Synthesis and Characterization of New Organometallic Benzo[b]thiophene Derivatives with Potential Antitumor Properties

The incorporation of organometallic moieties into the structure of known active drugs to improve their therapeutic properties has gained considerable interest in recent years. The benzo- [b]thiophene derivative raloxifene is a selective estrogen receptor modulator (SERM) that has been found to decrease breast cancer risk in postmenopausal women compared to placebo. The current data suggest that, in the postmenopausal setting, raloxifene may have the benefits of the widely used tamoxifen with fewer side effects. As part of a program designed toward the synthesis and biological screening of organometallic benzo[b]thiophene derivatives inspired by the structure of raloxifene, we have prepared a series of 2-benzoyl-3-ferrocenylbenzo[b]thiophenes where the benzoyl sub- stituent contains terminal tertiary alkylamino groups, expected to ensure affinity to the estrogen receptor. The synthetic strategy and full characterization (NMR, MS, X-ray diffraction, cyclic voltammetry) of the new ferrocenylbenzo[b]thiophenes is reported herein. Moreover, the new 2- benzoyl-3-ferrocenylbenzo[b]thiophene derivatives were tested for their cytotoxic properties against several human tumor cell lines. All the test compounds showed considerable cytotoxic activity; among these, [3-ferrocenyl-6-methoxybenzo[b]thiophen-2-yl][4-(piperazin-1-yl)methyl- phenyl]methanone (compound 13) is of note, showing IC50 values in the low-micromolar range and more than 1 order of magnitude lower than those of the reference compound, cisplatin. In addition, chemosensitivity tests on resistant phenotypes indicated that compound 13 elicited no cross-resistance with cisplatin, besides not being a potential multidrug-resistant (MDR) substrate. Moreover, caspase-3 activation analyses revealed that 13 induced a caspase-3-dependent apoptotic cell-death mechanism. Taken together, these data suggest that the new 2-benzoyl-3- ferrocenylbenzo[b]thiophenes, in particular compound 13, have potentially useful antitumor properties

Estudo comparativo do diagnóstico de câncer pulmonar entre tomografia computadorizada e broncoscopia Comparative study between computed tomography and bronchoscopy in the diagnosis of lung cancer

OBJETIVO: Analisar a tomografia computadorizada e a broncoscopia no diagnóstico do câncer pulmonar e verificar a eficácia destas técnicas perante a presença desta doença. Os parâmetros idade, gênero, hábitos tabágicos, tipos histológicos, estadiamento e terapêutica foram, igualmente, analisados. MATERIAIS E MÉTODOS: Foram analisados 70 pacientes do Serviço de Pneumologia do Hospital Distrital da Figueira da Foz, Coimbra, Portugal, que realizaram ambas as técnicas em estudo, tendo-se confirmado ou não a presença de câncer pulmonar. RESULTADOS: Diagnosticaram-se 37 tumores pulmonares, 23 casos no gênero masculino e 14 no feminino. Histologicamente, 40,54% eram adenocarcinomas, seguido do carcinoma escamoso (32,43% dos casos) e do carcinoma de pequenas células (18,92%). O estadiamento mostrou 6,70% no estádio IB, 23,30% no estádio IIIA comparativamente ao IIIB com 36,70%, encontrando-se 33,30% dos doentes no estádio IV. A quimioterapia isolada foi efetuada em 75,7% dos doentes. A sensibilidade da broncoscopia foi de 83,8%, a especificidade, de 81,8%, e a precisão, de 82,8%. A sensibilidade da tomografia computadorizada foi de 81,1%, a especificidade, de 63,6%, e a precisão, de 72,8%. CONCLUSÃO: Os resultados da broncoscopia confirmaram a sua importância no diagnóstico do câncer pulmonar, pela dependência deste no exame anatomopatológico do tecido ou células, obtido por várias técnicas de biópsia. A tomografia computadorizada apresentou boa sensibilidade, de 81,1%, contudo, a sua especificidade, de apenas 63,6%, resulta do número de falso-positivos (36,4%).<br>OBJECTIVE: To analyze the role of computed tomography and bronchoscopy in the diagnosis of lung cancer, evaluating the effectiveness of these techniques in the presence of this disease. Parameters such as age, gender, smoking habits, histological types, staging and treatment were also analyzed. MATERIALS AND METHODS: The sample of the present study included 70 patients assisted at the Department of Pneumology of Hospital Distrital da Figueira da Foz, Coimbra, Portugal, who were submitted to both diagnostic methods, namely, computed tomography and bronchoscopy, to confirm the presence or the absence of lung cancer. RESULTS: Thirty-seven patients (23 men and 14 women) were diagnosed with lung cancer. Histologically 40.54% were adenocarcinoma, followed by squamous carcinoma (32.43% cases) and small-cell lung cancer (18.92%). Staging showed 6.70% stage IB disease, 23.30% stage IIIA and 36.70% stage IIIB, and 33.30% stage IV. Chemotherapy alone was the first treatment of choice for 75.7% of patients. Bronchoscopy sensitivity was 83.8%, specificity 81.8%, and accuracy 82.8%. Computed tomography sensitivity was 81.1%, specificity 63.6%, and accuracy 72.8%. CONCLUSION: Bronchoscopy results corroborated the relevance of the method in the diagnosis of lung cancer, considering its dependence on the anatomopathological study of tissue or cells obtained through different biopsy techniques. Computed tomography presented good sensitivity (81.1%), however the specificity of only 63.6% is related to the rate of false-positive results (36.4%)

Hot of the breath: mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good.

The problem of the selection of accurate primary end-points for treatment studies in idiopathic pulmonary fibrosis (IPF) has recently been aired in a controversial paper from the USA.1 The limitations of current end-points are discussed and the authors conclude that all-cause mortality and all-cause nonelective hospitalisation best meet clinically meaningful end-point criteria. Much of the article is well argued and there is no quarrel with the view that current primary end-points are flawed. We also agree that all-cause mortality would, indeed, be the most clinically meaningful primary end-point and, therefore, the preferred primary end-point, were it not impractical, as discussed below. However, readers of the statement should reflect on the wise maxim that ‘the best may be the enemy of the good’. The purpose of our document is to provide a perspective on all-cause mortality as a primary end-point, endorsed by 52 European clinicians Including the authors (with one abstention), exploring the implications of the statement by Raghu and colleagues. We believe strongly that the adoption of the views of these authors by licensing bodies—with, by implication, a statistically significant mortality benefit a pre-requisite for drug registration—would set back progress in the treatment of IPF by a decade or more. It should be acknowledged at the outset that the statement of Raghu and colleagues does not make explicit recommendations with regard to drug licensing. Indeed, the authors declare that it is not their aim to make such recommendations and their intentions in this regard should not be questioned. However, if the statement has, indeed, been widely ‘misread’, the reasons for this are clear enough. Representatives of the US Food and Drug Administration (FDA) were active participants in a forum in Bethesda, Maryland (July 2011) which gave rise to the document as a proceedings statement.1 It is widely known

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.Peer reviewe