RESUMO
The proximicins A-C are naturally occurring cytotoxic γ-peptides that contain the unique 4-amino-furan-carboxylic acid. In contrast to the structurally related cytotoxic natural DNA binder netropsin and distamycin, both exhibiting as core building block N-methyl-4-amino-pyrrol-carboxylic acid, no DNA binding was observed for the procimicins. X-ray analysis of crystals of a protected 4-amino-furan-2-carboxylic acid dipeptide revealed a stretched conformation. In contrast, for netropsin and distamycin, sickle-shaped crystal conformations were observed. DFT-calculations elegantly confirm these conformational arrangements. The most stable conformers of the proximicins are linear whereas sickle-shaped conformations are less stable, having higher Gibbs energies. For netropsin, distamycin and the netropsin-proximicin-hybrid a sickle shaped conformation appears energetically favored. The reported results are consistent with the observations that the proximicins A-C do not bind to the DNA and have a different mode of action concerning their cytotoxic activity with respect to netropsin and distamycin.
Assuntos
Antibacterianos/química , Peptídeos/química , Teoria Quântica , Cristalografia por Raios X , Modelos Moleculares , Netropsina/análogos & derivados , Netropsina/química , Conformação ProteicaRESUMO
The total synthesis of the natural occurring polyamides proximicin A-C (3-5) has been accomplished. A short and efficient synthesis of a thus far unknown 4-amino-2-furan carboxylic acid was developed. Furthermore, this unique heterocyclic gamma-amino-acid was used for the synthesis of a new class of AT-selective DNA-binding agents derived from the natural products combining structural features of the proximicins with those from the known DNA-binding natural products netropsin (1) and distamycin (2).
Assuntos
DNA/química , Furanos/química , Netropsina/análogos & derivados , Nylons/síntese química , Aminoácidos/síntese química , Aminoácidos/química , DNA/metabolismo , Distamicinas/química , Distamicinas/farmacologia , Estrutura Molecular , Netropsina/síntese química , Netropsina/química , Netropsina/farmacologia , Nylons/químicaRESUMO
The proximicins A-C (1-3) are novel naturally occurring gamma-peptides with a hitherto unknown 2,4-disubstituted furan amino acid as a core structure. They show a moderate cytotoxic activity and induce upregulation of cell cycle regulating proteins (p53 and p21) and lead to cell cycle arrest in G0/G1-phase. Hybrid molecules combining structural motifs of the proximicins and of netropsin (4), a structurally related natural product, seem to have similar effects. Herein we describe the synthesis of a netropsin-proximicin-hybrid library and its evaluation regarding cytotoxicity and minor groove binding activity.
Assuntos
Antineoplásicos/síntese química , DNA/metabolismo , Netropsina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , DNA/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Netropsina/síntese química , Netropsina/toxicidade , Proteína Supressora de Tumor p53/metabolismoAssuntos
Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Netropsina/análogos & derivados , Netropsina/farmacologia , Proteína Supressora de Tumor p53/genética , Regulação para Cima/efeitos dos fármacos , Actinobacteria/química , Furanos , Estrutura Molecular , Netropsina/química , Netropsina/isolamento & purificaçãoRESUMO
The freshwater cyanobacterium Planktothrix rubescens produces the cyclooctapeptide cyclo(Pro-Gly-Leu-Val-Met-Phe-Gly-Val). The chemical structure is new. This homodetic cyclic octapeptide was named planktocyclin ( 1). It consists solely of proteinogenic l-amino acids and is a strong inhibitor of mammalian trypsin and alpha-chymotrypsin and a moderately active inhibitor of human recombinant caspase-8. Mass spectrometric and 2D-NMR spectroscopic data allowed the determination of its structure. Synthetic planktocyclin was identical to the natural product.