Anticancer activity of natural cytokinins: A structure–activity relationship study

Cytokinin ribosides (N⁶-substituted adenosine derivatives) have been shown to have anticancer activity both in vitro and in vivo. This study presents the first systematic analysis of the relationship between the chemical structure of cytokinins and their cytotoxic effects against a panel of human cancer cell lines with diverse histopathological origins. The results confirm the cytotoxic activity of N⁶-isopentenyladenosine, kinetin riboside, and N⁶-benzyladenosine and show that the spectrum of cell lines that are sensitive to these compounds and their tissues of origin are wider than previously reported. The first evidence that the hydroxylated aromatic cytokinins (ortho-, meta-, para-topolin riboside) and the isoprenoid cytokinin cis-zeatin riboside have cytotoxic activities is presented.Most cell lines in the panel showed greatest sensitivity to ortho-topolin riboside (IC₅₀ = 0.5–11.6 μM). Cytokinin nucleotides, some synthesized for the first time in this study, were usually active in a similar concentration range to the corresponding ribosides. However, cytokinin free bases, 2-methylthio derivatives and both O- and N-glucosides showed little or no toxicity. Overall the study shows that structural requirements for cytotoxic activity of cytokinins against human cancer cell lines differ from the requirements for their activity in plant bioassays. The potent anticancer activity of ortho-topolin riboside (GI₅₀ = 0.07–84.60 μM, 1st quartile = 0.33 μM, median = 0.65 μM, 3rd quartile = 1.94 μM) was confirmed using NCI₆₀, a standard panel of 59 cell lines, originating from nine different tissues. Further, the activity pattern of oTR was distinctly different from those of standard anticancer drugs, suggesting that it has a unique mechanism of activity. In comparison with standard drugs, oTR showed exceptional cytotoxic activity against NCI₆₀ cell lines with a mutated p53 tumour suppressor gene. oTR also exhibited significant anticancer activity against several tumour models in in vivo hollow fibre assays.     

Production of reactive oxygen species and reactive nitrogen species by angiosperm stigmas and pollen: potential signalling crosstalk?

Angiosperm stigmas exhibit high levels of peroxidase activity when receptive to pollen. To explore possible function(s) of this peroxidase activity we investigated amounts of reactive oxygen species (ROS), particularly hydrogen peroxide, in stigmas and pollen. Because nitric oxide (NO) was recently implicated in pollen tube growth, we also investigated amounts of NO in pollen and stigmas. Reactive oxygen species accumulation was assessed with confocal microscopy and light microscopy using ROS probes DCFH2-DA and TMB, respectively. NO was assayed using the NO probe DAF-2DA and confocal microscopy. Stigmas from various different angiosperms were found to accumulate ROS, predominantly H2O2, constitutively. In Senecio squalidus and Arabidopsis thaliana high amounts of ROS/H2O2 were localized to stigmatic papillae. ROS/H2O2 amounts appeared reduced in stigmatic papillae to which pollen grains had adhered. S. squalidus and A. thaliana pollen produced relatively high amounts of NO compared with stigmas; treating stigmas with NO resulted in reduced amounts of stigmatic ROS/H2O2. Constitutive accumulation of ROS/H2O2 appears to be a feature of angiosperm stigmas. This novel finding is discussed in terms of a possible role for stigmatic ROS/H2O2 and pollen-derived NO in pollen-stigma interactions and defence.     

Antioxidant activity of β-blockers: An effect mediated by scavenging reactive oxygen and nitrogen species?

The therapeutic effects of beta-blockers are normally explained by their capacity to block the beta-adrenoceptors, however, some of the beneficial cardiovascular effects shown by this group of compounds have already been associated with the antioxidant properties that some of them seem to possess. The beta-blockers atenolol, labetalol, metoprolol, pindolol, propranolol, sotalol, timolol, and carvedilol were tested for their putative scavenging activity for ROS (O(2)(-), H(2)O(2), HO(.), HOCl, and ROO(.)) and RNS ((.)NO and ONOO(-)). Some of the studied compounds are effective ROS and/or RNS scavengers, these effects being possibly useful in preventing oxidative damage verified in hypertension as well as in other cardiovascular diseases that frequently emerge in association with oxidative stress.     

Lead-hemoglobin interaction as a possible source of reactive oxygen species—A chemiluminescent study

Pb²⁺-hemoglobin interaction as a possible source of reactive oxygen species was investigated. It was found that the products of this reaction are able to promote peroxidase catalyzed luminol oxidation with light emission. Superoxide dismutase and catalase strongly inhibited this effect. A conclusion was done that the interaction between Pb²⁺ and oxyhemoglobin yields reactive oxygen species, possibly O₂^? and H₂O₂.     

Synthesis and structure–activity relationship study of novel quinazolinone-based inhibitors of MurA

MurA is an intracellular bacterial enzyme that is essential for peptidoglycan biosynthesis, and is therefore an important target for antibacterial drug discovery. We report the synthesis, in silico studies and extensive structure–activity relationships of a series of quinazolinone-based inhibitors of MurA from Escherichia coli. 3-Benzyloxyphenylquinazolinones showed promising inhibitory potencies against MurA, in the low micromolar range, with an IC₅₀ of 8 µM for the most potent derivative (58). Furthermore, furan-substituted quinazolinones (38, 46) showed promising antibacterial activities, with MICs from 1 µg/mL to 8 µg/mL, concomitant with their MurA inhibitory potencies. These data represent an important step towards the development of novel antimicrobial agents to combat increasing bacterial resistance.     

Antioxidant profile of dihydroxy- and trihydroxyphenolic acids-A structure–activity relationship study

Eight structurally similar dihydroxy and trihydroxyphenolic acids (protocatechuic acid, 3,4-dihydroxyphenylacetic acid, hydrocaffeic acid, caffeic acid, gallic acid, 3,4,5-trihydroxyphenylacetic acid, 3-(3,4,5-trihydroxyphenyl)propanoic acid and 3-(3,4,5-trihydroxyphenyl)propenoic acid) were examined for their total antioxidant capacity (TAC). Furthermore, their ability to scavenge peroxyl radicals, generated by AAPH in liposomes, was determined. The antioxidant/pro-oxidant activity of the compounds was screened using the 2′-deoxyguanosine assay. All compounds behave as radical scavengers, with 3,4,5-trihydroxyphenylacetic acid being the most potent. Nevertheless, in the lipid peroxidation assay an inverse ranking order was observed, 3,4-dihydroxyphenylacetic acid being the most effective compound. All the dihydroxylated compounds showed a pro-oxidant behaviour leading to an increase of 50% in 8-OH-dG induction. From the structure–antioxidant activity relationship studies performed it may be concluded that the number of phenolic groups and the type of the alkyl spacer between the carboxylic acid and the aromatic ring strongly influence the antioxidant activity.     

Synthesis,antibiotic activity and structure–activity relationship study of some 3-enaminetetramic acids

The synthesis and evaluation of 3-enaminetetramic acids as antibacterial agents is reported; contrary to the analogous 3-acyltetramic acids, the enaminetetramic acid class of compound exhibits modest antibacterial activity against a limited spectrum of organisms, and even that activity is strongly dependent on the identity of the tetramate ring substituents. Moreover, these compounds appear to have a different mode of action to the analogous 3-acyltetramic acids, and appear to offer more limited opportunity for further elaboration in drug discovery.     

Discovery and structure–activity relationship of thienopyridine derivatives as bone anabolic agents

A cell-based assay was performed for the discovery of novel bone anabolic agents. Alkaline phosphatase (ALPase) activity of ST2 cells was utilized as an indicator of osteoblastic differentiation, and thienopyridine derivative 1 was identified as a hit compound. 3-Aminothieno[2,3-b]pyridine-2-carboxamide was confirmed to be a necessary core structure for the enhancement of ALPase activity, and then optimization of the C4-substituent on the thienopyridine ring was carried out. Introduction of cyclic amino groups to the C4-position of the thienopyridine ring improved the activity. Especially, N-phenyl-homopiperazine derivatives were found to be strong enhancers of ALPase among this new series. Furthermore, 3-amino-4-(4-phenyl-1,4-diazepan-1-yl)thieno[2,3-b]pyridine-2-carboxamide (15k) was orally administered to ovariectomized (OVX) rats over 6 weeks for evaluating the effects on areal bone mineral density (aBMD), and statistically significant improvements in aBMD were observed from the dosage of 10 mg/kg/day.     

Synthesis,immunosuppressive activity and structure–activity relationship study of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidine analogues

The synthesis of a new series of 4-N-piperazinyl-thieno[2,3-d]pyrimidines is described. The synthetic route allows introducing structural variety at positions 2, 4 and 6 of the scaffold. Evaluation of their immunosuppressive activity in a Mixed Lymphocyte Reaction (MLR) assay revealed that the most potent compound has an IC₅₀-value of 66 nM and therefore deserves attention for further medicinal chemistry optimization.     

Synthesis and structure–activity relationship of thiobarbituric acid derivatives as potent inhibitors of urease

A series of thiobarbituric acid derivatives 1–27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1–27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC₅₀ values 18.1 ± 0.52, 16.0 ± 0.45, 16.0 ± 0.22, 14.3 ± 0.27, 6.7 ± 0.27, 10.6 ± 0.17, 19.2 ± 0.29, 18.2 ± 0.76 and 1.61 ± 0.18 μM, respectively, much better than the standard urease inhibitor thiourea (IC₅₀ = 21 ± 0.11 μM). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC₅₀ values 21.4 ± 1.04 and 21.5 ± 0.61μM, 22.8 ± 0.32, 25.2 ± 0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure–activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and ¹H NMR.     

Quantitative structure–activity relationship study on some benzodiazepine derivatives as anti-Alzheimer agents

A QSAR study was performed in an attempt to explore the pharmacophore of some benzodiazepine derivatives as anti-Alzheimer agents for the inhibition of -secretase. The study, which used the electrotopological state atom (ETSA) index, which encodes electronic and topological information, reveals the importance of two phenyl rings—one substituted and another unsubstituted, for the inhibition of the enzyme. Fluorine substitution on the substituted phenyl ring has an important contribution to the activity. R-configurations of the aliphatic chain substituents provide the exact conformation of the molecules to enter into the binding pockets of the receptor(s).Figure General structure of benzodiazepine containing -secretase inhibitors     

A study of structure–activity relationship and anion-controlled quinolinyl Ag(I) complexes as antimicrobial and antioxidant agents as well as their interaction with macromolecules

BioMetals - In this communication, we feature the synthesis and in-depth characterization of a series of silver(I) complexes obtained from the complexation of quinolin-4-yl Schiff base ligands...     

Discovery and structure–activity relationship analysis of Staphylococcus aureus sortase A inhibitors

Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structure–activity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC₅₀ values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors.     

Three-dimensional quantitative structure–activity relationship study on paullones as CDK inhibitors using CoMSIA and CoMFA

3D-QSAR studies were conducted on a series of paullones as CDK inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. Two methods were compared: the widely used comparative molecular field analysis (CoMFA) and the recently reported comparative molecular similarity indices analysis (CoMSIA). Systematic variations of some parameters in CoMSIA and CoMFA were performed to search for the best 3D-QSAR model. The computed results showed that the 3D-QSAR models from CoMSIA were clearly superior to those from CoMFA. Using the best model from CoMSIA analysis, a significant cross-validated q² was obtained and the predicted biological activities of the five compounds in the test set were in good agreement with the experimental values. The correlation results obtained from CoMSIA were graphically interpreted in terms of field contribution maps allowing physicochemical properties relevant for binding to be easily mapped back onto molecular structures. The features in the CoMSIA contour maps intuitively suggested where to modify a molecular structure in terms of physicochemical properties and functional groups in order to improve its binding affinity, which is very important for improving our understanding of the ligand-receptor interactions and in helping to design compounds with improved activity.     

Structure–activity relationship study of nitrosopyrimidines acting as antifungal agents

The design, synthesis, in vitro evaluation, and conformational study of nitrosopyrimidine derivatives acting as antifungal agents are reported. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines have displayed a significant antifungal activity against human pathogenic strains. In this paper, we report a new group of nitrosopyrimidines acting as antifungal agents. Among them, compounds 2a, 2b and 15, the latter obtained from a molecular modeling study, exhibited antifungal activity against Candida albicans, Candida tropicalis and Cryptococcus neoformans. We have performed a conformational and electronic analysis on these compounds by using quantum mechanics calculations in conjunction with Molecular Electrostatic Potentials (MEP) obtained from B3LYP/6–31G(d) calculations. Our experimental and theoretical results have led us to identify a topographical template which may provide a guide for the design of new nitrosopyrimidines with antifungal effects.     

Potent and orally bioavailable CCR4 antagonists: Synthesis and structure–activity relationship study of 2-aminoquinazolines

Starting with a series of CC chemokine receptor-4 (CCR4) antagonists developed in a previous study, the potency was improved by replacing the pyrrolidine moiety of N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 2 with a 3-(hydroxymethyl)piperidine. The resulting compound (1′-{4-[(4-chlorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}-1,4′-bipiperidin-3-yl)methanol 8ic was a strong inhibitor of human/mouse chemotaxis. Oral administration of 8ic showed anti-inflammatory activity in a murine model of acute dermatitis (oxazolone-induced contact hypersensitivity test) in a dose-dependent manner.