RESUMEN
A significant proportion of genetic disease cases arise from truncation of proteins caused by premature termination codons. In eukaryotic cells some aminoglycosides cause readthrough of premature termination codons during protein translation. Inducing readthrough of these codons can potentially be of therapeutic value in the treatment of numerous genetic diseases. A significant drawback to the repeated use of aminoglycosides as treatments is the lack of balance between their readthrough efficacy and toxicity. The synthesis and biological testing of designer aminoglycoside compounds is documented herein. We disclose the implementation of a strategy to reduce cellular toxicity and maintain readthrough activity of a library of compounds by modification of the overall cationic charge of the aminoglycoside scaffold through ring I modifications.
RESUMEN
Natural products that act as highly specific, small-molecule protein-binding agents and as modulators of protein-protein interactions are highly complex and exhibit functional groups with three-dimensional and stereochemical diversity. The complex three-dimensional display of chiral functional groups appears to be crucial for exhibiting specificity in protein binding and in differentiating between closely related proteins. The development of methods that allow a high-throughput access to three-dimensional, skelatally complex, polycyclic compounds having few asymmetric diversity sites is essential and a highly challenging task. In the postgenomic chemical biology age, in which there is a great desire to understand protein-protein interactions and to dissect protein networking-based signaling pathways by small molecules, the need for developing "stereocontrolled, diversity-oriented synthesis" methods to generate natural product-like libraries is of utmost importance.
Asunto(s)
Unión Proteica , Genómica , Modelos Moleculares , Conformación Molecular , Compuestos Orgánicos/síntesis química , Compuestos Orgánicos/química , EstereoisomerismoAsunto(s)
Alcaloides/síntesis química , Técnicas Químicas Combinatorias/métodos , Indoles/síntesis química , Compuestos Policíclicos/síntesis química , Alcaloides/química , Ciclización , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Indoles/química , Estructura Molecular , Compuestos Policíclicos/química , EstereoisomerismoRESUMEN
With the goal of developing a modular approach leading to different indoline alkaloid natural-product-like tricyclic derivatives having an unsaturated lactam (see compounds 13, 14, and 16), an aminoindoline-based bicyclic scaffold 10 was obtained from 9. The selective deprotection of the indoline NTeoc or benzylic NHAlloc in compound 10, followed by N-acryloylation and then subjection to a ring-closing metathesis reaction, successfully led to obtaining two different architectures (13/14 and 16) having an unsaturated lactam functionality. This modular solution-phase methodology was then developed on solid phase. To achieve this objective, the aminoindoline bicyclic scaffold having an additional hydroxyl group could be immobilized onto the solid support using alkylsilyl linker-based polystyrene macrobeads, giving 18. By applying a ring-closing metathesis approach, 20 (tricyclic derivative with seven-membered-ring unsaturated lactam) and 23 (tricyclic derivative with eight-membered-ring unsaturated lactam) were then obtained from 18 in a number of steps.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Indoles/síntesis química , Compuestos Policíclicos/síntesis química , Ciclización , Indoles/química , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Conformación Molecular , Compuestos Policíclicos/química , Sensibilidad y Especificidad , Soluciones/química , EstereoisomerismoRESUMEN
With the goal of developing a library synthesis of tetrahydroquinoline-derived natural-product-like small molecules, a practical synthesis of enantiomerically pure tetrahydroquinoline scaffold was achieved. An asymmetric aminohydroxylation reaction was the key step in this strategy. This scaffold was further immobilized onto the solid support for the library generation. The library was obtained from three diversity sites: (i) acylation of the hydroxyl group (R(1)), (ii) coupling of the Fmoc-protected amino acid to the amino group (R(2)), and (iii) amidation of the N-terminal amine group (R(3)).