RESUMEN
The oxytocinase subfamily of M1 zinc aminopeptidases comprises emerging drug targets, including the ER-resident aminopeptidases 1 and 2 (ERAP1 and ERAP2) and insulin-regulated aminopeptidase (IRAP); however, reports on clinically relevant inhibitors are limited. Here we report a new synthetic approach of high diastereo- and regioselectivity for functionalization of the α-hydroxy-ß-amino acid scaffold of bestatin. Stereochemistry and mechanism of inhibition were investigated by a high-resolution X-ray crystal structure of ERAP1 in complex with a micromolar inhibitor. By exploring the P1 side-chain functionalities, we achieve significant potency and selectivity, and we report a cell-active, low-nanomolar inhibitor of IRAP with >120-fold selectivity over homologous enzymes. X-ray crystallographic analysis of IRAP in complex with this inhibitor suggest that interactions with the GAMEN loop is an unappreciated key determinant for potency and selectivity. Overall, our results suggest that α-hydroxy-ß-amino acid derivatives may constitute useful chemical tools and drug leads for this group of aminopeptidases.
Asunto(s)
Aminopeptidasas , Insulina , Aminoácidos/farmacología , Aminopeptidasas/química , Cistinil Aminopeptidasa , Leucina/análogos & derivadosRESUMEN
Molecular design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody-drug conjugates are described. Among the new discoveries reported is the identification of new potent analogues within the tubulysin family that carry a C11 alkyl ether substituent, rather than the usual ester structural motif at that position, a fact that endows the former with higher plasma stability than that of the latter. Also described herein are X-ray crystallographic analysis studies of two tubulin-tubulysin complexes formed within the α/ß interface between two tubulin heterodimers and two highly potent tubulysin analogues, one of which exhibited a different binding mode to the one previously reported for tubulysin M. The X-ray crystallographic analysis-derived new insights into the binding modes of these tubulysin analogues explain their potencies and provide inspiration for further design, synthesis, and biological investigations within this class of antitumor agents. A number of these analogues were conjugated as payloads with appropriate linkers at different sites allowing their attachment onto targeting antibodies for cancer therapies. A number of such antibody-drug conjugates were constructed and tested, both in vivo and in vitro, leading to the identification of at least one promising ADC (Herceptin-LD3), warranting further investigations.
Asunto(s)
Inmunoconjugados , Preparaciones Farmacéuticas , Inmunoconjugados/farmacología , Relación Estructura-Actividad , Tubulina (Proteína) , Rayos XRESUMEN
Taking advantage of the C2-symmetry of the antitumor naturally occurring disorazole B1 molecule, a symmetrical total synthesis was devised with a monomeric advanced intermediate as the key building block, whose three-step conversion to the natural product allowed for an expeditious entry to this family of compounds. Application of the developed synthetic strategies and methods provided a series of designed analogues of disorazole B1, whose biological evaluation led to the identification of a number of potent antitumor agents and the first structure-activity relationships (SARs) within this class of compounds. Specifically, the substitutions of the epoxide units and lactone moieties with cyclopropyl and lactam structural motifs, respectively, were found to be tolerable for biological activities and beneficial with regard to chemical stability.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Oxazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Oxazoles/síntesis química , Oxazoles/química , Relación Estructura-ActividadRESUMEN
The oxytocinase subfamily of M1 aminopeptidases consists of three members, ERAP1, ERAP2 and IRAP that play several important biological roles, including key functions in the generation of antigenic peptides that drive human immune responses. They represent emerging targets for pharmacological manipulation of the immune system, albeit lack of selective inhibitors is hampering these efforts. Most of the previously explored small-molecule binders target the active site of the enzymes via strong interactions with the catalytic zinc(II) atom and, while achieving increased potency, they suffer in selectivity. Continuing our earlier efforts on weaker zinc(II) binding groups (ZBG), like the 3,4-diaminobenzoic acid derivatives (DABA), we herein synthesized and biochemically evaluated analogues of nine potentially weak ZBGs, based on differential substitutions of functionalized pyridinone- and pyridinethione-scaffolds, nicotinic-, isonicotinic-, aminobenzoic- and hydrazinobenzoic-acids. Crystallographic analysis of two analogues in complex with a metalloprotease (MMP-12) revealed unexpected binding topologies, consistent with the observed affinities. Our results suggest that the potency of the compounds as inhibitors of ERAP1, ERAP2 and IRAP is primarily driven by the occupation of active-site specificity pockets and their proper orientation within the enzymes.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Proteína Antagonista del Receptor de Interleucina 1/antagonistas & inhibidores , Zinc/química , Aminopeptidasas/metabolismo , Sitios de Unión , Diseño de Fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Menor/metabolismo , Modelos Moleculares , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad , Zinc/metabolismoRESUMEN
The targeted synthesis of metal-organic frameworks (MOFs) with open metal sites, following reticular chemistry rules, provides a straightforward methodology toward the development of advanced porous materials especially for gas storage/separation applications. Using a palladated tetracarboxylate metalloligand as a 4-connected node, we succeeded in synthesizing the first heterobimetallic In(III)/Pd(II)-based MOF with square-octahedron (soc) topology. The new MOF, formulated as [In3O(L)1.5(H2O)2Cl]·n(solv) (1), features the oxo-centered trinuclear clusters, [In3(µ3-O)(-COO)6], acting as trigonal-prismatic 6-connected nodes that linked together with the metalloligand trans-[PdCl2(PDC)2] (L4-) (PDC: pyridine-3,5-dicarboxylate) to form a 3D network. After successful activation of 1 using supercritical CO2, high-resolution microporous analysis revealed the presence of small micropores (5.8 Å) with BET area of 795 m2 g-1 and total pore volume of 0.35 cm3 g-1. The activated solid shows high gravimetric (92.3 cm3 g-1) and volumetric (120.9 cm3 cm-3) CO2 uptake at 273 K and 1 bar as well as high CO2/CH4 (15.4 for a 50:50 molar mixture) and CO2/N2 (131.7 for a 10:90 molar mixture) selectivity, with moderate Qst0 for CO2 (29.8 kJ mol-1). Slight modifications of the synthesis conditions led to the formation of a different MOF with an anionic framework, having a chemical formula [Me2NH2][In(L)]· n(solv) (2). This MOF is constructed from pseudotetrahedral, mononuclear [In(-COO)4] nodes bridged by four L4- linkers, resulting in a 3D network with PtS topology.
RESUMEN
Improved, streamlined total syntheses of natural tubulysins such as V (Tb45) and U (Tb46) and pretubulysin D (PTb-D43), and their application to the synthesis of designed tubulysin analogues (Tb44, PTb-D42, PTb-D47-PTb-D49, and Tb50-Tb120), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g., Tb111: IC50 = 40 pM against MES SA (uterine sarcoma) cell line; IC50 = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC50 = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure-activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inmunoconjugados/química , Inmunoconjugados/farmacología , Neoplasias/tratamiento farmacológico , Oligopéptidos/química , Oligopéptidos/farmacología , Ácidos Pipecólicos/química , Ácidos Pipecólicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Células HEK293 , HumanosRESUMEN
Endoplasmic reticulum aminopeptidase 2 assists with the generation of antigenic peptides for presentation onto Major Histocompatibility Class I molecules in humans. Recent evidence has suggested that the activity of ERAP2 may contribute to the generation of autoimmunity, thus making ERAP2 a possible pharmacological target for the regulation of adaptive immune responses. To better understand the structural elements of inhibitors that govern their binding affinity to the ERAP2 active site, we cocrystallized ERAP2 with a medium activity 3,4-diaminobenzoic acid inhibitor and a poorly active hydroxamic acid derivative. Comparison of these two crystal structures with a previously solved structure of ERAP2 in complex with a potent phosphinic pseudopeptide inhibitor suggests that engaging the substrate N-terminus recognition properties of the active site is crucial for inhibitor binding even in the absence of a potent zinc-binding group. Proper utilization of all five major pharmacophores is necessary, however, to optimize inhibitor potency.
RESUMEN
A streamlined total synthesis of N(14)-desacetoxytubulysin H (Tb1) based on a C-H activation strategy and a short total synthesis of pretubulysin D (PTb-D43) are described. Applications of the developed synthetic strategies and technologies to the synthesis of a series of tubulysin analogues (Tb2-Tb41 and PTb-D42) are also reported. Biological evaluation of the synthesized compounds against an array of cancer cells revealed a number of novel analogues (e.g., Tb14), some with exceptional potencies against certain cell lines [e.g., Tb32 with IC50 = 12 pM against MES SA (uterine sarcoma) cell line and 2 pM against HEK 293T (human embryonic kidney) cell line], and a set of valuable structure-activity relationships. The highly potent cytotoxic compounds discovered in this study are highly desirable as payloads for antibody-drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies.
Asunto(s)
Oligopéptidos/síntesis química , Oligopéptidos/farmacología , Línea Celular Tumoral , Células HEK293 , Humanos , Oligopéptidos/química , Relación Estructura-ActividadRESUMEN
A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Mesilato de Imatinib/análogos & derivados , Mesilato de Imatinib/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/síntesis química , Mesilato de Imatinib/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Relación Estructura-ActividadRESUMEN
Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.
Asunto(s)
Aminobenzoatos/farmacología , Aminopeptidasas/antagonistas & inhibidores , Aminopeptidasas/inmunología , Inhibidores Enzimáticos/farmacología , Aminobenzoatos/síntesis química , Aminobenzoatos/química , Aminopeptidasas/metabolismo , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Abstract Small molecules that inhibit angiogenesis are attractive drug candidates for cancer, retinopathies, and age-related macular degeneration. In vivo, phenotypic screening in zebrafish (Danio rerio) emerges as a powerful methodology to identify and optimize novel compounds with pharmacological activity. Zebrafish provides several advantages for in vivo phenotypic screens especially for angiogenesis, since it develops rapidly, externally, and does not rely on a functional cardiovascular system to survive for several days during development. In this study, we utilize a transgenic line that allows the noninvasive monitoring of angiogenesis at a cellular level. The inhibition of angiogenesis can be observed under a fluorescent stereoscope and quantified. To exemplify the versatility and robustness of the zebrafish screen, we have employed a series of 60 novel compounds that were designed based on a potent VEGFR2 inhibitor. Herein, we report their structure-based design, synthesis, and in vivo zebrafish screening for optimal activity, toxicity, and off-target effects, which revealed six reversible inhibitors of angiogenesis.
Asunto(s)
Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/genética , Ácidos Carboxílicos/química , Tiofenos/química , Secuencia de Aminoácidos , Animales , Cristalografía , Evaluación Preclínica de Medicamentos/métodos , Humanos , Datos de Secuencia Molecular , Imagen Óptica/métodos , Estructura Secundaria de Proteína , Pez CebraRESUMEN
Continuing our efforts towards understanding the principles governing ribosomal recognition and function, we have synthesized and evaluated a series of diversely functionalized 5,6-, 6,6- and 7,6-spiroethers. These compounds successfully mimic natural aminoglycosides regarding their binding to the decoding center of the bacterial ribosome. Their potential to inhibit prokaryotic protein production in vitro along with their antibacterial potencies have also been examined.
Asunto(s)
Antibacterianos/química , Éteres Cíclicos/química , Ribosomas/metabolismo , Compuestos de Espiro/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Éteres Cíclicos/síntesis química , Éteres Cíclicos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , ARN Ribosómico 16S/química , ARN Ribosómico 16S/metabolismo , Ribosomas/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Aminoglycoside-antibiotics represent important tools for studying the biological functions of RNA. An orthogonal protection strategy applied on 2-deoxystreptamine (2-DOS) revealed a series of key intermediates that enable its regioselective functionalization. Our approach allowed the construction of selected representatives of triazole-containing analogues with diverse molecular frameworks for biological evaluation regarding their binding and antibacterial potencies.
Asunto(s)
Antibacterianos/farmacología , Escherichia coli/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Triazoles/química , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Hexosaminas/síntesis química , Hexosaminas/química , Hexosaminas/farmacología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, as well as Insulin regulated aminopeptidase (IRAP) play key roles in antigen processing, and have recently emerged as biologically important targets for manipulation of antigen presentation. Taking advantage of the available structural and substrate-selectivity data for these enzymes, we have rationally designed a new series of inhibitors that display low micromolar activity. The selectivity profile for these three highly homologous aminopeptidases provides a promising avenue for modulating intracellular antigen processing.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Cistinil Aminopeptidasa/antagonistas & inhibidores , Retículo Endoplásmico/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Diseño de Fármacos , Humanos , Modelos MolecularesAsunto(s)
Bacterias/efectos de los fármacos , Éteres Cíclicos/síntesis química , Éteres Cíclicos/farmacología , Ribosomas/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Sitios de Unión , Química Clic , Éteres Cíclicos/química , Modelos Moleculares , Estructura Molecular , Ribosomas/metabolismo , Compuestos de Espiro/químicaRESUMEN
CYP1A1 and CYP1B1 are two extrahepatic enzymes that have been implicated in carcinogenesis and cancer progression. Selective inhibition of CYP1A1 and CYP1B1 by dietary constituents, notably the class of flavonoids, is a widely accepted paradigm that supports the concept of dietary chemoprevention. In parallel, recent studies have documented the ability of CYP1 enzymes to selectively metabolize dietary flavonoids to conversion products that inhibit cancer cell proliferation. In the present study we have examined the inhibition of CYP1A1 and CYP1B1-catalyzed EROD activity by 14 different flavonoids containing methoxy- and hydroxyl-group substitutions as well as the metabolism of the monomethoxylated CYP1-flavonoid inhibitor acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by recombinant CYP1A1 and CYP1B1. The most potent inhibitors of CYP1-EROD activity were the methoxylated flavones acacetin, diosmetin, eupatorin and the di-hydroxylated flavone chrysin, indicating that the 4'-OCH(3) group at the B ring and the 5,7-dihydroxy motif at the A ring play a prominent role in EROD inhibition. Potent inhibition of CYP1B1 EROD activity was also obtained for the poly-hydroxylated flavonols quercetin and myricetin. HPLC metabolism of acacetin by CYP1A1 and CYP1B1 revealed the formation of the structurally similar flavone apigenin by demethylation at the 4'-position of the B ring, whereas the flavone eupatorin-5-methyl ether was metabolized to an as yet unidentified metabolite assigned E(5)M1. Eupatorin-5-methyl ether demonstrated a submicromolar IC(50) in the CYP1-expressing cancer cell line MDA-MB 468, while it was considerably inactive in the normal cell line MCF-10A. Homology modeling in conjunction with molecular docking calculations were employed in an effort to rationalize the activity of these flavonoids based on their CYP1-binding mode. Taken together the data suggest that dietary flavonoids exhibit three distinct modes of action with regard to cancer prevention, based on their hydroxyl and methoxy decoration: (1) inhibitors of CYP1 enzymatic activity, (2) CYP1 substrates and (3) substrates and inhibitors of CYP1 enzymes.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Citocromo P-450 CYP1A1/antagonistas & inhibidores , Inhibidores Enzimáticos/metabolismo , Flavonas/metabolismo , Flavonoides/metabolismo , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Sitios de Unión , Línea Celular , Simulación por Computador , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1 , Inhibidores Enzimáticos/química , Flavonas/química , Flavonoides/química , Humanos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidad por SustratoRESUMEN
ERAP1 (endoplasmic reticulum aminopeptidase 1), ERAP2 and IRAP (insulin-regulated aminopeptidase) are three homologous enzymes that play critical roles in the generation of antigenic peptides. These aminopeptidases excise amino acids from N-terminally extended precursors of antigenic peptides in order to generate the correct length epitopes for binding on to MHC class I molecules. The specificity of these peptidases can affect antigenic peptide selection, but has not yet been investigated in detail. In the present study we utilized a collection of 82 fluorigenic substrates to define a detailed selectivity profile for each of the three enzymes and to probe structural and functional features of the S1 (primary specificity) pocket. Molecular modelling of the three S1 pockets reveals substrate-enzyme interactions that are critical determinants for specificity. The substrate selectivity profiles suggest that IRAP largely combines the S1 specificity of ERAP1 and ERAP2, consistent with its proposed biological function. IRAP, however, does not achieve this dual specificity by simply combining structural features of ERAP1 and ERAP2, but rather by an unique amino acid change at position 541. The results of the present study provide insights on antigenic peptide selection and may prove valuable in designing selective inhibitors or activity markers for this class of enzymes.
Asunto(s)
Aminopeptidasas/química , Aminopeptidasas/inmunología , Péptidos/química , Péptidos/inmunología , Secuencia de Aminoácidos , Aminopeptidasas/genética , Aminopeptidasas/metabolismo , Sitios de Unión , Epítopos/química , Epítopos/metabolismo , Humanos , Proteína Antagonista del Receptor de Interleucina 1/química , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Antígenos de Histocompatibilidad Menor , Modelos Moleculares , Técnicas de Sonda Molecular , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Péptidos/metabolismo , Unión Proteica/genética , Especificidad por SustratoRESUMEN
The potential of aminoglycoside antibiotics to induce premature stop codon read-through in eukaryotic systems has been reported recently, inspiring the evaluation of structural alterations within the Homo sapiens cytoplasmic decoding center on ligand binding. Here we report the employment of an affinity screen capable of monitoring conformational changes of adenines 1492 and 1493 in solution. Thus, changes induced by the presence of a ligand can be directly translated to binding affinities for the eukaryotic decoding center. Binding data for the eukaryotic ribosomal decoding center can be easily obtained by this method and are in excellent agreement with previously reported values measured by alternative techniques. Furthermore, a good correlation is obtained between the experimental binding affinities and the biological activity of the compounds examined. In addition, illustrating the generality of the assay, unnatural rigid aminoglycoside analogues of potential therapeutic significance were evaluated.
Asunto(s)
Aminoglicósidos/química , Antibacterianos/química , ARN Ribosómico 16S/química , Espectrometría de Fluorescencia/métodos , Secuencia de Bases , Humanos , Ligandos , Conformación de Ácido NucleicoRESUMEN
The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.
Asunto(s)
Diseño de Fármacos , ARN Ribosómico/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Alquenos/química , Secuencia de Bases , Glicósidos/química , Hidroxilación , Cetonas/química , Modelos Moleculares , Conformación Molecular , Compuestos Organometálicos/química , ARN Bacteriano/química , ARN Bacteriano/genética , ARN Bacteriano/metabolismo , ARN Ribosómico/química , ARN Ribosómico/genética , Compuestos de Espiro/síntesis química , Electricidad EstáticaRESUMEN
Previous work from our group described the synthesis and biological evaluation of new rigid, 6,6- and 6,7-spiro aminoglycosidic scaffolds targeting the bacterial ribosome. Herein we describe an improved synthetic protocol for their construction, and extend our study by further amino-functionalization of their 6,7-spiro analogs. The synthetic strategy, preparation and evaluation of some representative examples are reported.