ABSTRACT
The binding of four phenanthridine-guanidine peptides to DNA/RNA was evaluated via spectrophotometric/microcalorimetric methods and computations. The minor structural modifications-the type of the guanidine group (pyrrole guanidine (GCP) and arginine) and the linker length (presence or absence of glycine)-greatly affected the conformation of compounds and consequently the binding to double- (ds-) and single-stranded (ss-) polynucleotides. GCP peptide with shorter linker was able to distinguish between RNA (A-helix) and DNA (B-helix) by different circular dichroism response at 295â¯nm and thus can be used as a chiral probe. Opposed to the dominant stretched conformation of GCP peptide with shorter linker, the more flexible and longer linker of its analogue enabled the molecule to adopt the intramolecularly stacked form which resulted in weaker yet selective binding to DNA. Beside efficient organization of ss-polynucleotide structures, GCP peptide with shorter linker bound stronger to ss-DNA/RNA compared to arginine peptides which emphasize the importance of GCP unit.
Subject(s)
DNA , Glycine , Guanidine , Peptides , Phenanthridines , RNA , Base Pairing , Circular Dichroism , DNA/chemistry , Glycine/chemistry , Guanidine/chemistry , Molecular Conformation , Nucleic Acid Conformation , Peptides/chemistry , Phenanthridines/chemistry , RNA/chemistry , Spectrum Analysis , ThermodynamicsABSTRACT
Three novel spiroketals were prepared by a one-pot transformation of 6-O-methyl-9(E)-hydroxyiminoerythronolide A. We present the formation of a [4.5]spiroketal moiety within the macrolide lactone ring, but also the unexpected formation of a 10-C=11-C double bond and spontaneous change of stereochemistry at position 8-C. As a result, a thermodynamically stable structure was obtained. The structures of two new diastereomeric, unsaturated spiroketals, their configurations and conformations, were determined by means of NMR spectroscopy and molecular modelling. The reaction kinetics and mechanistic aspects of this transformation are discussed. These rearrangements provide a facile synthesis of novel macrolide scaffolds.
ABSTRACT
Series of novel peptide-bridged phenanthridine-nucleobase conjugates were prepared by solid phase peptide synthesis, which allowed easy and fast tuning of structure properties. Compounds were fully characterized in aqueous medium, pointing out to intramolecularly stacked structures. The stacked phenanthridine-thymine-phenanthridine system revealed characteristic excimeric fluorescence band and very specific CD spectrum. Studied compounds interact with double stranded DNA by intercalation, whereby binding is to minor extent influenced by attached thymine and amino-acid sequence of the peptide backbone.
ABSTRACT
Macrolides with 14- and 15-membered ring are characterized by high and extensive tissue distribution, as well as good cellular accumulation and retention. Since macrolide structures do not fit the Lipinski rule of five, macrolide pharmacokinetic properties cannot be successfully predicted by common models based on data for small molecules. Here we describe the development of the first models for macrolide cellular pharmacokinetics. By comparison of cellular accumulation and retention in six human primary cell cultures of leukocytic and lung origin, as well as in lung carcinoma cell line NCI-H292, this cell line was found to be an adequate representative cell type for modeling macrolide cellular pharmacokinetics. Accumulation and retention in the NCI-H292 cells, as well as various physicochemical properties, were determined for a set of 48 rationally designed basic macrolide compounds. Classification models for predicting macrolide cellular accumulation and retention were developed using relatively easily determined and conceptually simple descriptors: experimentally determined physicochemical parameters ChromlogD and CHI IAM, as well as a calculated number of positively charged atoms (POS). The models were further tested and improved by addition of 37 structurally diverse macrolide molecules.
Subject(s)
Macrolides/pharmacokinetics , Models, Biological , Cell Line, Tumor , Chemical Phenomena , Humans , Leukocytes/cytology , Leukocytes/metabolism , Lung/cytology , Lung/metabolism , Lung Neoplasms , Macrolides/chemistry , Primary Cell Culture , Respiratory Mucosa/cytology , Respiratory Mucosa/metabolism , Structure-Activity RelationshipABSTRACT
Series of novel peptide-bridged bis-phenanthridine derivatives as well as corresponding monomers were prepared by solid phase peptide synthesis, which allowed easy and fast tuning of compound properties. Interactions of new derivatives with double stranded DNA were strongly structure-dependent, among which the most interesting is bis-phenanthridine derivative forming intramolecular excimer, with specific fluorescence band sensitive to the pH as well as on the interactions with ds-DNA. Moreover, at variance to commonly high cytotoxic effects of phenanthridine derivatives, here studied monomeric as well as bis-phenanthridine derivatives exhibited negligible antiproliferative activity on a panel of human cell lines, which makes them promising lead compounds for development of new spectrophotometric markers.