24 research outputs found
Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3′,4′,5′-Trimethoxyphenyl)-2-Aryl-1H-Imidazole
We acknowledge “Proyecto de Excelencia de la Consejeria de Innovacion y Ciencia de la Junta de Andalucia, Spain ref. P12-CTS-696” for its financial support. We also acknowledge the support of the Life Science Research Net- work Wales grant no. NRNPGSep14008, an initiative funded through the Welsh Government’s Ser Cymru program.A novel series of tubulin polymerization inhibitors, based on the 1-(3′,4′,5′-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3′-chloro-4′-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation.Junta de Andalucía, Spain P12-CTS-696Welsh Government’s NRNPGSep1400
Choline kinase inhibitors EB-3D and EB-3P interferes with lipid homeostasis in HepG2 cells
A full understanding of the molecular mechanism of action of choline kinase α (ChoKα) inhibitors at
the cell level is essential for developing therapeutic and preventive approaches for cancer. The aim
of the present study was to evaluate the effects of the ChoKα inhibitors EB-3D and EB-3P on lipid
metabolism in HepG2 cells. We used [methyl-14C]choline, [1,2-14C]acetic acid and [2-3H]glycerol as
exogenous precursors of the corresponding phospholipids and neutral lipids. [Methyl-14C]choline was
also used to determine choline uptake. Protein levels were determined by Western blot. Ultrastructural
alterations were investigated by transmission electron microscopy. In this work, we demonstrate that
EB-3D and EB-3P interfere with phosphatidylcholine biosynthesis via both CDP-choline pathway and
choline uptake by the cell. Moreover, the synthesis of both diacylglycerols and triacylglycerols was
affected by cell exposure to both inhibitors. These effects were accompanied by a substantial decrease
in cholesterol biosynthesis, as well as alterations in the expression of proteins related to cholesterol
homeostasis. We also found that EB-3D and EB-3P lowered ChoKα protein levels. All these effects could
be explained by the modulation of the AMP-activated protein kinase signalling pathway. We show that
both inhibitors cause mitochondrial alteration and an endoplasmic reticulum stress response. EB-3D
and EB-3P exert effects on ChoKα expression, AMPK activation, apoptosis, endoplasmic reticulum
stress and lipid metabolism. Taken together, results show that EB-3D and EB-3P have potential anticancer
activity through the deregulation of lipid metabolism.This work was aided by the Andalusian Regional Government (P11-CVI-7859). The inhibitors were developed
under the Cei-Biotic Project CEI2013-MP-1 (University of Granada)
Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer
Choline kinase (ChoK) is the first enzyme of the Kennedy pathway leading to the
biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell
membranes. EB-3D is a novel choline kinase 1 (ChoK 1) inhibitor with potent antiproliferative
activity against a panel of several cancer cell lines. ChoK 1 is particularly overexpressed and
hyperactivated in aggressive breast cancer. By NMR analysis, we demonstrated that EB-3D is able to
reduce the synthesis of phosphocholine, and using flow cytometry, immunoblotting, and q-RT-PCR
as well as proliferation and invasion assays, we proved that EB-3D strongly impairs breast cancer cell
proliferation, migration, and invasion. EB-3D induces senescence in breast cancer cell lines through
the activation of the metabolic sensor AMPK and the subsequent dephosphorylation of mTORC1
downstream targets, such as p70S6K, S6 ribosomal protein, and 4E-BP1. Moreover, EB-3D strongly
synergizes with drugs commonly used for breast cancer treatment. The antitumorigenic potential
of EB-3D was evaluated in vivo in the syngeneic orthotopic E0771 mouse model of breast cancer,
where it induces a significant reduction of the tumor mass at low doses. In addition, EB-3D showed
an antimetastatic effect in experimental and spontaneous metastasis models. Altogether, our results
indicate that EB-3D could be a promising new anticancer agent to improve aggressive breast cancer
treatment protocols.This work was supported by funds from Istituto di Ricerca Pediatrica (IRP)-Città della Speranza and
Cassa di Risparmio di Padova e Rovigo—CARIPARO Foundation (project IRP13/05) and by the University of
Granada, (Cei-Biotic project CEI2013-MP-1), and Associazione Italiana per la Ricerca sul Cancro (AIRC) MFAG
18459 grant (R.R.). E.M. was supported by AIRC (21101) and V.S. by FIRC (16616) fellowships
Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
This research was funded by Convocatoria 2019 Proyectos de I + D + i − RTI Tipo B
“Ministerio de Innovación y Ciencia” grant number PID2019-109294RB-I00 and “Convocatoria 2020
Proyectos I + D + i del Programa Operativo FEDER 2020”, grant number B-CTS-216-UGR20. E.P
thanks the European Regional Development Fund (ERDF) project BioDrug (No. 1.1.1.5/19/A/004)
and the Latvian Council of Science (grant No. lzp-2020/2-0013) for financial support.Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the
development of new antitumor agents. In this work, we present a series of 41 compounds designed
based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as
bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that
some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature
substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed
by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head
have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the
growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in
inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound
induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate
that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential.Ministerio de Innovación y Ciencia PID2019-109294RB-I00FEDER 2020 B-CTS-216-UGR20European Regional Development Fund (ERDF) 1.1.1.5/19/A/004Latvian Council of Science lzp-2020/2-00
New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
This research was funded by Convocatoria 2019 Proyectos de I + D + i - RTI Tipo B
“Ministerio de Ciencia e Innovación” grant number PID2019–109294RB-I00, University of Granada,
Cei-BioticProject grant number CEI2013-MP-1, the Instituto de Salud Carlos III Subdirección General
de Redes y Centros de Investigación Cooperativa-Red de Investigación Cooperativa en Enfermedades
Tropicales (RICET: RD16/0027/0014), the Plan Nacional (SAF PID2019-109623RB-I002016-79957-R)
and the Junta de Andalucía (BIO-199).Supplementary Materials: The following are available online at https://www.mdpi.com/article/10.3390/pharmaceutics13111842/s1, Figure S1. Pf CKIC50 Curves Inhibition of Pf CK. Figure S2. IC50Curves. Figure S3. Spectra.In the fight against Malaria, new strategies need to be developed to avoid resistance of
the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy
approach based on the suppression of the starting materials uptake from the host by the parasite
has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds
that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline
uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds
reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory
activity, whereas an effect of the type of cationic heads used could be observed. SARs determined
that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of
the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to
cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good
inhibitory values have been related to the proposed mechanism of action, some of them still show
discrepancies and further studies are needed to determine their specific molecular target.Ministerio de Ciencia e Innovación PID2019–109294RB-I00University of Granada CEI2013-MP-1Plan Nacional (SAF PID2019-109623RB-I002016-79957-R)Junta de Andalucía (BIO-199)Instituto de Salud Carlos III (RICET: RD16/0027/0014
Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors
Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential
Nuevos derivados pirrólicos y pirazólicos: síntesis y evaluación biológica frente a óxido nítrico sintasa
Tesis Univ. Granada. Departamento de Química Farmacéutica y Orgánica. Leída en 200
Study needs of academic and professional guidance, Tutorial Action Plan BIOrienta2
Farmacia es la Licenciatura que ofrece una mejor formación curricular para aquellos profesionales
que quieren desarrollarse en el campo de la Biomedicina. No existe ninguna otra Licenciatura que
aúne conocimientos tan amplios en Ciencias de la Salud, Química, Microbiología, Parasitología,
Biología Molecular y Biotecnología, y que aborde la enseñanza de los aspectos relacionados con el
medicamento y las alteraciones fisio/patológicas a un nivel molecular como es la Licenciatura de
Farmacia. Para valorar el conocimiento de los alumnos de esta Licenciatura en las diversas
salidas profesionales en el área de Biomedicina, hemos realizado un estudio de las necesidades de los
mismos basado en encuestas de opinión. Este trabajo ha puesto de manifiesto la necesidad de crear un
Plan de Orientación Tutorial (PAT) enfocado a orientarlos sobre salidas profesionales en el área de
Biomedicina, de tal manera que se cubran las principales carencias puestas de manifiesto:
Motivación: si comprenden la utilidad de la Licenciatura en su futuro profesional se animarán
más a trabajar.
Orientación: Fundamentalmente en la elección de asignaturas e itinerarios profesionales relacionados
con la Biomedicina.
Información: Mediante charlas y conferencias en las que profesionales del área de la Biomedicina de
entes públicos y privados los orienten sobre las carreras de investigador en ambos ámbitos.
Nuestra experiencia como profesores e investigadores nos indica que aquellos alumnos que durante
sus estudios de Licenciatura se vinculan a un Departamento como alumnos internos o al menos
muestran algún interés por la investigación, no sólo se orientan profesionalmente mejor sino que
aumentan su rendimiento académico significativamente. Este hecho justifica por sí solo la puesta en
marcha del PAT.The Degree of Pharmacy offers the best instruction for those professionals that want to specialise in
the field of Biomedicine. It doesn't exist any other Degree offering to the students so wide knowledge
in Health Sciences, Chemistry, Microbiology, Parasitology, Molecular Biology and Biotechnology that deals with all the aspects related with drugs and physio/phatological alterations at a molecular level.
We have carried out a study of the students’ requirements based on opinion surveys at the Granada
University. This work has shown the necessity to create a PAT focused on the orientation of the
students in their professional development in the area of Biomedicine, in such a way that the following
needs are covered:
Motivation: The understanding of the usefulness of the Degree in their professional future will
encourage them to work more intensively.
Orientation: Mainly in the election of subjects and professional itineraries related with the
Biomedicine.
Information: Professionals of Biomedicine from both public institutions and private companies will
show them the different aspects of the research in both type institutions by means of chats and
conferences.
Our experience as professors and researchers shows that those students that are linked to a Department
during their Degree or that show some interest for the research, significantly increase both their academic and professional performance. This fact justifies the initiation of the PAT