ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemistry , Peptides/chemistry , Quantum Theory , Crystallography, X-Ray , Models, Molecular , Netropsin/analogs & derivatives , Netropsin/chemistry , Protein ConformationABSTRACT
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).
Subject(s)
DNA/chemistry , Furans/chemistry , Netropsin/analogs & derivatives , Nylons/chemical synthesis , Amino Acids/chemical synthesis , Amino Acids/chemistry , DNA/metabolism , Distamycins/chemistry , Distamycins/pharmacology , Molecular Structure , Netropsin/chemical synthesis , Netropsin/chemistry , Netropsin/pharmacology , Nylons/chemistryABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , DNA/metabolism , Netropsin/analogs & derivatives , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA/chemistry , Drug Screening Assays, Antitumor , Humans , Netropsin/chemical synthesis , Netropsin/toxicity , Tumor Suppressor Protein p53/metabolismSubject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase Inhibitor p21/genetics , Netropsin/analogs & derivatives , Netropsin/pharmacology , Tumor Suppressor Protein p53/genetics , Up-Regulation/drug effects , Actinobacteria/chemistry , Furans , Molecular Structure , Netropsin/chemistry , Netropsin/isolation & purificationABSTRACT
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.