Bozepinib: A Promising Selective Derivative Targeting Breast Cancer Stem Cells

Bozepinib is a potent antitumour compound that shows an IC50 of 0.166 μM against MDA-MB-231 human breast cancer cell line. It is also a very selective drug that presents a therapeutic index (TI) of 11.0 against MDA-MB-231 in relation to the normal MCF-10A. It is important to identify new cancer stem-like cells (CSCs) anticancer drugs to struggle against the resistance and the high risk of relapse in patients. In the present chapter, we show how bozepinib demonstrated selectivity on cancer cells and showed an inhibitory effect over kinases involved in carcinogenesis, proliferation and angiogenesis. Bozepinib inhibits HER-2 signaling pathway and JNK and ERK kinases. In addition, it has an inhibitory effect on AKT and VEGF together with anti-angiogenic and anti-migratory activities. Interestingly, bozepinib suppresses the formation of both mammo- and colonospheres and eliminated ALDH+ CSC subpopulations at a low micromolar range similar to salinomycin. It also induces the downregulation of SOX2, c-MYC and β-CATENIN and upregulation of the GLI-3 Hedgehog signaling repressor. Finally, bozepinib shows in vivo antitumor and anti-metastatic efficacy in xenotransplanted nude mice without presenting subacute toxicity. However, further studies in cancer patients are needed to confirm the therapeutic potential of bozepinib

Recent advances in the design of Choline kinase α inhibitors and the molecular basis of their inhibition

Up-regulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become of a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline-binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multi-functional potent drugs for the treatment of various human diseases

An opinion on the regulation of bone marrow adipose tissue by dietary fatty acids

Obesity has a significant impact on predisposition to various diseases and also affects the viabil­ity and choice of haematopoietic stem cells (HSCs) to favour myeloid cell production and/or turnover, all of which are extremely important for the functioning of immune system. As the production of blood cells and mobilization of HSCs and their progeny are regulated, at least in part, by multifaceted interactions through signals that come from the bone marrow (BM) microenvironment, it does not seem astonishing to assume that circumstances that cause alterations in BM structure will unavoidably cause alterations in mesenchymal cells such as adipocytes and lineages from HSCs. The existence of adipose tissue in BM or marrow fat (BMAT) is well known, although its origin, expansion, and functions are poorly understood. Inspired by other studies showing the potential role for olive oil and omega-3 long chain polyunsaturated fatty acids (omega-3 PUFAs) on BM health, and by our own preliminary findings showing the effects of monounsaturated (olive oil) but not saturated (milk cream) dietary fats to contain neutrophils and CD14high monocytes in BM during postprandial periods in healthy volunteers, herein we asked whether dietary fats (saturated fatty acids, SFAs, monounsatu­rated fatty acids, MUFAs, and omega-3 PUFAs) may be a candidate lifestyle factor to modulate the expansion, composition, and function of BMAT, the infiltration of adipose tissue macrophages (ATMs) in BMAT and the mobilization of HSCs and mature myeloid cells from BM during high-fat-induced obesity in mice. This is the first time that the interplay between different dietary fatty acids, obesity, and BM is addressed.Spanish Ministry of Science, Innovation and Universities AGL2016-80852-

The use of a web application – SciFinder to complement the Organic Chemistry teaching to the student of the Degree in Pharmacy

La necesidad de motivación del alumno, además de la adaptación de la actual enseñanza a los créditos ECTS, han sido los motores que nos han llevado a proponer el uso de una aplicación web denominada SciFinder en la enseñanza de la Química Orgánica. Se trata de una herramienta imprescindible en la investigación avanzada que se utiliza en cualquier laboratorio de síntesis química. La Universidad de Granada dispone de una suscripción que permite 6 usos simultáneos a la que el alumno puede acceder a través de un acceso directo a SciFinder on Web en el sólo es necesario registrarse como usuario. Permitir al alumno transportarse a un laboratorio virtual es una de las múltiples posibilidades que ofrece esta aplicación web ayudándoles a complementar los conocimientos científicos básicos que se han explicado en clase. Durante el desarrollo de los distintos temas que componen la asignatura se plantearán reacciones concretas que el alumno deberá ampliar con la información que esta aplicación les proporciona: reactivos empleados en dichas reacciones condiciones de reacción (estequiometría, tiempo, temperatura…) bibliografía actual. Al final del curso académico se evaluará esta nueva experiencia mediante encuestas de opinión del alumnado para determinar dos aspectos fundamentales de la misma, el aumento de interés por la asignatura durante el desarrollo del trabajo y la dificultad en la realización del mismo.The need to motivate the students, besides adapting the teaching to the ECTS credits, have been the driving force that leads us to propose the use of a web application called Sci Finder in the education of Organic Chemistry. It is an essential tool used in any advanced research laboratory of synthetic chemistry. The University of Granada provides a subscription with 6 simultaneous accesses. The students may accede directly to the SciFinder on Web being only necessary the registration as users. One of the many possibilities that offers this web application allows to the student be transported to a virtual laboratory and complement the basic scientific knowledge explained in class. During the development of the different topics, specific reactions will be presented to the student and they may increase the information by using this application: reagents of the reactions reaction conditions (stoichiometry, time, temperature…) up-to-date bibliography At the end of the academic year this new experience will be evaluate through opinion poll to the student in order to determinate two essential aspect, the interest increase for the subject during the development of this work and the difficulty in carrying out it

From Egg Yolk/κ-Carrageenan dispersions to gel systems: linear viscoelasticity and texture analysis

Versión post-printThe effect of pH (3.5 e 6) and polysaccharide concentration (0 e 0.5 wt%) on the linear viscoelastic behaviour of egg yolk/ k -Carrageenan (EY/ k C) mixtures in aqueous solution was studied by using Small Amplitude Oscillatory Shear (SAOS). Native egg yolk containing 45 wt% solids was used for all the samples. Thermally set EY/ k C gels were also studied by SAOS and texture analysis. A variety of linear viscoelastic behaviours depending on k C concentration and pH were exhibited by EY/ k C dispersions that may be explained in terms of the contributions of electrostatic attractive interactions and an exclusion volume effect between protein and polysaccharide macromolecules. This last effect seems to be domi- nant as pH shifts towards the isoelectric point (IEP) of egg yolk proteins, whereas, at pH far from the IEP a certain enhancement in the degree of compatibility, and even some k C autohydrolysis, seems to take place. The results obtained either from rheological or textural characterization of gels were consistent with that balance. In any case, the results obtained suggest that the microstructure of gels is governed by the protein ability to form gels, where hydrophobically driven interactions and subsequent cross linking among protein segments play a dominant role.MEC/FEDER (Project AGL 2007-65709, Spain) and ME (TME 2008-01144

1-(Benzenesulfonyl)-1,5-dihydro-4,1-benzoxazepine as a new scaffold for the design of antitumor compounds

Aim: Bozepinib is a potent and selective anticancer compound which chemical structure is made up of a benzofused seven-membered ring and a purine moiety. We previously demonstrated that the purine fragment does not exert antiproliferative effect per se. Methodology: A series of 1-(benzenesulfonyl)-4,1-benzoxazepine derivatives were synthesized in order to study the influence of the benzofused seven-membered ring in the biological activity of bozepinib by means of antiproliferative, cell cycle and apoptosis studies. Results & conclusion: Our results show that the methyleneoxy enamine sulfonyl function is essential in the antitumor activity of the structures and thus, it is a scaffold suitable for further modification with a view to obtain more potent antitumor compounds

N-Aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: design, synthesis, computational studies, and antitumor effect

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejmech.2023.115570.Funding This research was funded by the Consejería de Universidad, Inves- tigaci´on e Innovaci´on of the Junta de Andalucía and FEDER, Una manera de hacer Europa (P18-RT-1679, PT18-TP-4160, B-FQM-475- UGR18 and PAIDI-TC-PVT-PSETC-2.0.), the Research Results Transfer Office (OTRI) of the University of Granada (PR/17/006), the Spanish Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and PID2021.128109OB.I00) and the Health Institute Carlos III (DTS18/ 00121). C.D. thanks HECBioSim, the UK High End Computing Con- sortium for Biomolecular Simulation (hecbiosim.ac.uk), which is sup- ported by the EPSRC (EP/L000253/1) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund—Athenea3i. J.M.E.-R. thanks the Spanish Ministry of Education for a studentship (FPU 16/ 02061). A.M.-M. gratefully acknowledges funding from the HPC- Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897 (application number HPC17ARM6V). Funding for open access charge: Universidad de Granada / CBUA.Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and FEDER, Una manera de hacer Europa (P18-RT-1679, PT18-TP-4160, B-FQM-475- UGR18 and PAIDI-TC-PVT-PSETC-2.0.)Research Results Transfer Office (OTRI) of the University of Granada (PR/17/006),panish Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and PID2021.128109OB.I0)Health Institute Carlos III (DTS18/ 00121)EPSRC (EP/L000253/1)European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446HPC-Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897Funding for open access charge: Universidad de Granada / CBUA