitumor agents. Compounds 5h, 5j and 6 werepromising lead compounds development of novel HCV entry inhibition or antitumor agents.

Thiourea is a classical urease inhibitor usually as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thioureas with a tiny thiourea motif could theoretically bind into the active pocket as thiourea.

A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors.

Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated viasurface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics.

Compounds b2, b11and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in intact cell, with IC50 values being 90-to 450-fold and 5-to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed IC50 value of 0.060 ±0.004μM against cell-free urease, which bound to urea binding site with a very low KDvalue (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11was also demonstrated having very low cytotoxicity to mammalian cells.

These results revealed that N-monosubstituted aroylthioureas clearly bind the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by ure-ase-containing pathogens.

These results revealed that N-monosubstituted aroylthioureas clearly bind the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by ure-ase-containing pathogens.

1α,25-dihydroxyvitamin D3 (calcitriol) shows potent growth-inhibitory properties on different can-cer cell lines but its hypercalcemic effects have severely hampered its therapeutic application. Therefore, it is important todevelop synthetic calcitriol analogues that retain or even increase its antitumoral effects and lack hypercalcemic activity. Based on previous evidence of the potent antitumor effects of the synthetic alkynylphosphonate EM1 analogue, we have now synthesized a derivative called SG.

The aim of the present work is to evaluate the calcemic activity and the antitumor effect of SG, comparing these effects with those exerted by calcitriol and with those previously published for EM1. In addition, we propose to analyse by in silico studies the chemical structure-biological function relationship of these molecules.

We performed the synthesis of vinylphosphonate SG analogue; in vitro assays on different cancer cell lines; in vivo assays on mice; and in silico assays applying computational molecular modelling.

The SG compound lacks hypercalcemic activity, similar to the parent compound EM1. However, the antitumor ac-tivity was blunted, as no antiproliferative or antimigratory effects were observed. By in silico assays, we demostrated that SG analogue has lower affinity for the VDR-ligand binding domain than EM1 compound, due to lack of interaction with the important residues His305 and His397.

These results demonstrate that chemical modification in the lateral side chain of the SG analogue affects the antitumoral activity observed previously for EM1 but does not affect the calcemic activity. These results contribute to the rational design and synthesis of novel calcitriol analogues.

These results demonstrate that chemical modification in the lateral side chain of the SG analogue affects the antitumoral activity observed previously for EM1 but does not affect the calcemic activity. These results contribute to the rational design and synthesis of novel calcitriol analogues.Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors [such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)] in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. compound library chemical However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.