The 1,3-dipolar cycloaddition of azomethine ylides with DMAD in supercritical carbon dioxide is r... more The 1,3-dipolar cycloaddition of azomethine ylides with DMAD in supercritical carbon dioxide is reported. The photolysis reaction conditions were optimized with a suitable adjustment of pressure, temperature, irradiation time and co-solvent concentration leading to a more efficient reaction than in neat acetonitrile. Similar results were observed using thermal reaction conditions. Supercritical carbon dioxide with a minute co-solvent addition is shown to be a very efficient medium for promoting this type of cycloadditions.
The molecular architecture of spirocyclic compounds has been widely explored within the medicinal... more The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC 50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule's bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure-activity relationship open avenues for further development of spirocyclopentene-β-lactams as multivalent, highly active broad spectrum antimicrobial agents.
European Journal of Organic Chemistry, Sep 29, 2020
The synthesis of a library of 6-alkylidene-β-lactams, derived from 6-aminopenicillanic acid is re... more The synthesis of a library of 6-alkylidene-β-lactams, derived from 6-aminopenicillanic acid is reported. The 1,3-dipolar cycloaddition of these 6-alkylidenepenicillanates with nitrones was explored as an approach to synthesize novel chiral spiroisoxazolidine-β-lactams. Quantum chemical calculations, at the DFT level of theory, were carried out to elucidate the 3D structure of the synthesized compounds. The reported methodology, which involves the generation of three new consecutive stereogenic centers, proved to be regio-and stereoselective, leading to novel chiral spiroisoxazolidine-penicillanates efficiently.
Oxidation of polyunsaturated fatty acids (PUFA) in low-density lipoproteins (LDL) trapped in the ... more Oxidation of polyunsaturated fatty acids (PUFA) in low-density lipoproteins (LDL) trapped in the arterial intima plays a critical role in atherosclerosis. Though there have been many studies on the atherogenicity of oxidized derivatives of unsaturated fatty acid esters of cholesterol, the effects of the oxidation end-products of these esters has been ignored in the literature. Through lipidomics analyses of the plasma of cardiovascular disease patients and human endarterectomy specimens we identified and quantified cholesteryl hemiesters (ChE), end-products of oxidation of polyunsaturated-fatty acid esters of cholesterol. Cholesteryl hemiazelate (ChA) was the most prevalent ChE identified. Importantly human monocytes, monocyte-derived macrophages (MDM) and neutrophils exhibit inflammatory features when exposed to sub-toxic concentrations of ChA in vitro. ChA increases the secretion of proinflammatory cytokines such as IL-1β and IL-6 and modulates the surface markers profile of monoc...
The molecular architecture of spirocyclic compounds has been widely explored within the medicinal... more The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule’s bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-...
Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused meso-tetraarylchlorins, with different degr... more Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused meso-tetraarylchlorins, with different degrees of hydrophilicity (with methyl ester, hydroxymethyl, and carboxylic acid moieties), have been synthesized and their photophysical characterization as well as in vitro photocytotoxicity assessment against human melanoma and esophageal and bladder carcinomas was carried out. An integrated analysis of the photosensitizers’ performance, considering the singlet oxygen generation data, cell internalization, and intracellular localization, allowed to establish relevant structure-photoactivity relationships and the rationalization of the observed photocytotoxicity. In the diacid and monoalcohol series, chlorins derived from meso-tetraphenylporphyrin proved to be the most efficient photodynamic therapy agents, showing IC50 values of 68 and 344 nM against A375 cells, respectively. These compounds were less active against OE19 and HT1376 cells, the diacid chlorin with IC50 values still in the n...
Opioids are the drugs most commonly detected in overdose deaths and the second most consumed worl... more Opioids are the drugs most commonly detected in overdose deaths and the second most consumed worldwide. An analytical methodology has been optimized and fully validated for the determination of codeine, morphine, 6-acetylmorphine, 6-acetylcodeine, oxycodone, oxymorphone and fentanyl in whole blood and pericardial fluid. The internal standards used were codeine-d3, morphine-d3, 6-acetylmorphine-d3 and fentanyl-d5. Before solid-phase extraction, volumes of 250 μL of blood and pericardial fluid were subjected to a protein precipitation (with 750 μL of ice-cold acetonitrile) and a microwave-induced oximation was performed using a solution of 1% aqueous hydroxylamine hydrochloride in phosphate-buffered saline (1:2, v/v). Finally, the dried extracts were further derivatized with a solution of n-methyl-n-(trimethylsilyl) trifluoroacetamide + 5% trimethylchlorosilane under microwave irradiation. The chromatographic analysis was carried out using gas chromatography–mass spectrometry operatin...
Highlights d MANIO displays in vitro and in vivo p53-dependent antitumor activity d MANIO activat... more Highlights d MANIO displays in vitro and in vivo p53-dependent antitumor activity d MANIO activates WTp53 and restores WT-like function to mutp53 in CRC cells d MANIO binds to WT-and mutp53 proteins, enhancing their transcriptional activity d MANIO synergizes with conventional chemotherapeutics used in CRC therapy
Mastering Functional Group Interconversion is an important tool in Organic Chemistry. The ability... more Mastering Functional Group Interconversion is an important tool in Organic Chemistry. The ability to modulate the structure of a given scaffold is essential in any target synthesis and particularly relevant in areas such as Medicinal Chemistry and Materials Chemistry. The theme issue on Recent Advances on Functional Group Interconversion provides an overview on selected topics, briefly listed below, with particular emphasis on recent developments. Lima, Forezi et al. in "Functional Group Transformation in Naphthoquinones: Strategies for the Synthesis of Mono-and Bis(Amino-1,4-naphthoquinones)" discuss the functionalization of naphthoquinone derivatives, a class of compounds known for their activity against several biological targets. The review focused on the synthesis of aminonaphthoquinones from 1,4-naphtoquinone derivatives (1,4-naphthoquinone, juglone, lawsone, lapachol, menadione and 2,3-dihalo-1,4naphthoquinones) as well as on further transformations of aminonaphthoquinones. Data regarding the biological activity of some of the naphthoquinone derivatives is also included [1]. Pinho e Melo et al. in "Reduction of Oximes and Hydrazones: Asymmetric and Diastereoselective Approaches" report on the most relevant contributions on this topic, published in the last decade. The enantioselective and diastereoselective reduction of oximes and hydrazones is presented as a versatile synthetic strategy towards chiral amines, which are valuable building blocks in organic synthesis. The synthesis of hydroxylamines and hydrazines is also covered. The synthetic methodologies use to carry out these transformations are mainly metal-catalyzed hydrogenation/hydrogenolysis reactions, hydride donor reactions and electrochemical reactions [2]. Maria Manuel Marques et al. in "Toolbox for α-amination reactions" discuss the most recent protocols for α-amination of carbonyl compounds selected on the basis of synthetic utility, novelty and enantioselectivity. This comprehensive review covers the construction of the C-N bond between the α-position of a carbonyl and an amine using umpolung strategies in the ketone moiety and nucleophilic nitrogen sources, using the reaction of ketones/enolates with electrophilic nitrogen sources as well as via oxidative methodologies [3]. The theme issue ends with a very interesting review by Marcus Baumann et al. on "Functional Group Interconversion Reactions in Continuous Flow Reactors". The review describes key examples from the last decade of various functional group interconversion reactions carried out under continuous-flow conditions. The selected examples highlight the advantage of this modern and sustainable synthetic technology regarding safety, efficiency, reproducibility and scalability [4]. As Guest Editors, we would like to acknowledge all authors for providing excellent reviews and making the publication of this thematic issue possible.
Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, derived from 5,10,15,20-tetrakis(... more Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, derived from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, as impressive photosensitizers for photodynamic therapy of melanoma and esophagus cancer have been developed.
Ring-fused diphenylchlorins as potent low-dose photosensitizers for photodynamic therapy of bladd... more Ring-fused diphenylchlorins as potent low-dose photosensitizers for photodynamic therapy of bladder carcinoma and esophageal adenocarcinoma are described. All studied molecules were very active against HT1376 urinary bladder carcinoma and OE19 esophageal adenocarcinoma cell lines, showing IC 50 values below 50 nM. The in vivo evaluation of the more promising photosensitizer, using an OE19 tumor/chick embryo chorioallantoic membrane model, showed a tumor weight regression of 33% with a single photodynamic therapy treatment with the photosensitizer dose as low as 37 ng/embryo.
D-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and u... more D-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and used in the enantioselective alkylation of a variety of aromatic aldehydes with diethylzinc at room temperature. Excellent ee, up to >99%, and nearly complete conversions were observed. Structurally analogous L-cysteine derived thiazolidine ligands were also synthesized and tested for comparative purposes, resulting in very good, albeit slightly lower selectivities, up to 89%. The combined use of these two types of thiazolidines constitutes a very interesting strategy for synthesizing both (S) and (R) enantiomers of chiral secondary alcohols, thus leading the way to a myriad of useful optically active products with opposite absolute configurations.
The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehydederived alky... more The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehydederived alkynes and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3b]pyrrole derivatives. Tetrahydro-chromeno[4,3-b]pyrroles were obtained from the reaction of these secondary amino acids with O-propargylsalicylaldehyde. Interestingly, sarcosine reacted with ethyl 4-(2-formylphenoxy)but-2-ynoate to give a monocyclic pyrrole resulting from rearrangement of the initially formed 1,3-dipolar cycloadduct. Decarboxylative condensation of ethyl 4-(2formylphenoxy)but-2-ynoate with 1,3-thiazolidine-4-carboxylic acid afforded in a stereoselective fashion the expected chromeno-pyrrolo[1,2-c]thiazole, which structure was unambiguously established by X-ray crystallography. However, the 1H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the pyran ring was also isolated. The reaction with O-buta-2,3-dienyl salicylaldehyde afforded 3methylene-hexahydrochromeno[4,3-b]pyrrole. O-Allenyl salicylaldehyde reacted with sarcosine and 1,3-thiazolidine-4-carboxylic acid to give new type of chromeno-pyrroles. A mechanism proposal for the synthesis of these chromeno[2,3-b]pyrroles has been presented.
In this study, the UV induced photochemical reactions of two 2H-azirines-methyl 2-chloro-3-methyl... more In this study, the UV induced photochemical reactions of two 2H-azirines-methyl 2-chloro-3-methyl-2H-azirine-2-carboxylate (MCMAC) and methyl 3-methyl-2H-azirine-2-carboxylate (MMAC)-isolated in argon matrices are compared. For both compounds, irradiation with > 235 nm led to observation of two primary photoprocesses: (a) CAC bond cleavage, with production of nitrile ylides (P1-type products), and (b) CAN bond cleavage, with production of methylated ketene imines (P2-type products). However, subsequent photoprocesses were found to be diVerent in the two cases. In MCMAC, both primary photoproducts were shown to undergo further reactions: P1-type products decarboxylate, giving [(1-chloroethylidene)imino]ethanide, which bears a CBN + BC ¡ group (P3-type product); P2-type products decarbonylate, yielding a substituted ylidene methanamine (P4-type product). In MMAC, only P2-type primary photoproducts appeared to react, undergoing decarbonylation or decarboxylation (both reactions leading to P4-type products), whereas P1-type products were found to be non-reactive. The non-observation of any secondary photoproduct resulting from photolysis of P1-MMAC revealed the higher photostability of this species when compared with the corresponding photoproduct obtained from MCMAC. The CAN photochemical cleavage is an unusual process in aliphatic 2H-azirines. In the studied compounds, its preference over the commonly observed CAC azirine-ring bond photocleavage is attributed to the presence of electron withdrawing substituents (methylcarboxy group in both azirines and also the chlorine atom in MCMAC), which accelerates intersystem crossing towards the triplet state from where the cleavage of the CAN bond takes place. The lack of the chlorine atom in MMAC may be partially compensated by the sig-niWcantly higher stabilization of the P2-type photoproduct derived from this molecule (ca. ¡52 kJ mol ¡1) relatively to the reactant, when compared to that obtained from MCMAC (ca. ¡26 kJ mol ¡1). Nevertheless, the obtained results indicate that the methylcarboxy substituent plays the most important role in determining the photochemical behavior of these aliphatic 2H-azirines, in particular the preference they exhibit for the unusual CAN bond cleavage over the "classic" CAC bond cleavage.
ABSTRACT Isoquinolines have been synthesized from the redox-neutral dehydrative CN and CC cross-c... more ABSTRACT Isoquinolines have been synthesized from the redox-neutral dehydrative CN and CC cross-coupling between oximines and alkynes using a catalytic amount of (pentamethylcyclopentadiene)rhodium dichloride dimer {[RhCp*Cl2]2} and cesium acetate (CsOAc), a process that involves ortho CH activation of oximines and subsequent functionalization with alkynes. This redox-neutral catalytic isoquinoline synthesis operates under mild conditions, and is insensitive to moisture or air. A broad scope of coupling partners has been established, and a likely mechanism has been suggested.
Platinum(II) ring-fused chlorins as efficient theranostic agents: Dyes for tumor-imaging and phot... more Platinum(II) ring-fused chlorins as efficient theranostic agents: Dyes for tumor-imaging and photodynamic therapy of cancer,
Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2-and 3-alkyla... more Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2-and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMO heterodiene-HOMO dienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4′,3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.
The 1,3-dipolar cycloaddition of azomethine ylides with DMAD in supercritical carbon dioxide is r... more The 1,3-dipolar cycloaddition of azomethine ylides with DMAD in supercritical carbon dioxide is reported. The photolysis reaction conditions were optimized with a suitable adjustment of pressure, temperature, irradiation time and co-solvent concentration leading to a more efficient reaction than in neat acetonitrile. Similar results were observed using thermal reaction conditions. Supercritical carbon dioxide with a minute co-solvent addition is shown to be a very efficient medium for promoting this type of cycloadditions.
The molecular architecture of spirocyclic compounds has been widely explored within the medicinal... more The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC 50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule's bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-bl and Huh7 human cell lines. Overall, a family of new spirocyclopentene penicillanates with potent activity against HIV and/or Plasmodium was identified. The present structure-activity relationship open avenues for further development of spirocyclopentene-β-lactams as multivalent, highly active broad spectrum antimicrobial agents.
European Journal of Organic Chemistry, Sep 29, 2020
The synthesis of a library of 6-alkylidene-β-lactams, derived from 6-aminopenicillanic acid is re... more The synthesis of a library of 6-alkylidene-β-lactams, derived from 6-aminopenicillanic acid is reported. The 1,3-dipolar cycloaddition of these 6-alkylidenepenicillanates with nitrones was explored as an approach to synthesize novel chiral spiroisoxazolidine-β-lactams. Quantum chemical calculations, at the DFT level of theory, were carried out to elucidate the 3D structure of the synthesized compounds. The reported methodology, which involves the generation of three new consecutive stereogenic centers, proved to be regio-and stereoselective, leading to novel chiral spiroisoxazolidine-penicillanates efficiently.
Oxidation of polyunsaturated fatty acids (PUFA) in low-density lipoproteins (LDL) trapped in the ... more Oxidation of polyunsaturated fatty acids (PUFA) in low-density lipoproteins (LDL) trapped in the arterial intima plays a critical role in atherosclerosis. Though there have been many studies on the atherogenicity of oxidized derivatives of unsaturated fatty acid esters of cholesterol, the effects of the oxidation end-products of these esters has been ignored in the literature. Through lipidomics analyses of the plasma of cardiovascular disease patients and human endarterectomy specimens we identified and quantified cholesteryl hemiesters (ChE), end-products of oxidation of polyunsaturated-fatty acid esters of cholesterol. Cholesteryl hemiazelate (ChA) was the most prevalent ChE identified. Importantly human monocytes, monocyte-derived macrophages (MDM) and neutrophils exhibit inflammatory features when exposed to sub-toxic concentrations of ChA in vitro. ChA increases the secretion of proinflammatory cytokines such as IL-1β and IL-6 and modulates the surface markers profile of monoc...
The molecular architecture of spirocyclic compounds has been widely explored within the medicinal... more The molecular architecture of spirocyclic compounds has been widely explored within the medicinal chemistry field to obtain new compounds with singular three-dimensional pharmacophoric features and improved bioactivity. Herein, the synthesis of 68 new spirocyclopentene-β-lactams is described, resulting from a rational drug design and structural modulation of a highly promising lead compound BSS-730A, previously identified as having dual antimicrobial activity associated with a novel mechanism of action. Among this diverse library of new compounds, 22 were identified as active against HIV-1, with eight displaying an IC50 lower than 50 nM. These eight compounds also showed nanomolar activity against HIV-2, and six of them displayed micromolar antiplasmodial activity against both the hepatic and the blood stages of infection by malaria parasites, in agreement with the lead molecule’s bioactivity profile. The spirocyclopentene-β-lactams screened also showed low cytotoxicity against TZM-...
Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused meso-tetraarylchlorins, with different degr... more Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused meso-tetraarylchlorins, with different degrees of hydrophilicity (with methyl ester, hydroxymethyl, and carboxylic acid moieties), have been synthesized and their photophysical characterization as well as in vitro photocytotoxicity assessment against human melanoma and esophageal and bladder carcinomas was carried out. An integrated analysis of the photosensitizers’ performance, considering the singlet oxygen generation data, cell internalization, and intracellular localization, allowed to establish relevant structure-photoactivity relationships and the rationalization of the observed photocytotoxicity. In the diacid and monoalcohol series, chlorins derived from meso-tetraphenylporphyrin proved to be the most efficient photodynamic therapy agents, showing IC50 values of 68 and 344 nM against A375 cells, respectively. These compounds were less active against OE19 and HT1376 cells, the diacid chlorin with IC50 values still in the n...
Opioids are the drugs most commonly detected in overdose deaths and the second most consumed worl... more Opioids are the drugs most commonly detected in overdose deaths and the second most consumed worldwide. An analytical methodology has been optimized and fully validated for the determination of codeine, morphine, 6-acetylmorphine, 6-acetylcodeine, oxycodone, oxymorphone and fentanyl in whole blood and pericardial fluid. The internal standards used were codeine-d3, morphine-d3, 6-acetylmorphine-d3 and fentanyl-d5. Before solid-phase extraction, volumes of 250 μL of blood and pericardial fluid were subjected to a protein precipitation (with 750 μL of ice-cold acetonitrile) and a microwave-induced oximation was performed using a solution of 1% aqueous hydroxylamine hydrochloride in phosphate-buffered saline (1:2, v/v). Finally, the dried extracts were further derivatized with a solution of n-methyl-n-(trimethylsilyl) trifluoroacetamide + 5% trimethylchlorosilane under microwave irradiation. The chromatographic analysis was carried out using gas chromatography–mass spectrometry operatin...
Highlights d MANIO displays in vitro and in vivo p53-dependent antitumor activity d MANIO activat... more Highlights d MANIO displays in vitro and in vivo p53-dependent antitumor activity d MANIO activates WTp53 and restores WT-like function to mutp53 in CRC cells d MANIO binds to WT-and mutp53 proteins, enhancing their transcriptional activity d MANIO synergizes with conventional chemotherapeutics used in CRC therapy
Mastering Functional Group Interconversion is an important tool in Organic Chemistry. The ability... more Mastering Functional Group Interconversion is an important tool in Organic Chemistry. The ability to modulate the structure of a given scaffold is essential in any target synthesis and particularly relevant in areas such as Medicinal Chemistry and Materials Chemistry. The theme issue on Recent Advances on Functional Group Interconversion provides an overview on selected topics, briefly listed below, with particular emphasis on recent developments. Lima, Forezi et al. in "Functional Group Transformation in Naphthoquinones: Strategies for the Synthesis of Mono-and Bis(Amino-1,4-naphthoquinones)" discuss the functionalization of naphthoquinone derivatives, a class of compounds known for their activity against several biological targets. The review focused on the synthesis of aminonaphthoquinones from 1,4-naphtoquinone derivatives (1,4-naphthoquinone, juglone, lawsone, lapachol, menadione and 2,3-dihalo-1,4naphthoquinones) as well as on further transformations of aminonaphthoquinones. Data regarding the biological activity of some of the naphthoquinone derivatives is also included [1]. Pinho e Melo et al. in "Reduction of Oximes and Hydrazones: Asymmetric and Diastereoselective Approaches" report on the most relevant contributions on this topic, published in the last decade. The enantioselective and diastereoselective reduction of oximes and hydrazones is presented as a versatile synthetic strategy towards chiral amines, which are valuable building blocks in organic synthesis. The synthesis of hydroxylamines and hydrazines is also covered. The synthetic methodologies use to carry out these transformations are mainly metal-catalyzed hydrogenation/hydrogenolysis reactions, hydride donor reactions and electrochemical reactions [2]. Maria Manuel Marques et al. in "Toolbox for α-amination reactions" discuss the most recent protocols for α-amination of carbonyl compounds selected on the basis of synthetic utility, novelty and enantioselectivity. This comprehensive review covers the construction of the C-N bond between the α-position of a carbonyl and an amine using umpolung strategies in the ketone moiety and nucleophilic nitrogen sources, using the reaction of ketones/enolates with electrophilic nitrogen sources as well as via oxidative methodologies [3]. The theme issue ends with a very interesting review by Marcus Baumann et al. on "Functional Group Interconversion Reactions in Continuous Flow Reactors". The review describes key examples from the last decade of various functional group interconversion reactions carried out under continuous-flow conditions. The selected examples highlight the advantage of this modern and sustainable synthetic technology regarding safety, efficiency, reproducibility and scalability [4]. As Guest Editors, we would like to acknowledge all authors for providing excellent reviews and making the publication of this thematic issue possible.
Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, derived from 5,10,15,20-tetrakis(... more Novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, derived from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, as impressive photosensitizers for photodynamic therapy of melanoma and esophagus cancer have been developed.
Ring-fused diphenylchlorins as potent low-dose photosensitizers for photodynamic therapy of bladd... more Ring-fused diphenylchlorins as potent low-dose photosensitizers for photodynamic therapy of bladder carcinoma and esophageal adenocarcinoma are described. All studied molecules were very active against HT1376 urinary bladder carcinoma and OE19 esophageal adenocarcinoma cell lines, showing IC 50 values below 50 nM. The in vivo evaluation of the more promising photosensitizer, using an OE19 tumor/chick embryo chorioallantoic membrane model, showed a tumor weight regression of 33% with a single photodynamic therapy treatment with the photosensitizer dose as low as 37 ng/embryo.
D-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and u... more D-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and used in the enantioselective alkylation of a variety of aromatic aldehydes with diethylzinc at room temperature. Excellent ee, up to >99%, and nearly complete conversions were observed. Structurally analogous L-cysteine derived thiazolidine ligands were also synthesized and tested for comparative purposes, resulting in very good, albeit slightly lower selectivities, up to 89%. The combined use of these two types of thiazolidines constitutes a very interesting strategy for synthesizing both (S) and (R) enantiomers of chiral secondary alcohols, thus leading the way to a myriad of useful optically active products with opposite absolute configurations.
The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehydederived alky... more The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehydederived alkynes and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3b]pyrrole derivatives. Tetrahydro-chromeno[4,3-b]pyrroles were obtained from the reaction of these secondary amino acids with O-propargylsalicylaldehyde. Interestingly, sarcosine reacted with ethyl 4-(2-formylphenoxy)but-2-ynoate to give a monocyclic pyrrole resulting from rearrangement of the initially formed 1,3-dipolar cycloadduct. Decarboxylative condensation of ethyl 4-(2formylphenoxy)but-2-ynoate with 1,3-thiazolidine-4-carboxylic acid afforded in a stereoselective fashion the expected chromeno-pyrrolo[1,2-c]thiazole, which structure was unambiguously established by X-ray crystallography. However, the 1H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the pyran ring was also isolated. The reaction with O-buta-2,3-dienyl salicylaldehyde afforded 3methylene-hexahydrochromeno[4,3-b]pyrrole. O-Allenyl salicylaldehyde reacted with sarcosine and 1,3-thiazolidine-4-carboxylic acid to give new type of chromeno-pyrroles. A mechanism proposal for the synthesis of these chromeno[2,3-b]pyrroles has been presented.
In this study, the UV induced photochemical reactions of two 2H-azirines-methyl 2-chloro-3-methyl... more In this study, the UV induced photochemical reactions of two 2H-azirines-methyl 2-chloro-3-methyl-2H-azirine-2-carboxylate (MCMAC) and methyl 3-methyl-2H-azirine-2-carboxylate (MMAC)-isolated in argon matrices are compared. For both compounds, irradiation with > 235 nm led to observation of two primary photoprocesses: (a) CAC bond cleavage, with production of nitrile ylides (P1-type products), and (b) CAN bond cleavage, with production of methylated ketene imines (P2-type products). However, subsequent photoprocesses were found to be diVerent in the two cases. In MCMAC, both primary photoproducts were shown to undergo further reactions: P1-type products decarboxylate, giving [(1-chloroethylidene)imino]ethanide, which bears a CBN + BC ¡ group (P3-type product); P2-type products decarbonylate, yielding a substituted ylidene methanamine (P4-type product). In MMAC, only P2-type primary photoproducts appeared to react, undergoing decarbonylation or decarboxylation (both reactions leading to P4-type products), whereas P1-type products were found to be non-reactive. The non-observation of any secondary photoproduct resulting from photolysis of P1-MMAC revealed the higher photostability of this species when compared with the corresponding photoproduct obtained from MCMAC. The CAN photochemical cleavage is an unusual process in aliphatic 2H-azirines. In the studied compounds, its preference over the commonly observed CAC azirine-ring bond photocleavage is attributed to the presence of electron withdrawing substituents (methylcarboxy group in both azirines and also the chlorine atom in MCMAC), which accelerates intersystem crossing towards the triplet state from where the cleavage of the CAN bond takes place. The lack of the chlorine atom in MMAC may be partially compensated by the sig-niWcantly higher stabilization of the P2-type photoproduct derived from this molecule (ca. ¡52 kJ mol ¡1) relatively to the reactant, when compared to that obtained from MCMAC (ca. ¡26 kJ mol ¡1). Nevertheless, the obtained results indicate that the methylcarboxy substituent plays the most important role in determining the photochemical behavior of these aliphatic 2H-azirines, in particular the preference they exhibit for the unusual CAN bond cleavage over the "classic" CAC bond cleavage.
ABSTRACT Isoquinolines have been synthesized from the redox-neutral dehydrative CN and CC cross-c... more ABSTRACT Isoquinolines have been synthesized from the redox-neutral dehydrative CN and CC cross-coupling between oximines and alkynes using a catalytic amount of (pentamethylcyclopentadiene)rhodium dichloride dimer {[RhCp*Cl2]2} and cesium acetate (CsOAc), a process that involves ortho CH activation of oximines and subsequent functionalization with alkynes. This redox-neutral catalytic isoquinoline synthesis operates under mild conditions, and is insensitive to moisture or air. A broad scope of coupling partners has been established, and a likely mechanism has been suggested.
Platinum(II) ring-fused chlorins as efficient theranostic agents: Dyes for tumor-imaging and phot... more Platinum(II) ring-fused chlorins as efficient theranostic agents: Dyes for tumor-imaging and photodynamic therapy of cancer,
Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2-and 3-alkyla... more Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2-and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMO heterodiene-HOMO dienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4′,3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.
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Papers by T.m.v.d. Melo