M. Fernanda R. P. Proença

The Condensation of Salicylaldehydes and Malononitrile Revisited: Synthesis of New Dimeric Chromene Derivatives

The reaction of salicylic aldehydes with malononitrile was reinvestigated, and the reaction pathway was followed by 1H NMR spectroscopy. A delicate control of the experimental conditions allowed the synthesis of 2-imino-2H-chromene-3-carbonitriles 1, (2-amino-3-cyano-4H-chromen-4-yl)malononitriles 2, 4-amino-5-imino-2,7-dimethoxy-5H-chromeno[3,4-c]pyridine-1-carbonitrile 12, and (4,5-diamino-1-cyano-1,10b-dihydro-2H-chromeno[3,4-c]pyridin-2-ylidene)malononitrile 13. Two novel 2-iminochromene dimers, with structures 8 and 9, were isolated and fully characterized. The activity of compound 8a on Aspergillus spp. growth and on ochratoxin A production was evaluated. The results of the bioassays indicate that compound 8a, applied at concentrations of 2 mM, totally inhibited the growth of the fungi tested. Ochratoxin A production by Aspergillus alliaceus was reduced by about 93% with a 200 microM solution of this compound. A moderate inhibitory effect was observed for the analogous structure 8b, and no inhibition was registered for compounds 2 and 1, used as synthetic precursors of the dimeric species 8.

Controlled functionalization of carbon nanotubes by a solvent-free multicomponent approach

The present work reports the solvent-free, one-pot functionalization of multiwall carbon nanotubes (CNTs) based on the 1,3-dipolar cycloaddition of azomethine ylides using N-benzyloxycarbonyl glycine and formaldehyde. The surface morphology of the functionalized CNTs was investigated by scanning tunneling microscopy. The effect of temperature on the reaction was studied by thermogravimetry and X-ray photoelectron spectroscopy (XPS). XPS was a key technique for the detailed chemical analysis of the CNT surface. The formation of two major reaction products was observed, namely a cyclic benzyl carbamate and a pyrrolidine. The concentration of the two products varied with reaction temperature and time. At 180 °C, the main product was the cyclic benzyl carbamate, while at 250 °C the major product was the pyrrolidine. This simple, solvent-free chemical procedure yields CNTs with fine-tuned surface functionality.

Unzipping of Functionalized Multiwall Carbon Nanotubes Induced by STM

Carbon nanotubes (CNTs), functionalized by a cycloaddition reaction, were studied by ultrahigh vacuum scanning tunneling microscopy (STM). The STM images provided evidence for partial or total unzipping of the outer CNT layer. The formation of graphene ribbons was triggered by the STM tip, under specific operating conditions. A model for the unzipping is proposed, based on the perturbation of the pi-conjugation along the CNT surface induced by the cycloaddition reaction.

Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin.

A series of chalcone and flavonol derivatives were synthesized in good yield by an eco-friendly approach. A pharmacological evaluation was performed with the human colorectal carcinoma cell line HCT116 and revealed that the anticancer activity of flavonols was higher when compared with that of the respective chalcone precursors. The antiproliferative activity of halogenated derivatives increases as the substituent in the 3- or 4-positon of the B-ring goes from F to Cl and to Br. In addition, halogens in position 3 enhance anticancer activity in chalcones whereas for flavonol derivatives the best performance was registered for the 4-substituted derivatives. Flow cytometry analysis showed that compounds 3p and 4o induced cell cycle arrest and apoptosis as demonstrated by increased S, G2/M and sub-G1 phases. These data were corroborated by western blot and fluorescence microscopy analysis. In summary, halogenated chalcones and flavonols were successfully prepared and presented high anticancer activity as shown by their cell growth and cell cycle inhibitory potential against HCT116 cells, superior to that of quercetin, used as a positive control.

Synthesis of 9-hydroxyalkyl-substituted purines from the corresponding 4-(C-cyanoformimidoyl)imidazole-5-amines

The amino alcohols HO(CH2)n NH2(n= 2, 3 and 5) react readily with ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimidate 5 to give the amidines 6a-c, which cyclize in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to give the corresponding 4-(cyanoformimidoyl)imidazole-5-amines 7a-c, which can be isolated in the cases where n= 2 or 3.In the presence of aldehydes and ketones, the imidazoles 7a-d lead to the 6-carbamoyl-1,2-di-hydropurines 9a-f which, in some cases, are oxidised to the corresponding 6-carbamoylpurines.The reaction of the imidate 5 with 2-methoxyethylamine leads to the amidine 6d and, on treatment with DBU, the reactive imidazole 7d which can be used directly for further reaction.

In silico directed chemical probing of the adenosine receptor family

One of the grand challenges in chemical biology is identifying a small-molecule modulator for each individual function of all human proteins. Instead of targeting one protein at a time, an efficient approach to address this challenge is to target entire protein families by taking advantage of the relatively high levels of chemical promiscuity observed within certain boundaries of sequence phylogeny. We recently developed a computational approach to identifying the potential protein targets of compounds based on their similarity to known bioactive molecules for almost 700 targets. Here, we describe the direct identification of novel antagonists for all four adenosine receptor subtypes by applying our virtual profiling approach to a unique synthesis-driven chemical collection composed of 482 biologically-orphan molecules. These results illustrate the potential role of in silico target profiling to guide efficiently screening campaigns directed to discover new chemical probes for all members of a protein family.

(Z)-N3-(2-amino-1,2-dicyanovinyl)formamidrazone: a precursor in the synthesis of 1,5-diaminoimidazoles and 6-carbamoyl-1,2-dihydropurines

The reaction of ethyl (Z)-N-(2-amino-1,2-dicyanovinyl)formimidate with hydrazine monohydrate leads to (Z)-N3-(2-amino-1,2-dicyanovinyl)formamidrazone in almost quantitative yield. This compound proved to be an important starting material for the synthesis of the corresponding N1-isopropylidene-and N1-acetyl-formamidrazones.The amidrazones prepared promptly cyclize in the presence of base to give a 1,5-diamino-4-cyanoimidazole or a 1,5-diamino-4-(cyanoformimidoyl)imidazole, depending on the reaction conditions and mainly on the nature of the base used to induce cyclization.1,5-Diamino-4-(cyanoformimidoyl)imidazole was treated with carbonyl compounds and the 1,2-dihydropurines thus isolated indicated that the amino group in position 5 is more reactive than that in position 1.

Protective role of new nitrogen compounds on ROS/RNS-mediated damage to PC12 cells

Reactive oxygen (ROS) and nitrogen (RNS) species are known to be involved in many degenerative diseases. This study reports four new nitrogen compounds from organic synthesis, identified as FMA4, FMA7, FMA762 and FMA796, which differ mainly by the number of hydroxyl groups within their phenolic unit. Their potential role as antioxidants was evaluated in PC12 cells by assessing their protection against oxidative and nitrosative insults. The four compounds, and particularly FMA762 and FMA796, were able to protect cells against lipid peroxidation and intracellular ROS/RNS formation to a great extent. Their protective effects were likely mediated by their free radicals scavenging ability, as they appeared to be involved neither in the induction of natural antioxidant enzymes like GSH-PX and SOD, nor in the inhibition of NOS. Nevertheless, these results suggest a promising potential for these compounds as ROS/RNS scavengers in pathologies where oxidative/nitrosative stress are involved.

The chemistry of nitrilium salts. Part 3. The importance of triazinium salts in Houben–Hoesch reactions catalyzed by trifluoromethanesulphonic acid

In the presence of trifluoromethanesulphonic (triflic) acid, isobutyronitrile reacts with anisole, 1,3-dimethoxybenzene, resorcinol, 1,3,5-trimethoxybenzene, and phloroglucinol at room temperature to give acylation products. A study of the reactions of acetonitrile and isobutyronitrile with triflic acid has shown that these modified Houben–Hoesch reactions occur by initial cyclotrimerization of the nitriles to 1,3,5-triazinium triflate salts followed by a slow reaction of the salts with the aromatic substrate. Support for this comes from the isolation of 2-(4-methoxyphenyl)-2,4,6-tri-isopropyl-1,2-dihydro-1,3,5-triazine from the reaction between anisole, triflic acid, and isobutyronitrile. Similar 1,2-dihydro-s-triazines and their salts have been prepared by reaction of trimethyl-s-triazinium triflate with 1,3-(MeO)2C6H4, and tri-isopropyl-s-triazinium triflate with 1,3-(RO)2C6H4(R = H or Me) and 1,3,5-(MeO)3C6H3; these salts are easily hydrolyzed to the corresponding aromatic ketones. The salt [1,3,5-Me3C3N3H2]+ 2Ō3SCF3 also reacts with o-phenylenediamine to give 2-methylbenzimidazolinium triflate in 83% yield. Nitrilium salts [RCNMe]+Ō3SCF3(R = Me, Ph, or PhCH2) undergo rapid reactions with 1,3-(MeO)2C6H4 to form acylation products after hydrolysis, and N,N-dimethylaniline similarly affords 4-Me2NC6H4COMe on reaction with [MeCNMe]+Ō3SCF3 at room temperature.

Synthesis of novel 6-enaminopurines.

Two different approaches have been used for the synthesis of 6-enaminopurines 6 from 5-amino-4-cyanoformimidoyl imidazoles. In the first approach imidazoles 1 were reacted with ethoxymethylenemalononitrile or ethoxymethylenecyanoacetate under mild experimental conditions and this led to 9-substituted-6-(1-amino-2,2-dicyanovinyl) purines 6a-f or 9-substituted-6-(1-amino-2-cyano-2-methoxycarbonylvinyl) purines 6g-k. These reactions are postulated to occur through an imidazo-pyrrolidine intermediate 7, which rapidly rearranges to the 6-enaminopurine 6. In the second approach 6-methoxyformimidoyl purines 3, prepared in two efficient steps from 5-amino-4-cyanoformimidoyl imidazoles 1, were reacted with malononitrile and methylcyanoacetate with a mild acid catalysis (ammonium acetate or piperidinium acetate) to give 6-enaminopurines 6a, 6d, 6f, 6g and 6k in very good yields. Only low yields were obtained for the 6-enaminopurine 6j, as competing nucleophilic attack on C-8 of either 3d or 6jcauses ring opening with formation of pyrimido-pyrimidines 11 and 10a respectively.