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Agri-food waste management represent for several supply-chains a pending issue, since most of the lignocellulosic biomasses produced by the agricultural practices are often intended for energy production, due to their high disposal costs. Nanotechnology could represent a sustainable way to valorise agricultural waste by extracting highly performing nanomaterials and reusing them as nanocarriers or nanopesticides to protect crops. Cellulose and lignin, which are the main component of plant residues display antimicrobial properties when reduced to their nanosized forms, being able to act as innovative tools to counteract plant pathogens, both bacterial and fungal ones. In particularly cellulose can be extracted from different matrices to obtain cellulose nanocrystals (CNC), while lignin is often reduced in nanoparticles (LNP). In this mini review the current and most recent results in terms of antimicrobial activities against plant pathogens by waste-based lignocellulosic nanomaterial are showed.

We recently demonstrated that poly(ADP-ribose) polymerase (PARP)-1 is involved in angiogenesis and tumour aggressiveness. In this study we have compared the influence of abrogation of PARP-1 expression by stable gene silencing to that of the pharmacological inhibition of cellular PARP activity using PARP-1/-2 inhibitors on the chemosensitivity of tumour cells to the wide spectrum methylating agent temozolomide (TMZ) and to the N3-adenine selective methylating agent {1-methyl-4-[1-methyl-4-(3-methoxysulfonylpropanamido)pyrrole-2-carboxamido]-pyrrole-2-carboxamido}propane (Me-Lex). Silencing of PARP-1 in melanoma or cervical carcinoma lines enhanced in vitro sensitivity to TMZ and Me- Lex, and induced a higher level of cell accumulation at the G2/M phase of cell cycle with respect to controls. GPI 15427, which inhibits both PARP-1 and PARP-2, increased sensitivity to TMZ and Me-Lex both in PARP-1-proficient and - deficient cells. However, it induced different cell cycle modulations depending on PARP-1 expression, provoking a G2/M arrest only in PARP-1 silenced cells. Treatment of PARP-1 silenced cells with TMZ or Me-Lex resulted in a more extensive phosphorylation of Chk-1 and p53 as compared to PARP-1 proficient cells. The combination of the methylating agents with GPI 15427 increased Chk-1 and p53 phosphorylation both in PARP-1 proficient or deficient cells. When mice challenged with PARP-1 silenced melanoma cells were treated with the TMZ and PARP inhibitor combination there was an additional reduction in tumour growth with respect to treatment with TMZ alone. These results suggest the involvement of PARP-2 or other PARPs, in the repair of DNA damage provoked by methylating agents, highlighting the importance of targeting both PARP-1 and PARP-2 for cancer therapy.

The farnesoid X receptor (FXR) is activated by endogenous bile acids (BAs) and plays a variety of physiological roles related to modulation of gene transcription. In particular, FXR positively regulates the cholesterol catabolism while feedback inhibits the BA synthesis by repressing the expression of the CYP7A and CYP8B genes. We have previously shown that 6α-ethyl-CDCA (6ECDCA) is a potent and selective FXR agonist. In this paper we report an extensive structure−activity relationship for a series of synthetic bile acids. Our results indicate that the 6α position plays a fundamental role in determining affinity and that the side chain of BA is amenable to a variety of chemical modification. Although none of the new derivatives is more potent than 6ECDCA, we show here that a wide variability in efficacy, from full agonists to partial antagonists, can be obtained.

A series of 6α-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC50 = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.

Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear enzyme that has recently emerged as an important player in the mechanisms leading to postischemic neuronal death, and PARP inhibitors have been proposed as potential neuroprotective agents. With the aim of clarifying the structural basis responsible for PARP inhibition, we carried out a computational study on 46 inhibitors available through the literature. Our computational approach is composed of three parts. In the first one, representative PARP inhibitors have been docked into the crystallographic structure of the catalytic domain of PARP by using the Autodock 2.4 program. The docking studies thus carried out have provided an alignment scheme that has been instrumental for superimposing all the remaining inhibitors. Upon the basis of this alignment scheme, a quantitative structure−activity relationship (QSAR) analysis has been carried out after electrostatic and steric interaction energies have been computed with the RECEPTOR program. The QSAR analysis yielded a predictive model able to explain much of the variance of the 46-compound data set. The inspection of the QSAR coefficients revealed that the major driving force for potent inhibition is given by the extension of the contact surface between enzyme and inhibitors while electrostatic energy and hydrogen bonding capability play a minor role. Finally, the projection of the QSAR coefficients back onto the X-ray structure of the catalytic domain of PARP provides insights into the role played by specific amino acid residues. This information will be useful to address the design of new selective and potent PARP inhibitors.

Abstract. A number of 2-substituted 5'-N-ethylcarboxamidoadenosine (NECA) derivatives was investigated for their affinity and selectivity at human A₃ adenosine receptors. The compounds were tested in radioligand competition studies and modulation of adenylyl cyclase activity on membranes from CHO cell lines stably transfected with the four human adenosine receptor subtypes. In binding studies the most potent compound, 2-(3-hydroxy-3-phenyl)propyn-1-yl-NECA (PHPNECA), exhibited a subnanomolar affinity for A₃ adenosine receptors with a K_i value of 0.4 nM. As opposed to the limited A₃ selectivity of PHPNECA, a 100-fold selectivity compared to both A₁ and A_2A receptors was found for 2-(2-phenyl)ethynyl-NECA (PENECA; K_i 6 nM). The EC₅₀ values for activation of adenylyl cyclase via A_2A adenosine receptors were in good agreement with the respective K_i values from binding experiments. In contrast, IC₅₀ values for A₁ and A₃ receptor-mediated inhibition of adenylyl cyclase were shifted to higher values compared to the respective affinities determined in radioligand competition studies. Similar discrepancies between binding and functional data have been observed for the inhibitory A₁ adenosine receptor in previous studies. Therefore, the same A₃ selectivity of PENECA compared to A₁ receptors was found in binding and adenylyl cyclase inhibition whereas the selectivity compared to A_2A receptors that was detected in ligand binding was obscured in the functional assay. The series of compounds presented in this study identifies 2-substitution of the purine system as a promising target for the development of A₃-selective high-affinity ligands.

AbstractSubstituted purine and deazapurine nucleosides are of great interest in medicinal chemistry. Furthermore, 3′-deoxynucleosides exhibit a number of biological activities. In this research the coupling of 2,6-dichloro-1- or 3-deazapurine with protected 3′-deoxyribose is reported. Depending upon coupling conditions and base structure, different anomeric and isomeric mixtures have been obtained. Extensive studies, utilizing chemical and physical methods, have been performed to assign the correct configuration to the resulting nucleosides.

AbstractThe synthesis of 2-(hex-l-ynyl)adenosine derivatives substituted at the N6- and/or 5′-position was carried out on the basis that 2-(hex-l-ynyl)adenosine-5′-N-ethyluronamide (HENECA, 2) showed good affinity and different degree of selectivity for rat adenosine receptors. All new compounds were tested in radioligand binding and adenylyl cyclase assays with recently cloned human A1, A2A, A2B, and A3adenosine receptors.

The P2Y1 receptor is present in the heart, in skeletal and various smooth muscles, and in platelets, where its activation is linked to aggregation. Adenosine 3‘,5‘- and 2‘,5‘-bisphosphates have been identified as selective antagonists at the P2Y1 receptor (Boyer et al. Mol. Pharmacol. 1996, 50, 1323−1329) and have been modified structurally to increase receptor affinity (Camaioni et al. J. Med. Chem. 1998, 41, 183−190). We have extended the structure−activity relationships to a new series of deoxyadenosine bisphosphates with substitutions in the adenine base, ribose moiety, and phosphate groups. The activity of each analogue at P2Y1 receptors was determined by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit phospholipase C stimulation elicited by 10 nM 2-(methylthio)adenosine 5‘-diphosphate (antagonist effect). 2‘-Deoxyadenosine bisphosphate analogues containing halo, amino, and thioether groups at the 2-position of the adenine ring were more potent P2Y1 receptor antagonists than analogues containing various heteroatom substitutions at the 8-position. An N⁶-methyl-2-chloro analogue, 6, was a full antagonist and displayed an IC50 of 206 nM. Similarly, N⁶-methyl-2-alkylthio derivatives 10, 14, and 15 were nearly full antagonists of IC50 < 0.5 μM. On the ribose moiety, 2‘-hydroxy, 4‘-thio, carbocyclic, and six-membered anhydrohexitol ring modifications have been prepared and resulted in enhanced agonist properties. The 1,5-anhydrohexitol analogue 36 was a pure agonist with an EC50 of 3 μM, i.e., similar in potency to ATP. 5‘-Phosphate groups have been modified in the form of triphosphate, methyl phosphate, and cyclic 3‘,5‘-diphosphate derivatives. The carbocyclic analogue had enhanced agonist efficacy, and the 5‘-O-phosphonylmethyl modification was tolerated, suggesting that deviations from the nucleotide structure may result in improved utility as pharmacological probes. The N⁶-methoxy modification eliminated receptor affinity. Pyrimidine nucleoside 3‘,5‘-bisphosphate derivatives were inactive as agonists or antagonists at P2Y receptor subtypes.

AbstractA number of selective ligands for the different binding sites of adenosine have been synthesized and tested in several pharmacological models. The aim of these synthetic efforts is both to improve the knowledge of structure-activity relationships in the adenosine-related biological systems and to develop drugs from some of these molecules.

The synthesis of 2'-deoxy and 2',3'-dideoxy derivatives of 1-ß-D-ribofuranosyl-1,3,4,7-tetrahydro-2H-1,3-diazepin-2-one (2) was undertaken in order to find new cytidine deaminase (CDA) inhibitors and potential adjuvants in anticancer chemotherapy. Replacement of ribose by a 2-deoxyribose moiety led to compound 9 that appeared slightly more potent than 2 (Ki = 2.5 × 10-8 M). Remarkably, the corresponding α-2'-deoxynucleoside 10 acted as a very potent inhibitor of human placenta CDA, with a Ki = 7.5 × 10-8 M. Attempt to synthesize the 2',3'-dideoxy derivative of 2 led to N-[4,5-dihydroxy-1-(2-oxo-2,3,4,7-tetrahydro[1,3] diazepin-1-yl)-pentyl]-2,2,2-trifluoroacetamide (13), which is devoid of CDA inhibitory activity.

The molecular basis for recognition by human P2Y1 receptors of the novel, competitive antagonist 2‘-deoxy-N⁶-methyladenosine 3‘,5‘-bisphosphate (MRS 2179) was probed using site-directed mutagenesis and molecular modeling. The potency of this antagonist was measured in mutant receptors in which key residues in the transmembrane helical domains (TMs) 3, 5, 6, and 7 were replaced by Ala or other amino acids. The capacity of MRS 2179 to block stimulation of phospholipase C promoted by 2-methylthioadenosine 5‘-diphosphate (2-MeSADP) was lost in P2Y1 receptors having F226A, K280A, or Q307A mutations, indicating that these residues are critical for the binding of the antagonist molecule. Mutation of the residues His132, Thr222, and Tyr136 had an intermediate effect on the capacity of MRS 2179 to block the P2Y1 receptor. These positions therefore appear to have a modulatory role in recognition of this antagonist. F131A, H277A, T221A, R310K, or S317A mutant receptors exhibited an apparent affinity for MRS 2179 that was similar to that observed with the wild-type receptor. Thus, Phe131, Thr221, His277, and Ser317 are not essential for antagonist recognition. A computer-generated model of the human P2Y1 receptor was built and analyzed to help interpret these results. The model was derived through primary sequence comparison, secondary structure prediction, and three-dimensional homology building, using rhodopsin as a template, and was consistent with data obtained from mutagenesis studies. We have introduced a “cross-docking” procedure to obtain energetically refined 3D structures of the ligand−receptor complexes. Cross-docking simulates the reorganization of the native receptor structure induced by a ligand. A putative nucleotide binding site was localized and used to predict which residues are likely to be in proximity to agonists and antagonists. According to our model TM6 and TM7 are close to the adenine ring, TM3 and TM6 are close to the ribose moiety, and TM3, TM6, and TM7 are near the triphosphate chain.

Adenosine 3‘,5‘- and 2‘,5‘-bisphosphates previously were demonstrated to act as competitive antagonists at the P2Y1 receptor (Boyer et al. Mol. Pharmacol. 1996, 50, 1323−1329). 2‘- and 3‘-Deoxyadenosine bisphosphate analogues containing various structural modifications at the 2- and 6-positions of the adenine ring, on the ribose moiety, and on the phosphate groups have been synthesized with the goal of developing more potent and selective P2Y1 antagonists. Single-step phosphorylation reactions of adenosine nucleoside precursors were carried out. The activity of each analogue at P2Y1 receptors was determined by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit phospholipase C stimulation elicited by 10 nM 2-MeSATP (antagonist effect). Both 2‘- and 3‘-deoxy modifications were well tolerated. The N⁶-methyl modification both enhanced antagonistic potency (IC50 330 nM) of 2‘-deoxyadenosine 3‘,5‘-bisphosphate by 17-fold and eliminated residual agonist properties observed with the lead compounds. The N⁶-ethyl modification provided intermediate potency as an antagonist, while the N⁶-propyl group completely abolished both agonist and antagonist properties. 2-Methylthio and 2-chloro analogues were partial agonists of intermediate potency. A 2‘-methoxy group provided intermediate potency as an antagonist while enhancing agonist activity. An N¹-methyl analogue was a weak antagonist with no agonist activity. An 8-bromo substitution and replacement of the N⁶-amino group with methylthio, chloro, or hydroxy groups greatly reduced the ability to interact with P2Y1 receptors. Benzoylation or dimethylation of the N⁶-amino group also abolished or greatly diminished the antagonist activity. In summary, our results further define the structure−activity of adenosine bisphosphates as P2Y1 receptor antagonists and have led to the identification of the most potent antagonist reported to date for this receptor.

A series of new 2-(ar)alkenyl, both Z- and E-diastereomers, and 2-alkyl derivatives of adenosine-5‘-N-ethyluronamide (NECA) and adenosine were synthesized and evaluated for their interaction with the A1 and A2A adenosine receptors, to better understand the conformational requirements of the receptor area interacting with the substituents in the 2- and 5‘-positions. Partial reduction of the triple bond in 2-alkynyl derivatives of NECA led to compounds whose activity at the A2A receptor subtype was related to Z−E-isomerism, the E-diastereomers being more potent and selective than the Z-ones. Saturation of the side chain markedly reduced compound affinity at adenosine receptors. Specifically, compounds bearing an (E)-alkenyl chain, while maintaining the same affinity at A2A receptors as the corresponding alkynyl derivatives, showed an increase in A2A vs A1 selectivity. Hence, the new nucleosides (E)-2-hexenylNECA (12a) and (E)-2-(phenylpentenyl)NECA (12b) exhibited both high A2A receptor affinity (Ki = 1.6 and 3.5 nM, respectively) and A2A vs A1 selectivity (157- and 290-fold, respectively). Moreover, 12a displayed potent antiaggregatory activity, similar to that of the reference compound NECA. Comparison between NECA and adenosine derivatives further demonstrated that the 5‘-ethylcarboxamido group is critical for the A2A affinity. These studies indicated that the orientation of the substituent in the 2-position and the nature of the 5‘-group in adenosine derivatives are critical to achieve high affinity and selectivity at the A2A adenosine receptor subtype.

The synthesis of hydroxylamino derivatives of 1,7-dideazaadenosine and of 1,7-dideaza-2'-deoxyadenosine, starting from 4-nitro-1H-pyrrolo[2,3-b]pyridine (1), is described. None of the synthesized compounds are substrates of adenosine deaminase and two of them (3 and 18) are weak inhibitors.

5, 7-Dichloro-3H-imidazo[4, 5-b]pyridine (4) is a versatile base which can be coupled with a variety of sugar moieties and transformed in a series of 7-alkyl(aryl)amino-derivatives by reacting with the corresponding amines. In this paper synthesis, structure elucidation and ADA inhibitory activity of 2'-deoxyribonucleoside derivatives of N6-substituted 1-deazaapurines are described.

AbstractAdenosine deaminase (ADA) is an important catabolic enzyme which converts adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. ADA exists in two different isoenzymes, namely ADA1 and ADA2, whose balance in monocytes-macrophages seems to guarantee the homeostasis of adenine nucleosides. Modifications of the purine moiety or/and substitution of the sugar moiety of adenosine with aliphatic chains led to derivatives which are good ADA inhibitors.

AbstractIn a search for potent and selective adenosine agonists it has been found that 2-hexynyladenosine-5′-N-ethyluronamide (HENECA) displays high affinity at rat A2Areceptor combined with a good A2AvsA1selectivity. The finding that HENECA shows good affinity also for A3receptors prompted us to investigate the effect of various substituents in different positions of this molecule.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.