Teresa M V D Pinho e Melo

University of Coimbra | UC · Department of Chemistry

This review delves into the significant cellular and molecular responses triggered by UVR exposure in human skin, emphasizing the pivotal role of mutant p53 (mutp53) in the carcinogenic process elicited by radiation. By underlining the role of a functional p53 in safeguarding skin cells from UVR-induced damage, this work underscores the potential s...

Herein, we describe the development of a continuous flow approach to chiral spiropenicillanates with remarkable bioactive properties from 6‐alkylidenepenicillanates through phosphine‐catalyzed [3+2] annulation of allenoates or 1,3‐dipolar cycloaddition with diphenyldiazomethane. Model reactions were carried out using simple alkenes, such as methyl...

A new selective synthetic approach to indole derivatives bearing a tetrazole moiety has been developed. Arynes, generated in situ from o-(trimethylsilyl)aryl triflates and KF, reacted smoothly with 2-(2-benzyl-2H-tetrazol-5-yl)-2H-azirines to give 3-(2-benzyl-2H-tetrazol-5-yl)-indole derivatives with high selectivity. Deprotection of the tetrazole...

Background: This systematic review assessed the effectiveness of photodynamic therapy (PDT) in patients with recurrent oral squamous cell carcinoma (OSCC). Methods: Clinical studies on recurrent OSCC treated with PDT alone were included. Combined treatment strategies were excluded. The search was performed on Medline/Pubmed, Cochrane Library, Embas...

MANIO is an efficient p53-activating anticancer agent with remarkable selectivity to the p53 pathway and promising antitumor activity against colorectal cancer (CRC). Herein, a library of novel MANIO derivatives, including hydroxymethyl- and bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles, was synthesized by rational structural modulation. The ant...

Integrating the principles of green chemistry to develop sustainable processes.

There is growing evidence supporting the role of fibroblasts in all stages of atherosclerosis, from the initial phase to fibrous cap and plaque formation. In the arterial wall, as with macrophages and vascular smooth muscle cells, fibroblasts are exposed to a myriad of LDL lipids, including the lipid species formed during the oxidation of their pol...

Several novel organocatalysts derived from β‐ and γ‐lactam‐fused thiazolidines and L‐phenylalanine‐based thiazolidines were efficiently synthetized. These organocatalysts, as well as other previously developed thiazolidine‐derived thioureas, were tested in the asymmetric one‐pot Neber reaction of β‐ketoxime‐1H‐tetrazoles towards chiral 2‐(tetrazol‐...

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-di...

Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, p...

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 PUFA-esters of cholesterol, the effects of cholesteryl hemiesters (ChE), the oxidation end-products of these e...

A comprehensive study on the electronic spectral, photophysical and acid-base properties of phenyl- and methyl-oxime corrole derivatives and of triphenylcorrole (model corrole) has been performed, aiming to shed light on the existing species in the ground and excited states. Solvents and corrole concentration are found to govern the properties of t...

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 be...

Herein, the synthesis and anticancer activity evaluation of a series of novel β-carbolines is reported. The reactivity of nitrosoalkenes towards indole was explored for the synthesis of novel tryptophan analogs where the carboxylic acid was replaced by a triazole moiety. This tryptamine was used in the synthesis of 3-(1,2,3-triazol-4-yl)-β-carbolin...

Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information...

The first examples of the diastereoselective 1,3-dipolar cycloaddition reaction of nitrile oxides and 6-alkylidene penicillanates leading to chiral spiroisoxazoline-penicillanates are reported. The synthesis of this new type of penicillanate involved the selective generation of two consecutive stereogenic centers, including a quaternary chiral cent...

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 t...

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 mod...

Alzheimer´s disease (AD) is an intellectual disorder caused by organic brain damage and cerebral atrophy, characterized by the loss of memory, judgment, and abstract thinking followed by declining cognitive functions, language, and the ability to perform daily living activities. Many efforts have been made to decrease the effects of the disease but...

Flow chemistry is changing the face of synthetic organic chemistry laboratories in both academia and industry. The application of continuous flow processes for multistep reactions is becoming a golden rule for the sustainable synthesis of heterocycles. In this chapter, several recent examples of the application of flow processes for the synthesis o...

Photodynamic therapy (PDT) is a medical procedure useful for several benign conditions (such as wound healing and infections) and cancer. PDT is minimally invasive, presents few side effects, good scaring, and is able to minimal tissue destruction maintaining organ anatomy and function. Endoscopic access to the uterus puts PDT in the spotlight for...

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 car...

Chiral alkylidene-β-lactams and alkylidene-γ-lactams were synthesized and screened for their in vitro activity against four human cancer cell lines (melanoma, esophageal, lung and fibrosarcoma carcinoma). Alkylidene-β-lactams were synthesized via Wittig reaction of diverse phosphorus ylides with benzhydryl 6‐oxopenicillanate, derived from 6-aminope...

The molecular and crystal structures of N-picryl-m-phenolidine (or, 3-(2,4,6-trinitrophenylamino)phenol; TAP) were investigated by quantum chemical electronic structure calculations (including state-of-the-art fully-periodic DFT calculations for the crystal) and single crystal X-ray diffraction. The molecule of the compound has four low-energy conf...

Diels–Alder cycloaddition reaction is one of the most powerful strategies for the construction of six-membered carbocyclic and heterocyclic systems, in most cases with high regio- and stereoselectivity. In this review, an insight into the most relevant advances on sustainable Diels–Alder reactions since 2010 is provided. Various environmentally ben...

The Diels–Alder reaction of ethyl 3-(1-phenyl-1H-tetrazol-5-yl-1,2-diaza-1,3-butadiene-1-carboxylate with 2-acetyl-6-methyl-2,3-dihydro-4H-pyran (methyl vinyl ketone dimer) regioselectively afforded the corresponding 3-(tetrazol-5-yl)-hexahydro-7H-pyrano[2,3-c]pyridazine in quantitative yield. An X-ray crystal structure of this cycloadduct is repor...

Direct pulp capping consists of a procedure in which a material is directly placed over the exposed pulp to maintain dental vitality. Although still widely used in clinical practice, previous in vitro studies found that the biomaterial Life® presented high cytotoxicity, leading to cell death. This study aimed to identify the Life® constituents resp...

A novel derivative of the prominent ROY compound, 5-acetyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile (AcROY), was synthesized in a two-steps procedure by the nucleophilic aromatic substitution reaction between 1-fluoro-2-nitrobenzene and 2-aminothiophene-3-carbonitrile, followed by Friedel–Crafts acylation...

Objective: This review aims to systematically examine the effectiveness of photodynamic therapy for the treatment of patients with recurrent oral squamous cell carcinoma. Introduction: Oral squamous cell carcinoma is a significant public health problem, and is the seventh most common cancer. Its incidence is mainly due to tobacco use, alcohol co...

The DABCO-catalyzed [3 + 3] annulation between 3-nitro-2H-chromenes and benzyl 2,3-butadienoate has been developed as a route to 5H-chromeno[3,4-b]pyridine derivatives. Under optimal reaction conditions, 5H-chromeno[3,4-b]pyridines incorporating two allenoate units were obtained in moderate to good yields (30-76%). The same type of transformation c...

We demonstrate here that selective vibrational excitation of a moiety, remotely attached in relation to the molecular reaction site, might offer a generalized strategy for inducing bond-breaking/bond-forming reactions with exquisite precision. As a proof-of-principle, the electrocyclic ring-expansion of a benzazirine to a ketenimine was induced, in...

In atherosclerotic lesions, vascular smooth muscle cells (VSMCs) represent half of the foam cell population, characterized by an aberrant accumulation of undigested lipids within lysosomes. Loss of lysosome function impacts VSMCs homeostasis and disease progression. Understanding the molecular mechanisms underlying lysosome dysfunction in these cel...

The asymmetric reduction of oximes and hydrazones is an attractive and versatile strategy for the synthesis of chiral amines, which are valuable building blocks in organic synthesis. This review summarizes the relevant developments made in the last decade on the enantioselective and diastereoselective reduction of oximes and hydrazones involving me...

H-tunneling is a ubiquitous phenomenon, relevant to fields from biochemistry to materials science, but harnessing it for mastering the manipulation of chemical structures still remains nearly illusory. Here, we demonstrate how to switch on H-tunneling by conformational control using external radiation. This is outlined with a triplet 2-hydroxypheny...

Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity...

Spirocyclic molecules are widely recognized for their complex three‐dimensional features and structural rigidity. Among this class of molecules, the spiro‐lactams subclass stands out, being extensively explored due to its bioactivity and utility in a variety of scientific fields such as drug design and organic synthesis. Given the recognition of sp...

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 r...

Investigation of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, derived from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, as PDT agents against melanoma and esophagus cancer is disclosed. Diol and diester fluorinated ring-fused chlorins, including derivatives with 2-(2-hydroxyethoxy)ethanamino groups at the phenyl rings, were o...

The chemical behavior of steroidal N-sulfonyl-1-azadienes toward carbonyl compounds, in the presence of pyrrolidine, is described. With aldehydes, these azadienes participate in hetero-Diels-Alder reactions with the in situ generated enamines. The stereoselectivity results from the approach of the dienophiles from the less hindered α-face of the st...

OBJECTIVE A key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins in lysosomes. This event culminates with the loss of cell homeostasis, inflammation and cell death. In this study we propose to identify the chemical etiologica...

The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We...

Spiro-γ-lactams (spiropyrrolinin-2-ones) are a class of spirocyclic compounds that are present in a wide range of synthetic bioactive and naturally occurring molecules. The increasing attention to spirocyclic lactams in drug...

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 e...

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 capabil...

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...

The discovery of Pt-chlorin-type theranostic agents is described. Luminescent Pt(II) 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, with different degrees of hydrophilicity, have been synthesized and their in vitro photocytotoxicity against human melanoma, oesophageal and bladder carcinomas was studied. A di(hydroxymethyl)-substituted ch...

A one-pot diastereoselective synthesis of thiazolidine-ring fused systems derived from enantiomerically pure amino acids, L-cysteine or D-penicillamine, and achiral succindialdehyde is described as an experiment to be carried out by upper-division undergraduate students in a laboratory classroom. Reactions were performed under mild conditions, the...

The synthesis of bilanes and hexapyrroles containing an oxime functionality, prepared by two and three consecutive hetero-Diels-Alder reactions (or conjugated additions) between nitrosoalkenes and dipyrromethanes, is described. Bilanes underwent oxidative macrocyclization to afford a new class of trans-A2B-corroles. Porphyrins could also be obtaine...

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 deri...

Photodynamic therapy (PDT) is a minimally invasive strategy for clinically treating many cancerous conditions and pre-malignant lesions in animals and human beings. The combination of a tumor-selective photosensitizer (PS), molecular oxygen and targeted illumination produces highly cytotoxic reactive oxygen species (ROS) directly within the tumor c...

Aims To extend our previous studies on spirocyclic-β-lactams with anti-HIV and antiplasmodial properties to new spirocyclic-lactams in order to further explore structure-activity relationships. Background We have previously reported the synthesis of chiral spirocyclic-β-lactam derivatives via 1,3-dipolar cycloaddition of 6-diazopenicillanates with...

Regioselectivity in hetero Diels-Alder reactions can be observed in a simple reaction between a nonsymmetrical heterodiene and an unsymmetrical heterodienophile. A 9 h and easy to implement laboratory experiment is described, in which students can observe the regioselectivity of inverse "electron-demand" hetero Diels-Alder reactions of an azoalkene...

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.

The Cover Feature shows the relevance of flow processes in heterocyclic synthesis. Flow chemistry enables the preparation of a wide variety of heterocycle containing molecules with great value for our society, such as active pharmaceutical ingredients, natural products, and fine chemicals. This methodology has a great impact in both small‐scale and...

Flow Chemistry is a revolutionary field in Organic Chemistry. By changing the conventional methods and apparatus applied in the chemical synthesis, flow chemistry emerges as a game changer for organic synthesis laboratories, in both academia and industries. Considered as a sustainable practice, flow processes play an important role in the developme...

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 IC50 values below 50 nM. The in vivo evaluation of the more...