Self-assembly of phenylalanine derivatives

Since the pioneering work of Reches and Gazit in 2003, in which the formation of diphenylalanine (FF) nanotubes in aqueous solution was discovered, significant efforts have been made to develop a new generation of biomaterials based on the self-assembly of aromatic peptides. From recent investigations, the self-assembly of phenylalanine homopeptides can be understood by a combination of hydrogen bonding and repeated aromatic stacking interactions. In this Thesis, new phenylalanine homo-oligopeptide derivatives have been synthetized in order to test their self-assembly capability and to examine the influence of the chemical structure and the external conditions. Although, the terminal head-to-tail NH3 +···–OOC interactions in the unprotected homopeptides are shown to stabilize the peptide assemblies, chemical modulation has been introduced through the incorporation of the N- and C- protections, such as aromatic blocking groups (Chapter 4 and 5.2), azide-alkyne coupling groups (Chapter 3.2) or trifluoroacetate anion (Chapter 3.1). In Chapter 4, three FFFF-based peptides have been synthetized to study the role of the head-to-tail NH3 +···–OOC interactions in the assembly of FFFF-derivatives. Although these interactions are not possible upon the incorporation of the NFmoc and C-OBzl protections, defined hierarchical assemblies arising from p-p stacking interactions have been found. In Chapter 6, new hybrid polypeptide/polylactide conjugates have been prepared through ring opening polymerizations to reveal the effect of the constitutive polylactide block. Whereas the crystallization from the melt gave rise to spherulites from lamellar arrangements, previously reported phenylalanine-oligopeptide hierarchical morphologies have been observed from diluted solutions. We report that the homopeptide length also plays a significant role in the supramolecular organization of phenylalanine derivatives. First, in Chapter 5.2, theoretical calculations have indicated that the stability of Phe-homopeptides capped with two fluorenyl functionalities increases with the length of the Phe-segment, adopting an antiparallel b-sheet arrangement. While the existence of diverse polymorphs suggests that p-p stacking interactions involving fluorenyl groups result in different stable conformations, they are more versatile, in terms of molecular selfassociation, than hydrogen bonds. Besides, the capacity of FFF to assemble in very diverse supramolecular structures has been found to be greater than that exhibited by its homologues with an even number of Phe residues (Chapter 5.1). Additionally, spherulites from the prepared diblock copolymers with a distinctive lamellar disposition (i.e. flat-on or edge-on) and/or dendritic structures have been identified in function of the length of the PPhe block (Chapter 6). Results have evidenced not only the remarkable control exerted by the characteristics of the environment (i.e. the solvents mixture, temperature, the ionic strength, and the peptide concentration) in the organization of the assemblies, but also by the substrate (Chapter 5.3). Depending on the conditions, molecules can organize into bundled arrays of nanotubes, stacked braids, corkscrew-like, doughnut/volcano-like, spherulitic microstructures and/or triaxial ellipsoid-like nodules. Peptide···peptide interactions, peptide···surface interactions and the surface roughness have been detected as key factors for the shape, dimensions and stability of the hierarchical assemblies. The proposed mechanisms for the formation of supramolecular structures have reflected how the structural nucleation and hierarchical growing are controlled through the balance between peptide···peptide and peptide···solvent interactions, which in turn are regulated by the peptide concentration and the polarity of the solvent mixture used to dissolve the peptide, respectively. Tuning the structure of Phe-derivatives by changing the medium used in the mixture, as well as the surface, is a very attractive feature to expand the potential utility of peptide assemblies in different fields, for example as molecular carriers and delivery systems. The wide range of available surfaces offers a valuable tool for the development of bionanotechnological applications based on hierarchical peptide assemblies. Indeed, the ability of plasma treated polystyrene for stabilizing well-defined dendritic structures has been found to be particularly noticeableEn aquesta tesis, nous homooligopèptids derivats de fenilalanina ha estat sintetitzats per tal d'estudiar la seva capacitat d'autoorganització i examinar la influencia de l'estructura química i les condicions externes. Encara que les interaccions NH3+···-OOC cap-a-cua en els homopèptids desprotegits mostren estabilitzar les estructures peptídiques, s'han introduït funcionalitzacions químiques a través de la incorporació de proteccions a N- i C-, com per exemple, grups bloquejadors aromàtics, grups d'acoblament azida-alquí, l'anió trifluoroacetat o un bloc de polilàctide. Diferents capítols estan dedicats a mostrar que la llargada del bloc d'homopèptid també juga un paper rellevant en l'organització supramolecular dels derivats de fenilalanina. Els resultats publicats evidencien no només el control que exerceixen les característiques de l'ambient sinó també del substrat. Les interaccions pèptid··· pèptid, pèptid···superfície i la rugositat superficial han estat assenyalades com a factors clau que defineixen la forma, les dimensions i l'estabilitat de les estructures jerarquitzades

Self-assembly of phenylalanine derivatives

Versió amb diverses seccions retallades, per drets de l'editorSince the pioneering work of Reches and Gazit in 2003, in which the formation of diphenylalanine (FF) nanotubes in aqueous solution was discovered, significant efforts have been made to develop a new generation of biomaterials based on the self-assembly of aromatic peptides. From recent investigations, the self-assembly of phenylalanine homopeptides can be understood by a combination of hydrogen bonding and repeated aromatic stacking interactions. In this Thesis, new phenylalanine homo-oligopeptide derivatives have been synthetized in order to test their self-assembly capability and to examine the influence of the chemical structure and the external conditions. Although, the terminal head-to-tail NH3 +···–OOC interactions in the unprotected homopeptides are shown to stabilize the peptide assemblies, chemical modulation has been introduced through the incorporation of the N- and C- protections, such as aromatic blocking groups (Chapter 4 and 5.2), azide-alkyne coupling groups (Chapter 3.2) or trifluoroacetate anion (Chapter 3.1). In Chapter 4, three FFFF-based peptides have been synthetized to study the role of the head-to-tail NH3 +···–OOC interactions in the assembly of FFFF-derivatives. Although these interactions are not possible upon the incorporation of the NFmoc and C-OBzl protections, defined hierarchical assemblies arising from p-p stacking interactions have been found. In Chapter 6, new hybrid polypeptide/polylactide conjugates have been prepared through ring opening polymerizations to reveal the effect of the constitutive polylactide block. Whereas the crystallization from the melt gave rise to spherulites from lamellar arrangements, previously reported phenylalanine-oligopeptide hierarchical morphologies have been observed from diluted solutions. We report that the homopeptide length also plays a significant role in the supramolecular organization of phenylalanine derivatives. First, in Chapter 5.2, theoretical calculations have indicated that the stability of Phe-homopeptides capped with two fluorenyl functionalities increases with the length of the Phe-segment, adopting an antiparallel b-sheet arrangement. While the existence of diverse polymorphs suggests that p-p stacking interactions involving fluorenyl groups result in different stable conformations, they are more versatile, in terms of molecular selfassociation, than hydrogen bonds. Besides, the capacity of FFF to assemble in very diverse supramolecular structures has been found to be greater than that exhibited by its homologues with an even number of Phe residues (Chapter 5.1). Additionally, spherulites from the prepared diblock copolymers with a distinctive lamellar disposition (i.e. flat-on or edge-on) and/or dendritic structures have been identified in function of the length of the PPhe block (Chapter 6). Results have evidenced not only the remarkable control exerted by the characteristics of the environment (i.e. the solvents mixture, temperature, the ionic strength, and the peptide concentration) in the organization of the assemblies, but also by the substrate (Chapter 5.3). Depending on the conditions, molecules can organize into bundled arrays of nanotubes, stacked braids, corkscrew-like, doughnut/volcano-like, spherulitic microstructures and/or triaxial ellipsoid-like nodules. Peptide···peptide interactions, peptide···surface interactions and the surface roughness have been detected as key factors for the shape, dimensions and stability of the hierarchical assemblies. The proposed mechanisms for the formation of supramolecular structures have reflected how the structural nucleation and hierarchical growing are controlled through the balance between peptide···peptide and peptide···solvent interactions, which in turn are regulated by the peptide concentration and the polarity of the solvent mixture used to dissolve the peptide, respectively. Tuning the structure of Phe-derivatives by changing the medium used in the mixture, as well as the surface, is a very attractive feature to expand the potential utility of peptide assemblies in different fields, for example as molecular carriers and delivery systems. The wide range of available surfaces offers a valuable tool for the development of bionanotechnological applications based on hierarchical peptide assemblies. Indeed, the ability of plasma treated polystyrene for stabilizing well-defined dendritic structures has been found to be particularly noticeableEn aquesta tesis, nous homooligopèptids derivats de fenilalanina ha estat sintetitzats per tal d'estudiar la seva capacitat d'autoorganització i examinar la influencia de l'estructura química i les condicions externes. Encara que les interaccions NH3+···-OOC cap-a-cua en els homopèptids desprotegits mostren estabilitzar les estructures peptídiques, s'han introduït funcionalitzacions químiques a través de la incorporació de proteccions a N- i C-, com per exemple, grups bloquejadors aromàtics, grups d'acoblament azida-alquí, l'anió trifluoroacetat o un bloc de polilàctide. Diferents capítols estan dedicats a mostrar que la llargada del bloc d'homopèptid també juga un paper rellevant en l'organització supramolecular dels derivats de fenilalanina. Els resultats publicats evidencien no només el control que exerceixen les característiques de l'ambient sinó també del substrat. Les interaccions pèptid··· pèptid, pèptid···superfície i la rugositat superficial han estat assenyalades com a factors clau que defineixen la forma, les dimensions i l'estabilitat de les estructures jerarquitzades.Postprint (published version

Surface mediated hierarchical assemblies of highly hydrophobic phenylalanine-based peptides

This is the pre-peer reviewed version of the following article: E. Mayans, G. Fabregat, R. Juárez, C. Cativiela, J. Puiggalí, C. Alemán, ChemistrySelect 2017, 2, 1133, which has been published in final form at DOI 10.1002/slct.201601436. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."We report the noticeable control exerted by the surface in the self-assembly of a highly hydrophobic triphenylalanine peptide with fluorenyl functionalities blocking the two ends. The remarkable differences observed among the polymorphic hierarchical assemblies obtained onto silanized glass, scratched glass, stainless steel, exfoliated mica, silicon wafer, carbon, polytetrafluoroethylene, plasma-functionalized, polystyrene and nitrocellulose substrates are consequence of the balance between peptide···peptide and peptide···surface interactions. This balance is greatly influenced by the surface characteristics, as defined by the wettability (hydrophobicity or hydrophilicity) and roughness (degree of flatness and regularity). Furthermore, very stable dendritic structures, in which primary frameworks nucleated from the center grow according to a 4-fold pseudo-symmetry branching, have been obtained onto hydrophilic treated polystyrene.Peer ReviewedPostprint (author's final draft

Hierarchical self-assembly of di-, tri- and tetraphenylalanine peptides capped with two fluorenyl functionalities: from polymorphs to dendrites

Homopeptides with 2, 3 and 4 phenylalanine (Phe) residues and capped with fluorenylmethoxycarbonyl and fluorenylmethyl esters at the N-terminus and C-terminus, respectively, have been synthesized to examine their self-assembly capabilities. Depending on the conditions, the di-and triphenylalanine derivatives self-organize into a wide variety of stable polymorphic structures, which have been characterized: stacked braids, doughnut-like shapes, bundled arrays of nanotubes, corkscrew-like shapes and spherulitic microstructures. These highly aromatic Phe-based peptides also form incipient branched dendritic microstructures, even though they are highly unstable, making their manipulation very difficult. Conversely, the tetraphenylalanine derivative spontaneously self-assembles into stable dendritic microarchitectures made of branches growing from nucleated primary frameworks. The fractal dimension of these microstructures is similar to 1.70, which provides evidence for self-similarity and two-dimensional diffusion controlled growth. DFT calculations at the M06L/6-31G(d) level have been carried out on model beta-sheets since this is the most elementary building block of Phe-based peptide polymorphs. The results indicate that the antiparallel beta-sheet is more stable than the parallel one, with the difference between them growing with the number of Phe residues. Thus, the cooperative effects associated with the antiparallel disposition become more favorable when the number of Phe residues increases from 2 to 4, while those of the parallel disposition remained practically constant.Peer ReviewedPostprint (author's final draft

Self-assembly of diphenylalanine with preclick components as capping groups

Alkyne and azide, which are commonly used in the cycloaddition reaction recognized as “click chemistry”, have been used as capping groups of two engineered diphenylalanine (FF) derivatives due to their ability to form weak intermolecular interactions (i.e. dipole–π and π–π stacking). In Poc-FF-N3, alkyne and azide act as N- and C-terminal capping groups, respectively, while such positions are exchanged in N3-FF-OPrp. The self-assembly of such two synthesized peptides has been extensively studied in their “pre-click” state, considering the influence of three different factors: the peptide concentration, the polarity of the medium, and the nature of the substrate. Poc-FF-N3 assembles into microfibers that, depending on the medium and the substrate, can aggregate hierarchically in supramolecular structures with different morphologies. The most distinctive one corresponds to very stable birefringent dendritic-like microstructures, which are derived from the ordered agglomeration of microfibers. These branched supramolecular structures, which are observed under a variety of conditions, are relatively uncommon in short FF sequences. At the molecular level, Poc-FF-N3 organizes in antiparallel β-sheets stabilized by N–H⋯O intermolecular hydrogen bonds and re-enforced by weak interactions between the azide and alkyne groups of neighbouring molecules. In contrast, N3-FF-OPrp exhibits a very poor tendency to organize into structures with a well-defined morphology. Theoretical calculations on model complexes indicate that the tendency of the latter peptide to organize into small amorphous agglomerates is due to its poor ability to form specific intermolecular interactions in comparison with Poc-FF-N3. The implications of the weak interactions induced by the alkyne and azide groups, which strengthen peptide⋯peptide hydrogen bonds and π-ladders due to the stacked aromatic phenyl side groups, are discussed.Peer ReviewedPostprint (author's final draft

Self-assembly of tetraphenylalanine peptides

Three different tetraphenylalanine (FFFF) based peptides that differ at the N- and C-termini have been synthesized by using standard procedures to study their ability to form different nanoassemblies under a variety of conditions. The FFFF peptide assembles into nanotubes that show more structural imperfections at the surface than those formed by the diphenylalanine (FF) peptide under the same conditions. Periodic DFT calculations (M06L functional) were used to propose a model that consists of three FFFF molecules defining a ring through head-to-tail NH3 +¿-OOC interactions, which in turn stack to produce deformed channels with internal diameters between 12 and 16 Å. Depending on the experimental conditions used for the peptide incubation, N-fluorenylmethoxycarbonyl (Fmoc) protected FFFF self-assembles into a variety of polymorphs: ultra-thin nanoplates, fibrils, and star-like submicrometric aggregates. DFT calculations indicate that Fmoc-FFFF prefers a parallel rather than an antiparallel ß-sheet assembly. Finally, coexisting multiple assemblies (up to three) were observed for Fmoc-FFFF-OBzl (OBzl = benzyl ester), which incorporates aromatic protecting groups at the two peptide terminals. This unusual and noticeable feature is attributed to the fact that the assemblies obtained by combining the Fmoc and OBzl groups contained in the peptide are isoenergetic. Variety show! Three different tetraphenylalanine-based peptides that differ at the N- and C-termini have been synthesized by using standard procedures to study their ability to form different nanoassemblies (e.g., nanotubes, see figure) under a variety of conditions.Peer ReviewedPostprint (author's final draft

Self-assembly of phenylalanine derivatives

Since the pioneering work of Reches and Gazit in 2003, in which the formation of diphenylalanine (FF) nanotubes in aqueous solution was discovered, significant efforts have been made to develop a new generation of biomaterials based on the self-assembly of aromatic peptides. From recent investigations, the self-assembly of phenylalanine homopeptides can be understood by a combination of hydrogen bonding and repeated aromatic stacking interactions. In this Thesis, new phenylalanine homo-oligopeptide derivatives have been synthetized in order to test their self-assembly capability and to examine the influence of the chemical structure and the external conditions. Although, the terminal head-to-tail NH3 +···–OOC interactions in the unprotected homopeptides are shown to stabilize the peptide assemblies, chemical modulation has been introduced through the incorporation of the N- and C- protections, such as aromatic blocking groups (Chapter 4 and 5.2), azide-alkyne coupling groups (Chapter 3.2) or trifluoroacetate anion (Chapter 3.1). In Chapter 4, three FFFF-based peptides have been synthetized to study the role of the head-to-tail NH3 +···–OOC interactions in the assembly of FFFF-derivatives. Although these interactions are not possible upon the incorporation of the NFmoc and C-OBzl protections, defined hierarchical assemblies arising from p-p stacking interactions have been found. In Chapter 6, new hybrid polypeptide/polylactide conjugates have been prepared through ring opening polymerizations to reveal the effect of the constitutive polylactide block. Whereas the crystallization from the melt gave rise to spherulites from lamellar arrangements, previously reported phenylalanine-oligopeptide hierarchical morphologies have been observed from diluted solutions. We report that the homopeptide length also plays a significant role in the supramolecular organization of phenylalanine derivatives. First, in Chapter 5.2, theoretical calculations have indicated that the stability of Phe-homopeptides capped with two fluorenyl functionalities increases with the length of the Phe-segment, adopting an antiparallel b-sheet arrangement. While the existence of diverse polymorphs suggests that p-p stacking interactions involving fluorenyl groups result in different stable conformations, they are more versatile, in terms of molecular selfassociation, than hydrogen bonds. Besides, the capacity of FFF to assemble in very diverse supramolecular structures has been found to be greater than that exhibited by its homologues with an even number of Phe residues (Chapter 5.1). Additionally, spherulites from the prepared diblock copolymers with a distinctive lamellar disposition (i.e. flat-on or edge-on) and/or dendritic structures have been identified in function of the length of the PPhe block (Chapter 6). Results have evidenced not only the remarkable control exerted by the characteristics of the environment (i.e. the solvents mixture, temperature, the ionic strength, and the peptide concentration) in the organization of the assemblies, but also by the substrate (Chapter 5.3). Depending on the conditions, molecules can organize into bundled arrays of nanotubes, stacked braids, corkscrew-like, doughnut/volcano-like, spherulitic microstructures and/or triaxial ellipsoid-like nodules. Peptide···peptide interactions, peptide···surface interactions and the surface roughness have been detected as key factors for the shape, dimensions and stability of the hierarchical assemblies. The proposed mechanisms for the formation of supramolecular structures have reflected how the structural nucleation and hierarchical growing are controlled through the balance between peptide···peptide and peptide···solvent interactions, which in turn are regulated by the peptide concentration and the polarity of the solvent mixture used to dissolve the peptide, respectively. Tuning the structure of Phe-derivatives by changing the medium used in the mixture, as well as the surface, is a very attractive feature to expand the potential utility of peptide assemblies in different fields, for example as molecular carriers and delivery systems. The wide range of available surfaces offers a valuable tool for the development of bionanotechnological applications based on hierarchical peptide assemblies. Indeed, the ability of plasma treated polystyrene for stabilizing well-defined dendritic structures has been found to be particularly noticeableEn aquesta tesis, nous homooligopèptids derivats de fenilalanina ha estat sintetitzats per tal d'estudiar la seva capacitat d'autoorganització i examinar la influencia de l'estructura química i les condicions externes. Encara que les interaccions NH3+···-OOC cap-a-cua en els homopèptids desprotegits mostren estabilitzar les estructures peptídiques, s'han introduït funcionalitzacions químiques a través de la incorporació de proteccions a N- i C-, com per exemple, grups bloquejadors aromàtics, grups d'acoblament azida-alquí, l'anió trifluoroacetat o un bloc de polilàctide. Diferents capítols estan dedicats a mostrar que la llargada del bloc d'homopèptid també juga un paper rellevant en l'organització supramolecular dels derivats de fenilalanina. Els resultats publicats evidencien no només el control que exerceixen les característiques de l'ambient sinó també del substrat. Les interaccions pèptid··· pèptid, pèptid···superfície i la rugositat superficial han estat assenyalades com a factors clau que defineixen la forma, les dimensions i l'estabilitat de les estructures jerarquitzades

Self-assembly of phenylalanine derivatives

Versió amb diverses seccions retallades, per drets de l'editorSince the pioneering work of Reches and Gazit in 2003, in which the formation of diphenylalanine (FF) nanotubes in aqueous solution was discovered, significant efforts have been made to develop a new generation of biomaterials based on the self-assembly of aromatic peptides. From recent investigations, the self-assembly of phenylalanine homopeptides can be understood by a combination of hydrogen bonding and repeated aromatic stacking interactions. In this Thesis, new phenylalanine homo-oligopeptide derivatives have been synthetized in order to test their self-assembly capability and to examine the influence of the chemical structure and the external conditions. Although, the terminal head-to-tail NH3 +···–OOC interactions in the unprotected homopeptides are shown to stabilize the peptide assemblies, chemical modulation has been introduced through the incorporation of the N- and C- protections, such as aromatic blocking groups (Chapter 4 and 5.2), azide-alkyne coupling groups (Chapter 3.2) or trifluoroacetate anion (Chapter 3.1). In Chapter 4, three FFFF-based peptides have been synthetized to study the role of the head-to-tail NH3 +···–OOC interactions in the assembly of FFFF-derivatives. Although these interactions are not possible upon the incorporation of the NFmoc and C-OBzl protections, defined hierarchical assemblies arising from p-p stacking interactions have been found. In Chapter 6, new hybrid polypeptide/polylactide conjugates have been prepared through ring opening polymerizations to reveal the effect of the constitutive polylactide block. Whereas the crystallization from the melt gave rise to spherulites from lamellar arrangements, previously reported phenylalanine-oligopeptide hierarchical morphologies have been observed from diluted solutions. We report that the homopeptide length also plays a significant role in the supramolecular organization of phenylalanine derivatives. First, in Chapter 5.2, theoretical calculations have indicated that the stability of Phe-homopeptides capped with two fluorenyl functionalities increases with the length of the Phe-segment, adopting an antiparallel b-sheet arrangement. While the existence of diverse polymorphs suggests that p-p stacking interactions involving fluorenyl groups result in different stable conformations, they are more versatile, in terms of molecular selfassociation, than hydrogen bonds. Besides, the capacity of FFF to assemble in very diverse supramolecular structures has been found to be greater than that exhibited by its homologues with an even number of Phe residues (Chapter 5.1). Additionally, spherulites from the prepared diblock copolymers with a distinctive lamellar disposition (i.e. flat-on or edge-on) and/or dendritic structures have been identified in function of the length of the PPhe block (Chapter 6). Results have evidenced not only the remarkable control exerted by the characteristics of the environment (i.e. the solvents mixture, temperature, the ionic strength, and the peptide concentration) in the organization of the assemblies, but also by the substrate (Chapter 5.3). Depending on the conditions, molecules can organize into bundled arrays of nanotubes, stacked braids, corkscrew-like, doughnut/volcano-like, spherulitic microstructures and/or triaxial ellipsoid-like nodules. Peptide···peptide interactions, peptide···surface interactions and the surface roughness have been detected as key factors for the shape, dimensions and stability of the hierarchical assemblies. The proposed mechanisms for the formation of supramolecular structures have reflected how the structural nucleation and hierarchical growing are controlled through the balance between peptide···peptide and peptide···solvent interactions, which in turn are regulated by the peptide concentration and the polarity of the solvent mixture used to dissolve the peptide, respectively. Tuning the structure of Phe-derivatives by changing the medium used in the mixture, as well as the surface, is a very attractive feature to expand the potential utility of peptide assemblies in different fields, for example as molecular carriers and delivery systems. The wide range of available surfaces offers a valuable tool for the development of bionanotechnological applications based on hierarchical peptide assemblies. Indeed, the ability of plasma treated polystyrene for stabilizing well-defined dendritic structures has been found to be particularly noticeableEn aquesta tesis, nous homooligopèptids derivats de fenilalanina ha estat sintetitzats per tal d'estudiar la seva capacitat d'autoorganització i examinar la influencia de l'estructura química i les condicions externes. Encara que les interaccions NH3+···-OOC cap-a-cua en els homopèptids desprotegits mostren estabilitzar les estructures peptídiques, s'han introduït funcionalitzacions químiques a través de la incorporació de proteccions a N- i C-, com per exemple, grups bloquejadors aromàtics, grups d'acoblament azida-alquí, l'anió trifluoroacetat o un bloc de polilàctide. Diferents capítols estan dedicats a mostrar que la llargada del bloc d'homopèptid també juga un paper rellevant en l'organització supramolecular dels derivats de fenilalanina. Els resultats publicats evidencien no només el control que exerceixen les característiques de l'ambient sinó també del substrat. Les interaccions pèptid··· pèptid, pèptid···superfície i la rugositat superficial han estat assenyalades com a factors clau que defineixen la forma, les dimensions i l'estabilitat de les estructures jerarquitzades