The CXCR4/CXCL12 axis plays a role in cancer metastases, stem cell mobilization and chemosensitization. Proof of concept for efficient CXCR4 inhibition has been demonstrated in stem cell mobilization prior to autologous transplantation in hematological malignancies. Nevertheless CXCR4 inhibitors suitable for prolonged use as required for anticancer therapy are not available. To develop new CXCR4 antagonists a rational, ligand-based approach was taken, distinct from the more commonly used development strategy. A three amino acid motif (Ar-Ar-X) in CXCL12, also found in the reverse orientation (X-Ar-Ar) in the vMIP-II inhibitory chemokine formed the core of nineteen cyclic peptides evaluated for inhibition of CXCR4-dependent migration, binding, P-ERK1/2-induction and calcium efflux. Peptides R, S and I were chosen for evaluation in in vivo models of lung metastases (B16-CXCR4 and KTM2 murine osteosarcoma cells) and growth of a renal cells xenograft. Peptides R, S, and T significantly reduced the association of the 12G5-CXCR4 antibody to the receptor and inhibited CXCL12-induced calcium efflux. The four peptides efficiently inhibited CXCL12-dependent migration at concentrations as low as 10 nM and delayed CXCL12-mediated wound healing in PES43 human melanoma cells. Intraperitoneal treatment with peptides R, I or S drastically reduced the number of B16-CXCR4-derived lung metastases in C57/BL mice. KTM2 osteosarcoma lung metastases were also reduced in Balb/C mice following CXCR4 inhibition. All three peptides significantly inhibited subcutaneous growth of SN12C-EGFP renal cancer cells. A novel class of CXCR4 inhibitory peptides was discovered. Three peptides, R, I and S inhibited lung metastases and primary tumor growth and will be evaluated as anticancer agents.
The introduction of modifications into oligonucleotides is important for a large number of applications in the nucleic acids field. However, the method of solid-phase DNA synthesis presents significant challenges for incorporating many useful modifications that are unstable to the conditions for preparing synthetic DNA. Here we report that boranephosphonate diesters undergo facile nucleophilic substitution in a stereospecific manner upon activation by iodine. We have subsequently used this reactivity to post-synthetically introduce modifications including azides and fluorophores into DNA by first synthesizing boranephosphonate-linked 2'-deoxyoligonucleotides and then treating these oligomers with iodine and various nucleophiles. In addition, we show that this reaction is an attractive method for preparing stereodefined phosphorus-modified oligonucleotides. We have also examined the mechanism of this reaction and show that it proceeds via an iodophosphate intermediate. Beyond nucleic acids synthesis, due to the ubiquity of phosphate derivatives in natural compounds and therapeutics, this stereospecific reaction has many potential applications in organophosphorus chemistry.
A synthetic process was developed to modify pectin samples under solvent free conditions, obtaining pectin at increasing concentration of palmitic, oleic, and linoleic acids. The weight loss of the modified powders showed a degradation path very similar to the pure pectin, indicating that the pristine structure was preserved after the chemical modification. A decreasing mass of evaporating water on increasing the fatty acid concentration, in particular for the palmitic acid modification, indicated a reduced water sorption by the modified powders. Differential scanning calorimetry confirmed the thermogravimetric results and in addition indicated the crystallization of the lateral chains in the case of palmitic-acid-modified pectins. This result was confirmed by X-ray diffractograms of the palmitic acid samples, indicating the main crystallization of the form C, although possible orientation phenomena can be inferred. The sorption curves of either the pristine pectin or the modified samples showed a dual sorption behavior. The sorption curves were interpreted by the BET and GAB equations, both giving very similar results. Palmitic acid modification was very effective in reducing all sorption parameters, whereas in the case of oleic and linoleic acids, only at high concentrations was the hydrophobic influence detected.
The synthesis of previously unknown derivatives of boranephosphonate that contain amine substitutions at boron and the incorporation of these derivatives into the backbone of DNA oligonucleotides is described. These derivatives result from iodine-mediated replacement of one BH hydride of a boranephosphonate linkage by pyridine, various substituted pyridines, other aromatic amines, and certain unsaturated amines. Oligonucleotides containing these backbone modifications show enhanced uptake, relative to unmodified DNA, in mammalian cells. The redox behavior of the boranephosphonate and pyridinium boranephosphonate conjugated linkages has also been studied.
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