<?xml version="1.0" encoding="ISO-8859-1"?><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id>2304-0106</journal-id>
<journal-title><![CDATA[Anales de la Academia de Ciencias de Cuba]]></journal-title>
<abbrev-journal-title><![CDATA[Anales de la ACC]]></abbrev-journal-title>
<issn>2304-0106</issn>
<publisher>
<publisher-name><![CDATA[Academia de Ciencias de Cuba]]></publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id>S2304-01062023000200018</article-id>
<title-group>
<article-title xml:lang="es"><![CDATA[Nuevos inhibidores de aminopeptidasa N, aminopeptidasa A y dipeptidil peptidasa IV con potenciales aplicaciones biomédicas en cáncer]]></article-title>
<article-title xml:lang="en"><![CDATA[New inhibitors of aminopeptidase N, aminopeptidase A and dipeptidyl peptidase IV with potential biomedical applications in cancer]]></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Pascual Alonso]]></surname>
<given-names><![CDATA[Isel]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Arrebola Sánchez]]></surname>
<given-names><![CDATA[Yarini]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Charli]]></surname>
<given-names><![CDATA[Jean Louis]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Sánchez Ramírez]]></surname>
<given-names><![CDATA[Belinda]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Díaz Guevara]]></surname>
<given-names><![CDATA[Lisset]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Valdés Tresanco]]></surname>
<given-names><![CDATA[Mario Ernesto]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Valiente Flores]]></surname>
<given-names><![CDATA[Pedro A.]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Rivera Méndez]]></surname>
<given-names><![CDATA[Laura]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[García Rodríguez]]></surname>
<given-names><![CDATA[Gabriela]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Almeida García]]></surname>
<given-names><![CDATA[Fabiola]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Bergado Baez]]></surname>
<given-names><![CDATA[Gretchen]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Chávez]]></surname>
<given-names><![CDATA[María de los Ángeles]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Chappé Pacheco]]></surname>
<given-names><![CDATA[Mae]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Pedroso Reynaldo]]></surname>
<given-names><![CDATA[Alejandro]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
</contrib-group>
<aff id="Af1">
<institution><![CDATA[,Universidad de La Habana Centro de Estudios de Proteínas Facultad de Biología]]></institution>
<addr-line><![CDATA[ La Habana]]></addr-line>
<country>Cuba</country>
</aff>
<aff id="Af2">
<institution><![CDATA[,Universidad Nacional Autónoma de México Instituto de Biotecnología ]]></institution>
<addr-line><![CDATA[ Distrito Federal]]></addr-line>
<country>Mexico</country>
</aff>
<aff id="Af3">
<institution><![CDATA[,Centro de Inmunología Molecular  ]]></institution>
<addr-line><![CDATA[ La Habana]]></addr-line>
<country>Cuba</country>
</aff>
<aff id="Af4">
<institution><![CDATA[,Instituto Nacional de Oncología y Radiobiología  ]]></institution>
<addr-line><![CDATA[ La Habana]]></addr-line>
<country>Cuba</country>
</aff>
<pub-date pub-type="pub">
<day>00</day>
<month>08</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="epub">
<day>00</day>
<month>08</month>
<year>2023</year>
</pub-date>
<volume>13</volume>
<numero>2</numero>
<copyright-statement/>
<copyright-year/>
<self-uri xlink:href="http://scielo.sld.cu/scielo.php?script=sci_arttext&amp;pid=S2304-01062023000200018&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.sld.cu/scielo.php?script=sci_abstract&amp;pid=S2304-01062023000200018&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.sld.cu/scielo.php?script=sci_pdf&amp;pid=S2304-01062023000200018&amp;lng=en&amp;nrm=iso"></self-uri><abstract abstract-type="short" xml:lang="es"><p><![CDATA[RESUMEN  Introducción:  El cáncer constituye la segunda causa principal de muerte en nuestro país y en el mundo. Dentro de los blancos atractivos para el diseño de nuevos agentes anticancerígenos encontramos las aminopeptidasas. En particular, dentro de la familia M1, la aminopeptidasa neutra (APN, EC 3.4.11.2) y la aminopeptidasa ácida (APA, EC 3.4.11.7) y dentro de la familia S9 de las peptidasas serino, la enzima dipeptidil peptidasa IV (DPP-IV, EC 3.4.14.5) son blancos establecidos para el desarrollo de nuevos anticancerígenos debido a su sobreexpresión en diferentes tipos de cáncer. Teniendo en cuenta la relevancia biomédica de la inhibición de APN, APA y DPP-IV, el presente trabajo tiene como objetivo la identificación de nuevos inhibidores de estas enzimas con potenciales aplicaciones biomédicas.  Métodos:  Para la identificación de nuevos inhibidores de las enzimas en estudio se abordaron 2 estrategias de trabajo: a) identificación y caracterización bioquímica de nuevos inhibidores de APN, APA y DPP-IV de baja masa molecular para lo cual se realizaron cribados virtuales en la base de compuestos de baja masa molecular HitFinder, Maybrigde (ThermoFisher) y, b) caracterización bioquímica de la inhibición de APA, APA y DPP-IV por bestatina y bacitracina como nuevos inhibidores de estas enzimas. Posteriormente, se procedió a la validación cinética de los nuevos inhibidores identificados, se realizaron estudios de relación estructura: función in silico, se evaluó la biodistribución en modelo de rata así como se evaluaron sus efectos citotóxicos sobre líneas tumorales APN+/DPP-IV+.  Resultados:  Se identificaron y validaron cinéticamente 5 nuevos inhibidores duales de APN, APA y DPP-IV con mecanismos de inhibición de tipo no competitivo en la mayoría de los casos. Los estudios in silico de los complejos enzima: inhibidor permitieron la identificación de residuos no conservados dentro de la correspondiente familia y que sientan las bases para el diseño racional de inhibidores de APN, APA y DPP-IV altamente selectivos y con mayores potencialidades biomédicas. Se identificaron por primera vez la presencia de APN y DPP-IV en líneas tumorales de cáncer de alta incidencia y mortalidad en Cuba y el mundo, mediante una metodología establecida en el presente trabajo. Los nuevos inhibidores tienen efectos promisorios sobre estas líneas tumorales APN+/DPP-IV+. Como conclusiones, se informan por primera vez nuevos inhibidores de APN, APA y DPP-IV, con diferentes mecanismos de inhibición, algunos de ellos de tipo no competitivos, que resultan más ventajosos desde el punto de vista terapéutico que inhibidores competitivos, con efectos promisorios sobre líneas tumorales relacionadas con canceres de alta incidencia y mortalidad en Cuba.]]></p></abstract>
<abstract abstract-type="short" xml:lang="en"><p><![CDATA[ABSTRACT  Introduction:  Cancer is the second leading cause of death in our country and in the world. Within the attractive targets for the design of new anticarcinogenic agents we find aminopeptidases. In particular, within the M1 family, the neutral aminopeptidase (APN, EC 3.4.11.2), the acid aminopeptidase (APA, EC 3.4.11.7) and within the S9 family of serine peptidases, the enzyme dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5); the before mentioned are targets established for the development of new anticancer agents due to their over-expression in different types of cancer. Considering the biomedical relevance of the inhibition of APN, APA and DPP-IV, the main goal of this paper is to identify new inhibitors of these enzymes with potential biomedical applications.  Methods:  They were addressed two strategies for the identification of new inhibitors of the enzymes under study: a) identification and biochemical characterization of new low molecular mass inhibitors of APN, APA and DPP-IV, for which virtual screenings were carried out in the base of low molecular mass compounds HitFinder, Maybridge (ThermoFisher), and b) biochemical characterization of the inhibition of APN, APA and DPP-IV by bestatin and bacitracin as new inhibitors of these enzymes. Subsequently, it was carried out the kinetic validation of the new identified inhibitors, they were carried out in silico structure: function relationship studies, it was also evaluated the biodistribution in a rat model as well as their cytotoxic effects on APN+/DPP-IV+ tumor lines.  Results:  They were identified and kinetically validated five new dual inhibitors of APN, APA and DPP-IV with non-competitive inhibition mechanisms in most cases. In silico studies of Enzyme: inhibitor complexes allowed the identification of non-conserved residues within the corresponding family and this lays the foundations for the rational design of highly selective APN, APA and DPP-IV inhibitors with greater biomedical potential. They were identified for the first time, using a methodology established in this work the presence of APN and DPP-IV in cancer tumor lines with high incidence and mortality in Cuba and the world. The new inhibitors have promising effects on these APN+/DPP-IV+ tumor lines. Conclusions: They are reported for the first-time new inhibitors of APN, APA and DPP-IV, with different inhibition mechanisms, some of them non-competitive, which are more advantageous from the therapeutic point of view than competitive inhibitors, with promising effects on tumor lines related to cancers with high incidence and mortality in Cuba.]]></p></abstract>
<kwd-group>
<kwd lng="es"><![CDATA[Aminopeptidasa N]]></kwd>
<kwd lng="es"><![CDATA[Aminopeptidasa A]]></kwd>
<kwd lng="es"><![CDATA[Dipeptidil peptidasa IV]]></kwd>
<kwd lng="es"><![CDATA[inhibidores]]></kwd>
<kwd lng="es"><![CDATA[cáncer]]></kwd>
<kwd lng="en"><![CDATA[aminopeptidase N]]></kwd>
<kwd lng="en"><![CDATA[aminopeptidase A]]></kwd>
<kwd lng="en"><![CDATA[dipeptidyl peptidase IV]]></kwd>
<kwd lng="en"><![CDATA[inhibitors]]></kwd>
<kwd lng="en"><![CDATA[cáncer]]></kwd>
</kwd-group>
</article-meta>
</front><back>
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