Solution-phase synthesis of branched DNA hybrids via H-phosphonate dimers.

A method for the solution-phase synthesis of branched oligonucleotides with tetrahedral or pseudo-octahedral geometry is described that involves the coupling of 3'-H-phosphonates of protected dinucleoside phosphates and organic core molecules. The dimer building blocks are produced by a synthesis that requires no chromatographic purification and that produces the dimer H-phosphonates in up to 44% yield in less than three days of laboratory work. A total of seven different branched hybrids were prepared, including a new hybrid of the sequence (CG)(4)TBA, where TBA stands for tetrakis(p-hydroxybiphenyl)adamantane that assembles into a material from micromolar aqueous solution upon addition of MgCl(2).

Bioconjugation via azide-Staudinger ligation: an overview.

Bioconjugation techniques using organic azides are compared in this critical review. A particular focus is on chemical ligation reactions and their application to chemical biology (179 references).

Antitumor activity of ribonuclease multimers created by site-specific covalent tethering.

Site-specific cross-linking can generate homogeneous multimeric proteins of defined valency. Pancreatic-type ribonucleases are an especially attractive target, as their natural dimers can enter mammalian cells, evade the cytosolic ribonuclease inhibitor (RI), and exert their toxic ribonucleolytic activity. Here, we report on the use of eight distinct thiol-reactive cross-linking reagents to produce dimeric and trimeric conjugates of four pancreatic-type ribonucleases. Both the site of conjugation and, to a lesser extent, the propinquity of the monomers within the conjugate modulate affinity for RI, and hence cytotoxicity. Still, the cytotoxicity of the multimers is confounded in vitro by their increased hydrodynamic radius, which attenuates cytosolic entry. A monomeric RI-evasive variant of bovine pancreatic ribonuclease (RNase A) inhibits the growth of human prostate and lung tumors in mice. An RI-evasive trimeric conjugate inhibits tumor growth at a lower dose and with less frequent administration than does the monomer. This effect is attributable to an enhanced persistence of the trimers in circulation. On a molecular basis, the trimer is ∼300-fold more efficacious and as well tolerated as erlotinib, which is in clinical use for the treatment of lung cancer. These data encourage the development of mammalian ribonucleases for the treatment of human cancers.

Stable organic azides based on rigid tetrahedral methane and adamantane structures as high energetic materials.

A four-folded azidation of tetrakis(4-iodophenyl)methane and -adamantane leads to stable organic azides, but yet energetic materials, measured by differential scanning calorimetry (DSC). The rigid and symmetrical structures can be useful for new polymer and nanomaterial developments in material sciences as well as bioconjugations, after 1,3-dipolar cycloaddition reactions with terminal alkynes to 1,2,3-triazoles.