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Objetivo principal: Evaluar la sintomatología menopáusica, hábitos de vida y condiciones sociodemográficas de una muestra poblacional de mujeres entre 45 y 60 años de Almería (España), y analizar qué variables influyen en la aparición de síntomas climatéricos. Metodología: Se obtuvieron datos de 130 mujeres participantes a través de cuestionarios. La severidad de los síntomas menopáusicos se evaluó con el cuestionario Menopause Rating Scale (MRS). Resultados principales: En promedio, las mujeres postmenopáusicas presentaron mayor edad, Índice de Masa Corporal (IMC) y frecuencia de no tener pareja estable. Se observó una sintomatología total mayor (moderada), así como somático-vegetativa y urogenital en mujeres postmenopáusicas. La adherencia a la dieta mediterránea y el ejercicio físico redujeron la sintomatología somático-vegetativa y psicológica, respectivamente. Conclusión principal: Mantener hábitos de vida saludables como el ejercicio y la dieta mediterránea pueden disminuir la sintomatología menopáusica y mejorar la calidad de vida de mujeres en esta fase.

This research was funded by Agencia Estatal de Investigacion, Ministerio de Ciencia, Innovacion y Universidades (MICIU) from Spain, and was co-funded by FEDER-EU (project nos. PGC2018-102047-B-I00 and CTQ2017-85821-R), Junta de Andalucia (research group FQM-283), and University of Granada (project ref. PPJIA2019-03)., The contributions of the undergraduate student Patricia Quirantes-Gualda and the technical and human support from SGIker (UPV/EHU) are gratefully acknowledged., In the extensive field of metal ions, their interactions with nucleic acids, and their constituents, the main aim of this work is to develop a metal chelate suitable to recognize two molecules of an adenine nucleoside. For this purpose, the dinuclear chelate Cu-2 (mu-EDTA) (ethylenediaminetetraacetate(4-) ion (EDTA)) is chosen as a bicephalic receptor model for N9-(2-hydroxyethyl)adenine (9heade). A one-pot synthesis is reported to obtain the compound [Cu-2(mu(2)-EDTA)(9heade)(2)(H2O)(4)]center dot 3H(2)O, which has been characterized by single-crystal X-ray diffraction and various spectral, thermal, and magnetic methods. The complex unit is a centro-symmetric molecule, where each Cu (II) center is chelated by a half-EDTA, and is further surrounded by an N7-dentate 9heade nucleoside and two non-equivalent trans-O-aqua molecules. The metal chelate-nucleoside molecular recognition is referred to as an efficient cooperation between the Cu-N7(9heade) coordination bond and a (9heade)N6-H center dot center dot center dot O(carboxyl, EDTA) interligand interaction. Theoretical calculations are also made to account for the relevance of this interaction. The extreme weakness with which each water molecule binds to the metal center disturbs the thermal stability and the infrared (FT-IR) and electron spin resonance (ESR) spectra of the compound., Agencia Estatal de Investigacion, Ministerio de Ciencia, Innovacion y Universidades (MICIU) from Spain, European Commission PGC2018-102047-B-I00 CTQ2017-85821-R, Junta de Andalucia, University of Granada PPJIA2019-03

Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in the US with a 5-year survival rate of about 5%. Most patients have advanced metastatic disease mainly due to the lack of an effective early detection, and an extremely poor prognosis. Advancing in the fight against PC requires developing novel observable biomarkers at preclinical stages for early detection. Areas covered: This manuscript is an overview of different PC diagnostic modalities and the latest innovations made to enhance early PC detection through the patents published from 2011 to 2017. It also comments on the ongoing clinical trials and highlights the main challenges to be addressed in the future. Expert opinion: At present, real efforts are being made to identify new specific biomarkers with a potential clinical applicability, and to develop new devices that integrate several biomarkers in order to be more sensitive and specific for the early detection of PC. Although many biomarkers have been patented recently, they will not reach the clinic until they have been validated by clinical trials. We believe that the high-throughput screening of '-omic' technologies to detect tumor-specific molecular alterations can lead to an enhanced understanding of the disease mechanisms and the discovery of new clinical diagnostic biomarkers.

Three mixed-ligands of Cd(II) coordination polymers were unintentionally obtained: {[Cd(&micro, 3-EDTA)(Him)&middot, Cd(Him)(H2O)2]&middot, H2O}n (1), {[Cd(&micro, 4-CDTA)(Hade)&middot, Cd(Hade)2]}n (2), and {[Cd(&micro, 3-EDTA)(H2O)&middot, Cd(H9heade)(H2O)]&middot, 2H2O}n (3), having imidazole (Him), adenine (Hade) or 9-(2-hydroxyethyl)adenine (9heade) as the N-heterocyclic coligands. Compounds 2 and 3 were obtained by working with an excess of corresponding N-heterocyclic coligands. The single-crystal X-ray diffraction structures and thermogravimetric analyses are reported. The chelate moieties in all three compounds exhibit hepta-coordinated Cd centers, whereas the non-chelated Cd center is five-coordinated in 1 and six-coordinated in 2 and 3. Him and Hade take part in the seven-coordinated chelate moieties in 1 and 2, respectively. In contrast, 9heade is unable to replace the aqua ligand of the chelate [Cd (EDTA) (H2O)] moiety in 3. The thermogravimetric analysis (TGA) behavior of [Cd (H2EDTA) (H2O)]&middot, 2H2O in 1 and 3 leads to a residue of CdO, whereas the N-rich compound 2 yields CdO&middot, Cd(NO3)2 as a residue. Density functional theory (DFT) calculations along with molecular electrostatic potential (MEP) and quantum theory of atoms-in-molecules computations were performed in adenine (compound 2) and (2-hydroxyethyl)adenine (compound 3) to analyze how the strength of the H-bonding and &pi, stacking interactions, respectively, are affected by their coordination to the Cd-metal center.

The study of the metal binding pattern of N-methyladenines (1-, 3-, 7- or 9-Meade) towards CuII-iminodiacetate-like chelates is addressed on the basis of XRD crystal structures of sixteen novel ternary compounds. Except for three compounds, all others feature an square-based Cu(II) coordination, type 4 + 1, and the efficient cooperation of a Cu N7 bond with an intra-molecular N6-H⋯O(coord. carboxylate) interligand interaction as the major metal-binding pattern. The three referred exceptions to this behavior are: (1) the compound [Cu(MIDA)(7Meade)(H2O)]·4H2O, which evidence the Cu N3 binding pattern; the (2) [Cu(IDA)(1Meade)(H2O)2]·4H2O, which molecular recognition consist in the Cu N9 bond and a (distal aqua)⋯⋯N3(1Meade) intra-molecular interaction, within an octahedral Cu(II) center; and (3) [Cu(IDA)(9Meade)(H2O)2]·3H2O, also with a 4 + 1 + 1 Cu(II) coordination, where the Cu N7 bond exists along with an extremely weak N6-H⋯O(coord. carboxylate) interaction (3.33 A, 140.2°). This former interaction is determined by packing forces that promote the participation of the N6 H group in a ‘trifurcated’ H-bond. In conclusion, the cooperation between the Cu N7 bond (not possible for 7Meade) and the intra-molecular N6-H⋯O interaction is clearly favored (a) by the H-accepting role of the O-coordinated carboxylate atoms from the iminodiacetate ligands in mer-NO2 conformation and (b) in compounds where the Cu(II) atom exhibits an elongated square-base pyramidal coordination, type 4 + 1.

Eight Cu(II) complexes with N-(p-, m- or o-trifluoromethylbenzyl)iminodiacetate chelators (x-3F ligands) have been synthesized to promote C-F/H interligand interactions involving the F3C-group: {[Cu(μ2-p-3F)(H2O)]·3H2O]}n (1), [Cu(m-3F)(H2O)2] (2), [Cu(p-3F)(Him)(H2O)] (3), [Cu(m-3F)(Him)(H2O)] (4), [Cu(o-3F)(Him)(H2O)] (5), [Cu2(p-3F)2(H5Meim)2(H2O)2] (6), [Cu(m-3F)(H5Meim)(H2O)] (7) and [Cu(o-3F)(H5Meim)(H2O)] (8) [Him and H5Meim = imidazole and the “remote” tautomer 5-methylimidazole, respectively]. The compounds were studied by single crystal X-ray diffraction, FT-IR, electronic spectra and coupled thermogravimetric + FT-IR methods. The conformation of the iminodiacetate chelating moiety (IDA) is fac-NO+O(apical) in 1 and mer-NO2 in 2-8. The fac-IDA conformation observed in 1 is related to its polymeric structure and the coordination of a O’-carboxylate donor, from an adjacent complex unit, trans to the Cu-N(IDA) bond. The mer-IDA conformation in 2 is in agreement with similar compounds with an aqua ligand trans to the corresponding Cu-N(IDA) bond. As expected, the ternary complexes 3-8 feature a mer-IDA conformation. Some of the studied complexes exhibit disorder in the –CF3 group and C-H···F inter-ligand interactions along with conventional N-H···O and O-H···O interactions. The thermal decomposition of all studied compounds under air flow produces variable amounts of trifluorotoluene.

Three (R,S)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purine derivatives (1–3) and three (R,S)-9-(2,3-dihydro-1,4-benzoxathiin-2-ylmethyl)-9H-purine derivatives (4–6) showed relevant activity against human breast cancer cell line MCF-7, when assayed as racemates. The relevant structural analogy among these compounds stimulated us to evaluate and compare their chromatographic behaviour with five polysaccharide-based chiral stationary phases (CSPs). For a column screening purpose, four cellulose-based (Chiralcel OD-H, Chiralpak IB, Lux Cellulose-2, and Sepapak-4; CSPs 1–4, respectively) and an amylose-based (Lux Amylose-2; CSP 5) CSPs were initially assayed by employing the same “standard” eluent mixture. With CSP 2, the performance from “non standard” eluent systems was also evaluated. The different type and position of the substituents onto the carbamate moiety, the coated or immobilized nature of the modified polymer chain, and the different type of winding as well as the eluent composition were found to deeply affect the enantiorecognition mechanism. While the different winding of the polymer and the derived different morphology of the binding cleft in the 2,5-disubstituted chloromethyl phenyl carbamate amylose-based CSP 5 was found to be unsuited to get profitable enantio-discriminations of all the analyzed compounds, CSP 3 and CSP 4 produced the highest α and R S values in the enantioselective analysis of four out of six racemates (that is 1–3 and 6). In CSP 2, the conformational change of the polysaccharide chain upon immobilization produced a profound influence on the chromatographic behaviour of compounds 1–6. A relevant improvement of the enantioresolution quality of CSP 2 was obtained when used in combination with “non standard” solvents as constituents of the mobile phase mixture.

Synthesis and crystal structures of two novel ternary copper(II) complexes with a NO2S-tripodal tetradentate chelator and acyclovir (acv) are reported, providing new insights into the metal binding pattern (MBP) of this synthetic purine nucleoside. N,N-bis(carboxymethyl)-S-benzylcysteaminate(2-) (BCBC) and N,N,N0,N0,-tetrakis(carboxymethyl)cysteaminate(4-) (TCC) chelators supply S-thioether or S-disulfide donor atoms, respectively. In [Cu(BCBC)(acv)]2.5MeOH0.5H2O and [Cu2(TCC)(acv)2]6H2O the copper(II) atom exhibits an asymmetrical elongated octahedral coordination (type 4+1+1⁄, where (⁄) indicates a very weak coordination bond, 3 Å), and acv displays the rather uncommon N7,O6-chelating mode, (early reported by Turel for trans-[Cu(acv)2(H2O)2](NO3)2 (with a Cu–O6(acv) bond distance of 2.7 Å). The weakness of the (acv)O6...Cu interaction is related to the shortness of the Cu-S(thioether or disulfide) apical/distal bonds. A ‘molecular form’ of the binary parent-complex [Cu2(TCC)(H2O)2] (4) is also reported and features a relevant intra-molecular stabilization by two symmetry related (aqua)O–H O(carboxylate) interactions (2.722(1) Å, 169.0º) linking together both halves of the complex molecule. The structure of H2BCBC and its hemi-acetone solvate H2BCBC·0.5C3H6O shows distinct intra-molecular H-bonding stabilizations in their H2BCBC± zwitterions.

The cancer stem cell (CSC) theory is current strategy of cancer treatment. Cancers follow pathways of cancer stem cell such as Notch, Wnt and Hedgehog can be addressed with natural products or synthetic drugs to diminish the chance of new tumours. The cancer growth can also be suppressed by aiming the tumourigenic stem cells alone, instead of targeting at reducing complete tumour dimension. The recurrence of tumours after years of disease-free survival has prompted interest in the concept that cancers may have a stem cell basis. Current assumption holds thatlt; 5% of the tumour mass may be chemo-resistant and radio-resistant, harbouring stem-like properties that impel tumour survival, development, and metastasis. There is intense an investigation to interpret CSCs based on self-renewal and multi-lineage differentiation. Nevertheless, no successful targeted therapies have reached the clinic. The ionophore antibiotic salinomycin that selectively kills breast CSCs seems to be a promising anticancer drug. Clinical trials conducted by the NIH (National Institute of Health) on several synthetic drugs demonstrate the current importance of the issue and predict a bright future for such molecular weapons against cancer.

Five novel ternary copper(II) complexes with the N,O2,S-tripodal tetradentate chelators N,N-bis(carboxymethyl)-S-benzylcysteaminate(2-) ion (BCBC) or N,N,N′,N′-tetrakis(carboxymethyl)cystaminate(4-) ion (TCC) and adenine (Hade), 2,6-diaminopurine (Hdap), 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen) as co-ligand were synthesized and characterized by X-ray diffraction and other physical methods: [Cu2(BCBC)2(μ2-N3,N7-H(N9)ade)(H2O)2]·H2O (1), [Cu2(BCBC)2(μ2-N7,N9-H(N3)dap)(H2O)2]·4H2O (2), [Cu2(μ2-TCC)(H(N9)ade)2(H2O)2]·10H2O (3), [Cu2(μ2-TCC)(bpy)2]·15H2O (4) and [Cu2(μ2-TCC)(phen)2]·14H2O (5). The crystal structure of H4TCC·3H2O was also determined. All ternary Cu(II) complexes have molecular structures. The N-(2-mercaptoethyl)-iminodiacetate moieties of BCBC or TCC ligands play a NO2 + S-tripodal tetradentate role, with the S-(thioether or disulfide) atom as the apical/distal donor of the copper(II) center. In 1–3, the iminodiacetate moiety exhibits a mer-NO2 conformation (two nearly coplanar chelate rings) while in 4 and 5 (with bpy or phen as coligand) it displays a fac-NO + O (apical/distal) conformation. We conclude that the formation of the Cu–S(thioether or disulfide) bonds is strongly favored by the N-branched topology of the S-ligands in the reported compounds.

Two polymorphs of 2,6-dichloropurine, C(5)H(2)Cl(2)N(4), have been crystallized and identified as the 9H- and 7H-tautomers. Despite differences in the space group and number of symmetry-independent molecules, they exhibit similar hydrogen-bonding motifs. Both crystal structures are stabilized by intermolecular N-H···N interactions that link adjacent molecules into linear chains, and by some nonbonding contacts of the C-Cl···π type and by π-π stacking interactions, giving rise to a crossed two-dimensional herringbone packing motif. The main structural difference between the two polymorphs is the different role of the molecules in the π-π stacking interactions.

A novel and efficient synthetic method has been developed for the preparation of alkylated aminopurines (N,N-dimethyl-, 2-chloro-N-methyl-, and N-methyladenines) with achiral and chiral 3,4-dihydro-2H-1,5-benzoxathiepin-3-ol by the Mitsunobu reaction under microwave-assisted conditions. This reaction reveals a complete inversion of the stereogenic centre of the secondary alcohol giving an alkylated purine linked to a homochiral six-membered ring. Fifty novel purine derivatives have been prepared. Alkylation sites have been determined by 2D NMR techniques and for three compounds have been confirmed by X-ray crystallography. The N-9/N-3 regioselectivity can be justified by the electronic effects of the substituents at positions 2 and 6 of the purine.

A novel and efficient synthetic method has been developed for the preparation of alkylated aminopurines (N,N-dimethyl-, 2-chloro-N-methyl-, and N-methyladenines) with achiral and chiral 3,4-dihydro-2H-1,5-benzoxathiepin-3-ol by the Mitsunobu reaction under microwave-assisted conditions. This reaction reveals a complete inversion of the stereogenic centre of the secondary alcohol giving an alkylated purine linked to a homochiral six-membered ring. Fifty novel purine derivatives have been prepared. Alkylation sites have been determined by 2D NMR techniques and for three compounds have been confirmed by X-ray crystallography. The N-9/N-3 regioselectivity can be justified by the electronic effects of the substituents at positions 2 and 6 of the purine., This study was supported by the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria) through the project no. PI10/00592 and by the ERDF (European Regional Development Fund). The M. E. G. R. FPU grant AP2007 02954 from the Ministerio de Ciencia e Innovación of Spain is greatly acknowledged. The project "Factoría de Cristalización" Consolider Ingenio 2010 (CSD2006 00015) provided X ray structural facilities for this work.

The issue of chiral drug is now a major theme in the design, discovery and development of new drugs. It has been shown for many pharmaceuticals that only one enantiomer contains the desired activity, and the synthesis of such drug molecules in their optically pure form is becoming increasingly important. Mitsunobu reaction was carried out between (R)- and (S)-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol and purines under microwave irradiation. A contraction into a six-membered ring takes place with concomitant inversion at the stereocentre with excellent enatiomeric excesses giving rise to the homochiral 9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purines. The anti-tumour activity of all enantiomers is reported against the caspase-3-deficient MCF-7 and the wild type SKBR-3 human breast cancer cells. The most active homochiral compound displays an IC50 of 1.85 μM and induces inhibition of the translation initiation factor eIF2α. All homochiral compounds included in this study show different apoptotic effects between both enantiomers with levels up to 99%. We have analyzed caspase-mediated apoptotic pathways on enantiomers and racemates. We have found a homochiral derivative that activates the canonical intrinsic caspase-8/caspase-3 apoptotic pathway on the MCF-7 cells, and a racemic compound that induces caspase-2 activation. Moreover, we demonstrate the involvement of caspase activation during cell death induced by these compounds in SKBR-3 cells.

The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/ Herceptin™ and cetuximab/Erbitux™ ) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa™ and erlotinib/Tarceva™). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb™), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.