Thieno[3,2-c]pyran-4-one based novel small molecules: their synthesis, crystal structure analysis and in vitro evaluation as potential anticancer agents

Novel thieno[3,2-c]pyran-4-one based small molecules were designed as potential anticancer agents. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of few steps such as Gewald reaction, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of thiophene ring followed by the fused pyranone moiety and then functionalization at C-7 position of the resultant thieno[3,2-c]pyran-4-one framework. Some of the compounds synthesized showed selective growth inhibition of cancer cells in vitro among which two compounds for example, 5d and 6c showed IC(50) values in the range of 2.0-2.5 μM. The crystal structure analysis of an active compound along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.     

Conformationally restricted novel pyrazole derivatives: synthesis of 1,8-disubstituted 5,5-dimethyl-4,5-dihydro-1H-benzo[g]indazoles as a new class of PDE4 inhibitors

A number of novel 1,8-disubstituted 5,5-dimethyl-4,5-dihydro-1H-benzo[g]indazoles based on a conformationally restricted pyrazole framework have been designed as potential inhibitors of PDE4. All these compounds were readily prepared by using simple chemistry strategy. The in vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized along with the X-ray single crystal data of a representative compound is presented.     

Ultrasound mediated catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones leading to novel quinoline derivatives: their evaluation as potential anti-cancer agents

A facile and catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones has been accomplished via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde with various aromatic amines in the presence of ultrasound. Some of these compounds were converted to the corresponding 2-(3-(hydroxymethyl)quinolin-2-yl)phenols and further structure elaboration of a representative quinoline derivative is presented. Molecular structure of two representative compounds was confirmed by single crystal X-ray diffraction study. Many of these compounds were evaluated for their anti-proliferative properties in vitro against four cancer cell lines and several compounds were found to be active. Further in vitro studies indicated that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Pharmacophore mapping of diverse classes of farnesyltransferase inhibitors

Protein farnesyltransferase (FTase) is a zinc-dependent enzyme that catalyzes the attachment of a farnesyl lipid group to the sulfur atom of a cysteine residue of numerous proteins involved in cell signaling including the oncogenic H-Ras protein. Pharmacophore models were developed by using Catalyst HypoGen program with a training set of 22 farnesyltransferase inhibitors (FTIs), which were carefully selected with great diversity in both molecular structure and bioactivity for discovering new potent FTIs. The best pharmacophore hypothesis (Hypo 1), consisting of four features, namely, one hydrogen-bond acceptor (HBA), one hydrophobic point (HY), and two ring aromatics (RA), has a correlation coefficient of 0.961, a root mean square deviation (RMSD) of 0.885, and a cost difference of 62.436, suggesting that a highly predictive pharmacophore model was successfully obtained. For the test series, a classification scheme was used to distinguish highly active from moderately active and inactive compounds on the basis of activity ranges. Hypo 1 was validated with 181 test set compounds, which has a correlation coefficient of 0.713 between estimated activity and experimentally measured activity. The model was further validated by screening a database spiked with 25 known inhibitors. The model picked up all 25 known inhibitors giving an enrichment factor of 10.892. The results demonstrate that the hypothesis derived in this study can be considered to be a useful and reliable tool in identifying structurally diverse compounds with desired biological activity.     

Biochemical profiles of hydatid cyst fluids of Echinococcus granulosus of human and animal origin in Libya.

A comparative study on the biochemical parameters in hydatid cyst fluids of sheep, goats, camels, cattle and human cystic forms of Echinococcus granulosus has been made in Libya. Quantitative variations in the levels of sodium, potassium, calcium, cholesterol, glucose, urea, creatinine and gamma glutamyl transpeptidase (gamma GT) were found in the cystic fluids of different host origins although these differences were statistically insignificant compared with the hydatid fluids of sheep. However, the concentration of triglycerides and proteins were significantly elevated in the cyst fluids of sheep compared with the other fluids studied. Similarities in the biochemical composition of different hydatid cyst fluids suggest the existence of sheep strains of E. granulosus in human and other domestic animal intermediate hosts in Libya.     

Studies on turnover rates of rat gamma-glutamyltranspeptidase after chronic ethanol administration in vivo

Chronic ethanol administration to rats was shown to result in a significant increase of hepatic and serum GGT activities, contrasting to the decreased levels observed in pancreas, intestine, brain, and kidney by the new alcock regimen method. The kinetics of rat GGT synthesis and degradation in vivo among the different sources after chronic ethanol administration has been studied by use of acivicin, which irreversibly inactivates GGT. The comparison of kinetics of GGT return after acivicin injection showed that the kidney and serum GGT exhibits biphasic half-lives in contrast to liver, pancreatic, intestinal, and brain GGT half-lives in chronic ethanol-administered rats. The present studies on kinetics of GGT synthesis (Ks) and degradation (Kd) in vivo would seem to indicate the existence of three types of systems. That is, Ks rather than Kd may be preferential in liver and serum whereas Kd is apparently increased in kidney and intestine without noticeable change in Ks. The reverse phenomenon is also observed for pancreas and brain. These findings suggest that the contributions of alterations in the rates of GGT synthesis and degradation to changing levels of GGT have been evaluated as a mechanism for enzyme adaptation in animal tissues as a change from the control diet to the ethanol diet.     

Solvent effect on copper-catalyzed azide-alkyne cycloaddition (CuAAC): synthesis of novel triazolyl substituted quinolines as potential anticancer agents

A regioselective route to novel mono triazolyl substituted quinolines has been developed via copper-catalyzed azide-alkyne cycloaddition (CuAAC) of 2,4-diazidoquinoline with terminal alkynes in DMF. The reaction provided bis triazolyl substituted quinolines when performed in water in the presence of Et(3)N. A number of the compounds synthesized showed promising anti-proliferative properties when tested in vitro especially against breast cancer cells.     

Discovery of 3-acetyl-4-hydroxy-2-pyranone derivatives and their difluoridoborate complexes as a novel class of HIV-1 integrase inhibitors

HIV-1 integrase (IN) has emerged as an important therapeutic target for anti-HIV drug development. Its uniqueness to the virus and its critical role in the viral life cycle makes IN suitable for selective inhibition. The recent approval of Raltegravir (MK-0518) has created a surge in interest and great optimism in the field. In our ongoing IN drug design research, we herein report the discovery of substituted analogs of 3-acetyl-4-hydroxy-2-pyranones and their difluoridoborate complexes as novel IN inhibitors. In many of these compounds, complexation with boron difluoride increased the potency and selectivity of IN inhibition. Compound 9 was most active with an IC(50) value of 9 microM and 3 microM for 3'-processing and strand transfer inhibition, respectively.     

ELM server: A new resource for investigating short functional sites in modular eukaryotic proteins

Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein-protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more.     

Evaluation of cytogenetic effects of lambda-cyhalothrin on human lymphocytes

The genotoxic and cytotoxic potential of lambda-cyhalothrin (LCT), a synthetic pyrethroid insecticide, was investigated on human lymphocytes cultured in vitro. Utilizing the trypan blue dye exclusion technique assay, the LC50 of LCT was found to be 28 microM. Based on the LC50 value, it is seen that LCT was highly toxic to lymphocyte cultures, among other pyrethroid group of pesticides. Chromosomal aberrations induced by LCT were determined using metaphase plate-spreads of lymphocytes. The chromosomal analysis was recorded using Medi-Image software technology. The analysis revealed that more satellite associations and gaps were found, which were statistically significant (p < 0.05) when compared to controls. Comet assay was used to assess the possibility of LCT to induce the damage in DNA, where the increase in comet tail length relates to the extent of DNA single strand breaks. The results presented here indicate that in vitro assays could be used as indicators of cytotoxicity and genotoxicity of the pesticide.