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Steroidal 1-azadienes react with cyclic ketones to afford hexacyclic steroids via annulation reaction while the reaction with aldehydes gives pentacyclic steroids via hetero-Diels–Alder reactions.
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The synthesis and anti-microbial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and... more
The synthesis and anti-microbial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-β-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information. Among the tested compounds, two spirocyclopentenyl-β-lactams were identified as having remarkable nanomolar activity against HIV-1. Additionally, the same molecules showed promising antiplasmodial activity, inhibiting both the hepatic and blood stages of Plasmodium infection.
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Quantum mechanical tunneling of heavy‐atoms and vibrational excitation chemistry are unconventional and scarcely explored types of reactivity. Once fully understood, they might bring new avenues to conduct chemical transformations,... more
Quantum mechanical tunneling of heavy‐atoms and vibrational excitation chemistry are unconventional and scarcely explored types of reactivity. Once fully understood, they might bring new avenues to conduct chemical transformations, providing access to a new world of molecules or ways of exquisite reaction control. In this context, we present here the discovery of two isomeric benzazirines exhibiting differential tunneling‐driven and vibrationally‐induced reactivity, which constitute exceptional results for probing into the nature of these phenomena. The isomeric 6‐fluoro‐ and 2‐fluoro‐4‐hydroxy‐2H‐benzazirines (3‐a and 3′‐s) were generated in cryogenic krypton matrices by visible‐light irradiation of the corresponding triplet nitrene 32‐a, which was produced by UV‐light irradiation of its azide precursor. The 3′‐s was found to be stable under matrix dark conditions, whereas 3‐a spontaneously rearranges (τ1/2 ∼64 h at 10 and 20 K) by heavy‐atom tunneling to 32‐a. Near‐IR‐light irradiation at the first OH stretching overtone frequencies (remote vibrational antenna) of the benzazirines induces the 3′‐s ring‐expansion reaction to a seven‐member cyclic ketenimine, but the 3‐a undergoes 2H‐azirine ring‐opening reaction to triplet nitrene 32‐a. Computations demonstrate that 3‐a and 3′‐s have distinct reaction energy profiles, which explain the different experimental results. The spectroscopic direct measurement of the tunneling of 3‐a to 32‐a constitutes a unique example of an observation of a species reacting only by nitrogen tunneling. Moreover, the vibrationally‐induced sole activation of the most favorable bond‐breaking/bond‐forming pathway available for 3‐a and 3′‐s provides pioneer results regarding the selective nature of such processes.
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The synthesis of 2-(tetrazol-5-yl)-2H-azirines is reported for the first time. Using the Neber approach, β-ketoxime-1H-tetrazoles were converted into the target 2H-azirines bearing phenyl, furan-2-yl, thiophen-2-yl, or pyrrol-2-yl... more
The synthesis of 2-(tetrazol-5-yl)-2H-azirines is reported for the first time. Using the Neber approach, β-ketoxime-1H-tetrazoles were converted into the target 2H-azirines bearing phenyl, furan-2-yl, thiophen-2-yl, or pyrrol-2-yl substituents at C-3. It was demonstrated that the alkaloid-mediated Neber reaction allows the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines.
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A comprehensive study on the electronic spectral, photophysical and acid–base properties of phenyl- and methyl-oxime corrole derivatives. Influence of the solvents (THF, DMSO and ACN) and concentration.
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The reaction can be run in different solvents or even without a solvent.
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A novel derivative of ROY, AcROY, was synthesized and studied in this work, where 3 different colored polymorphs were identified. The observed polymorphism of AcROY is an interesting case of packing-determined color polymorphism.
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Hetero‐Diels‐Alder reactions of hydrazones or oximes with furylmethanes give annulated pyridazines and oxazines, respectively, which are easily transformed into the title compounds.
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The reactivity of 2,2‐bis(furan‐2‐yl)propane towards nitroso‐ and azoalkenes was explored. The expected hetero‐Diels–Alder adducts, 4a,7a‐dihydro‐4H‐furo[2,3‐e][1,2]oxazines and 4a,7a‐dihydrofuro[3,2‐c]pyridazines, were obtained in good... more
The reactivity of 2,2‐bis(furan‐2‐yl)propane towards nitroso‐ and azoalkenes was explored. The expected hetero‐Diels–Alder adducts, 4a,7a‐dihydro‐4H‐furo[2,3‐e][1,2]oxazines and 4a,7a‐dihydrofuro[3,2‐c]pyridazines, were obtained in good yield. The furo‐oxazines were easily converted into the corresponding bis(furan‐2‐yl)methanes bearing an open‐chain oxime. Interestingly, the synthesized furo‐pyridazines showed a different chemical behavior. In the presence of HCl, they underwent a rearrangement giving 6‐(2‐oxobutyl)‐1,6‐dihydropyridazine derivatives in a process having as its key step a furan ring‐opening reaction. The synthesis of 4a,7a‐dihydrofuro[3,2‐c]pyridazines from 2‐methylfuran and the subsequent acid‐catalysed rearrangement to the corresponding 6‐(2‐oxopropyl)‐1,6‐dihydropyridazines was also achieved.
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This work describes the first and unprecedented examples of inverse electron demand Diels–Alder reactions of 5-(1-nitrosovinyl)-1-phenyl-1H-tetrazole, generated in situ from the corresponding bromooxime, with electron rich alkenes and... more
This work describes the first and unprecedented examples of inverse electron demand Diels–Alder reactions of 5-(1-nitrosovinyl)-1-phenyl-1H-tetrazole, generated in situ from the corresponding bromooxime, with electron rich alkenes and heterocycles, providing in good overall yields tetrazolyl-1,2-oxazines and -oximes. Upon subsequent reduction these allowed the access to 5-(1-aminoalkyl)-1H-tetrazoles, paving the way for a new entry into this important class of compounds, bioisosteres
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A one-pot regio- and stereoselective synthesis of a dipyrromethane and a bis(indolyl)methane based on two consecutive reactions of nitrosoalkenes with pyrrole or indole, respectively, is described as an experiment to be carried out by... more
A one-pot regio- and stereoselective synthesis of a dipyrromethane and a bis(indolyl)methane based on two consecutive reactions of nitrosoalkenes with pyrrole or indole, respectively, is described as an experiment to be carried out by upper-division undergraduate students in a laboratory classroom. Importantly, the ability of electrophilic conjugated nitrosoalkenes to react via Michael addition or hetero-Diels-Alder reactions with electron-rich heterocycles will provide an opportunity for students to acknowledge alternative reaction pathways underlying certain transformations. Reactions were performed under mild conditions using water as a solvent, followed by purification through column chromatography on silica gel, and characterization of the desired products by NMR and IR spectroscopy. This laboratory experiment combines organic synthesis, determination of the purity of compounds (TLC analysis and melting point measurements), as well as structural analysis (interpretation of 1D NMR spectra). Several important organic chemistry concepts, such as stereo- and regioselectivity, in situ generation and reactivity of conjugated nitrosoalkenes, conjugated 1,4-addition reactions, and cycloaddition reactions, are also discussed.info:eu-repo/semantics/publishedVersio
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Corroles and hexaphyrins are porphyrinoids with great potential for diverse applications. Like porphyrins, many of their applications are based on their unique capability to interact with light, i.e., based on their photophysical... more
Corroles and hexaphyrins are porphyrinoids with great potential for diverse applications. Like porphyrins, many of their applications are based on their unique capability to interact with light, i.e., based on their photophysical properties. Corroles have intense absorptions in the low-energy region of the uv-vis, while hexaphyrins have the capability to absorb light in the near-infrared (NIR) region, presenting photophysical features which are complementary to those of porphyrins. Despite the increasing interest in corroles and hexaphyrins in recent years, the full potential of both classes of compounds, regarding biological applications, has been hampered by their challenging synthesis. Herein, recent developments in the synthesis of corroles and hexaphyrins are reviewed, highlighting their potential application in photodynamic therapy.
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A successful one-pot methodology for the synthesis of chiral 2-tetrazolyl-2H-azirines has been established, resorting to organocatalysis. The protocol involves the in situ tosylation of β-ketoxime-1H-tetrazoles followed by the Neber... more
A successful one-pot methodology for the synthesis of chiral 2-tetrazolyl-2H-azirines has been established, resorting to organocatalysis. The protocol involves the in situ tosylation of β-ketoxime-1H-tetrazoles followed by the Neber reaction, in the presence of chiral organocatalysts. Among the organocatalysts studied a novel thiourea catalyst derived from 6β-aminopenicillanic acid afforded excellent enantioselectivities.
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This review presents the most recent developments on the synthesis of dipyrromethanes, covering classical synthetic strategies, using acid catalyzed condensation of pyrroles and aldehydes or ketones, and recent breakthroughs which allow... more
This review presents the most recent developments on the synthesis of dipyrromethanes, covering classical synthetic strategies, using acid catalyzed condensation of pyrroles and aldehydes or ketones, and recent breakthroughs which allow the synthesis of these type of heterocycles with new substitution patterns.
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Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out. Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel... more
Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out. Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to n...
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Porphyrins are known therapeutic agents for photodynamic therapy of cancer and also imaging agents for NIR fluorescence imaging, MRI, or PET. A combination of interesting features makes tetrapyrrolic macrocycles suitable for use as... more
Porphyrins are known therapeutic agents for photodynamic therapy of cancer and also imaging agents for NIR fluorescence imaging, MRI, or PET. A combination of interesting features makes tetrapyrrolic macrocycles suitable for use as theranostic agents whose full potential can be achieved using nanocarriers. This review provides an overview on nanotheranostic agents based on polymeric micelles and porphyrins developed so far.
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The synthesis and reactivity of a steroidal N-sulfonyl-1-azadiene, derived from 16-dehydropregnenolone acetate, toward carbonyl compounds under enamine catalysis is disclosed. An unexpected annulation reaction was observed involving an... more
The synthesis and reactivity of a steroidal N-sulfonyl-1-azadiene, derived from 16-dehydropregnenolone acetate, toward carbonyl compounds under enamine catalysis is disclosed. An unexpected annulation reaction was observed involving an initial stereoselective conjugate addition of the in situ generated enamine to the steroidal 1-azadiene. The developed diastereoselective synthetic methodology is a novel approach to a new class of chiral pentacyclic and hexacyclic steroids.
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The synthesis, photophysical behaviour and photosensitization ability of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused 5,15-diphenylchlorins against melanoma cells are described. All studied chlorins were found to be extremely... more
The synthesis, photophysical behaviour and photosensitization ability of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused 5,15-diphenylchlorins against melanoma cells are described. All studied chlorins were found to be extremely active against melanoma cell lines A375 showing IC50 values below 20 nM. Furthermore, a dihydroxymethyl diphenylchlorin was identified as an excellent candidate to allow modulating of different types of cell death, apoptosis vs. necrosis, by varying its concentration. This can be explored as a tool to improve the effectiveness of PDT since inflammatory response resulting from necrotic cell death after PDT can activate the antitumor immune response with implications also regarding the vascular damage. This feature combined with very low cytotoxicity against human melanoma cells in the absence of light activation and against human fibroblast HFF-1 cells makes this chlorin a candidate of choice as a photosensitizer for PDT. A comprehensive photophysical i...
Research Interests: Chemistry, Organic Chemistry, Oncology, Medicinal Chemistry, Cytotoxicity, and 15 moreCancer Research, Porphyrins, Apoptosis, Medicine, Photodynamic Therapy, Humans, Reactive Oxygen Species, Melanoma, Cell Death, Programmed cell death, Photochemotherapy, Cell Survival, Photosensitizer, Molecular Structure, and Pharmacology and pharmaceutical sciences
Furans have been explored as a scaffold for the synthesis of a range of heterocyclic compounds, exploring their dienophilic behaviour towards nitroso‐ and azoalkenes as the first step. Acid‐catalysed rearrangements of these cycloadducts,... more
Furans have been explored as a scaffold for the synthesis of a range of heterocyclic compounds, exploring their dienophilic behaviour towards nitroso‐ and azoalkenes as the first step. Acid‐catalysed rearrangements of these cycloadducts, 4a,7a‐dihydro‐4H‐furo[2,3‐e][1,2]oxazines and 1,4,4a,7a‐tetrahydrofuro[3,2‐c]pyridazines, were studied. Using 1 equiv. of TFA, the bicyclic heterocycles derived from furan and 2‐methylfuran were converted into furans bearing side‐chains incorporating oxime and hydrazone groups by ring‐opening of the six‐membered ring with the concomitant aromatization of the furan ring. The use of TFA as solvent led to rearrangement via spirocyclic intermediates, followed by furan ring‐opening to afford functionalized isoxazoles or pyrazoles. Furthermore, furo‐oxazines derived from 2,5‐dimethylfuran, in which furan aromatization is precluded, were converted efficiently into 6H‐1,2‐oxazines through a furan ring‐opening reaction upon thermolysis in the presence of a c...
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Novel near-infrared luminescent compounds based on platinum(II) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins are described. These compounds have high photostability and display light emission, in particular simultaneous... more
Novel near-infrared luminescent compounds based on platinum(II) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins are described. These compounds have high photostability and display light emission, in particular simultaneous fluorescence and phosphorescence emission in solution at room temperature, in the biologically relevant 700-850 nm red and near-infrared (NIR) spectral region, making them excellent materials for biological imaging. The simultaneous presence of fluorescence and phosphorescence emission at room temperature, with the phosphorescence strongly quenched by oxygen whereas fluorescence remains unaffected, allows these compounds to be used as ratiometric oxygen sensors in chemical and biological media. Both steady-state (fluorescence vs phosphorescence intensities) and dynamic (dependence of phosphorescence lifetimes upon oxygen concentration) luminescence approaches can be used. Photocytotoxicity studies against human melanocytic melanoma cells (A375) indicate t...
Research Interests: Pharmacology, Biochemistry, Physiology, Biophysics, Chemistry, and 15 moreOrganic Chemistry, Photochemistry, Biotechnology, Cancer, Fluorescence, Cell Biology, Medicine, Photodynamic Therapy, Luminescence, Oxygen, Room Temperature, Nir, Phosphorescence, Compound, and Pharmacology and pharmaceutical sciences
A novel synthetic approach to bis(indolyl)methanes has been established. Our one-pot synthetic strategy based on two consecutive hetero-Diels-Alder cycloaddition reactions of electrophilic conjugated nitrosoalkenes with indoles was... more
A novel synthetic approach to bis(indolyl)methanes has been established. Our one-pot synthetic strategy based on two consecutive hetero-Diels-Alder cycloaddition reactions of electrophilic conjugated nitrosoalkenes with indoles was extended to a range of new 1-hydroxyiminomethyl-bis(indolyl)methanes. Furthermore, a similar and broad range approach was applied to the synthesis of previously unknown 1-hydrazonomethyl-bis(indolyl)methanes. The biological evaluation of the new bis(indolyl)methanes as anti-cancer agents was investigated.