Publications by authors named "Rozas I"

Considering the broad use of the trifluoromethyl functional group (-CF) in medicinal chemistry and taking into account the recent concerns on the negative environmental effects of CF containing compounds, we are searching for "greener" alternatives. Thus, different chemical groups (i. e.

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Tyrosine kinases (TKs) are emerging as important targets in cancer therapy and some of their inhibitors, TKIs ( imatinib and nilotinib), are FDA-approved drugs that are used as selective anti-cancer therapeutics against cell lines that overexpress TKs. Many examples of metal-based complexes functionalised with TKIs are reported in the literature but very few have been functionalised with platinum. Here we report the design, a detailed computational analysis/simulation, the complete chemical characterisation and the preliminary biological evaluation of two novel Pt(IV) anticancer pro-drugs based on cisplatin tethered with a derivative of either imatinib or nilotinib in the axial position.

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Objective: To analyze the risk factors associated with hemorrhagic cystitis (HC) severity and the treatment strategies available in HC patients following allogeneic hematopoietic stem cell transplantation (AHSCT).

Materials And Methods: A retrospective study of medical records was carried out. Patients with HC following AHSCT treated from 2017 to 2021 were divided into two groups according to severity -mild and severe.

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Background: Hepatic veno-occlusive disease or sinusoidal obstruction syndrome is a potentially life-threatening complication of hematopoietic stem cell transplantation.

Objective: To assess the usefulness of point shear-wave elastography (pSWE) for the early diagnosis of sinusoidal obstruction syndrome (SOS) in children.

Materials And Methods: A retrospective study was carried out in 43 patients with suspected SOS assessed between March 2018 and November 2021.

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Considering the importance of the 2019 outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in the coronavirus disease 2019 (COVID-19) pandemic, an overview of two proteases that play an important role in the infection by SARS-CoV-2, the main protease of SARS-CoV-2 (M) and the host transmembrane protease serine 2 (TMPRSS2), is presented in this review. After summarising the viral replication cycle to identify the relevance of these proteases, the therapeutic agents already approved are presented. Then, this review discusses some of the most recently reported inhibitors first for the viral M and next for the host TMPRSS2 explaining the mechanism of action of each protease.

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We present a general efficient green method for the preparation of nitro N,N'-diaryl thioureas via a one-pot method using cyrene as a solvent with almost quantitative yields. This confirmed the viability of cyrene as a green alternative to THF in the synthesis of thiourea derivatives. After screening different reducing conditions, the nitro N,N'-diaryl thioureas were selectively reduced using Zn dust in the presence of water and acid to the corresponding amino N,N'-diaryl thioureas.

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Invited for the cover of this issue is the group of Cristina Trujillo at Trinity College Dublin and the University of Manchester. The image depicts a market run by hydrogen bond acceptors in which hydrogen-bond-donor "customers" are choosing their preferred binding mode "vegetable". Read the full text of the article at 10.

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This computational work studies the different hydrogen bond (HB) binding modes that can be established between neighbouring HB donors and acceptors in structures with relevance in catalysis and biology. To analyse the electronic effect on the σ-hole, unsubstituted HB donors and ones with two different substituents, an electron withdrawing (EWG), and an electron donating (EDG) group, were studied. Upon complexation, three different binding modes were observed: bifurcated, parallel, and zigzag.

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Aiming to improve the binding to Guanine quadruplexes of different topologies, docking studies of porphyrin diphenyl guanidine conjugates previously prepared with an O or a S bridge between the diphenyl moiety and a newly design derivative with an SO bridge were carried out using different guanine quadruplexes of different topologies (four parallel, one antiparallel and one hybrid). Positive results were obtained from these computational studies drove us to prepare the SO bridge conjugate improving the synthetic route previously reported by us. Biophysical experiments such as UV-thermal melting and circular dichroism indicated the lack of binding to the double stranded DNA and poor binding of the new derivative prepared to any of the guanine quadruplexes studied.

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Staphylococcus aureus infections have become a major challenge in health care due to increasing antibiotic resistance. We aimed to design small molecule inhibitors of S. aureus surface proteins to be developed as colonization inhibitors.

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Novel aryl guanidinium analogues containing the pyridazin-3(2)-one core were proposed as minor groove binders (MGBs) with the support of molecular docking studies. The target dicationic or monocationic compounds, which show the guanidium group at different positions of the pyridazinone moiety, were synthesized using the corresponding silyl-protected pyridazinones as key intermediates. Pyridazinone scaffolds were converted into the adequate bromoalkyl derivatives, which by reaction with ,'-di-Boc-protected guanidine followed by acid hydrolysis provided the hydrochloride salts - in good yields.

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Aims: We have recently described a novel guanidinium-based compound, VP79s, which induces cytotoxicity in various cancer cell lines. Here, we aim to investigate the activity of VP79s and associated mechanisms of action in multiple myeloma (MM) cells in vitro and ex vivo.

Main Methods: The effects of VP79s on cell viability and induction of apoptosis was examined in a panel of drug-sensitive and drug-resistant MM cell lines, as well as ex vivo patient samples and normal donor lymphocytes and platelets.

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We previously identified a guanidinium-based lead compound that inhibited BRAF through a hypothetic type-III allosteric mechanism. Considering the pharmacophore identified in this lead compound (i.e.

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Compounds with excellent receptor engagement displaying α-AR antagonist activity are useful not only for therapeutic purposes (e.g. antidepressants), but also to help in the crystallization of this particular GPCR.

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A range of guanidine-based pyridines, and related compounds, have been prepared (19 examples). These compounds were evaluated in relation to their competitive inhibition of bovine pancreatic trypsin. Results demonstrate that compounds in which the guanidinyl substituent can form an intramolecular hydrogen bond (IMHB) with the pyridinyl nitrogen atom (6a-p) are better trypsin inhibitors than their counterparts (10-13) that are unable to form an IMHB.

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The first conceptualised class of dual-binding guanine quadruplex binders has been designed, synthesised and biophysically studied. These compounds combine diaromatic guanidinium systems and neutral tetra-phenylporphyrins (classical binding moiety for guanine quadruplexes) by means of a semi-rigid linker. An extensive screening of a variety of guanine quadruplex structures and double stranded DNA via UV-vis, FRET and CD experiments revealed the preference of the conjugates towards guanine quadruplexes.

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Intramolecular interactions have been proven to be the key to conformational control in drug-design. While chalcogen interactions have been shown to be present in certain ligands of the GK-GKRP target protein, in the present study, intramolecular chalcogen interactions through selenium are found to be even more promising since they form stronger interactions. Also, the flexibility/rigidity of the carbon backbone of the corresponding ligands is crucial in the conformational stability.

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There is a growing interest in the cancer cell growth inhibitory effects of organotin (IV) compounds and, accordingly, a new series of dimethyl-, di-(n-butyl)-, diphenyl- and chloro-phenyl tin(IV) complexes with a Schiff base core were prepared. Their binding to DNA was assessed by UV thermal denaturation showing no interaction and by UV-vis titration exhibiting moderate interaction by intercalation. Complexes having n-butyl substituents were more potent and cytotoxic against human leukemia, breast and cervical cancer cell lines than other organotin(IV) complexes tested.

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A theoretical study has been carried out at the M062X/6-311++G(d,p) computational level to search for a rationale on ligands' affinity toward α-adrenoceptors by estimating the nature and strength of intramolecular hydrogen bonds potentially formed (by means of the QTAIM and NBO approaches) as well as the degree of deviation from planarity that could be observed in some of the compounds. Four different families have been studied: thiophen-2-yl, 3-carboxylatethiophen-2-yl esters, 3-cyanothiophen-2-yl, and 2-thiazolyl guanidinium derivatives. In the case of the thiophen-2-yl guanidines not substituted in the 3 position, nonplanarity was always observed, whereas in the thiazole series, intramolecular hydrogen bonds were identified between the guanidinium and the thiazole ring forcing the systems to planarity.

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The macromolecule that carries genetic information, DNA, is considered as an exceptional target for diseases depending on cellular division of malignant cells ( cancer), microbes ( bacteria) or parasites ( protozoa). To aim for a comprehensive review to cover all aspects related to DNA targeting would be an impossible task and, hence, the objective of the present review is to present, from a medicinal chemistry point of view, recent developments of compounds targeting the minor groove of DNA. Accordingly, we discuss the medicinal chemistry aspects of heterocyclic small-molecules binding the DNA minor groove, as novel anticancer, antibacterial and antiparasitic agents.

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Considering our hypothesis that the guanidinium moiety in the protein kinase type III inhibitor interacts with a phosphate of ATP within the hinge region, the nature of the interactions established between a model isouronium and the phosphate groups of ATP was computationally analysed indicating that an isouronium derivative of will interact in a similar manner with ATP. Thus, a number of compounds were prepared to assess the effect of the guanidinium/isouronium substitution on cancer cell growth; additionally, the molecular shortening and conformational change induced by replacing the di-substituted guanidine-linker of by an amide was explored. The effect of these compounds on cell viability was tested in human leukaemia, breast cancer and cervical cancer cell lines and the resulting IC values were compared with those of the lead compound .

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On the basis of the cyclization reactions reported by Danishefsky et al. of Meldrum's acid hydroxylethyl and anilinoethyl derivatives, the cyclization of the sulfamidomethylene and ureidomethylene derivatives was attempted without success. To understand the lack of reactivity of these compounds versus the successful cyclization of the ethyl derivatives, the corresponding mechanisms of reaction for both processes have been explored by means of MP2/6-311+G(d,p) calculations in an aqueous environment.

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A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule.

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The first DFT study of the cycloaddition of benzaldehyde with homophthalic anhydride under the influence of a bifunctional organocatalyst is reported. The catalyst first binds and then deprotonates the anhydride, leading to a squaramide-bound enolate, which then adds to the aldehyde with activation of the electrophile by the catalyst's ammonium ion.

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Searching for improved antagonists of α-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6-311++G(p,d) computational level] confirming that thiophene and thiazole will be good 'ring equivalents' to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α-adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α-adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues.

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