ABSTRACT
A huge unleashed potential lies hidden in the large and diverse pool of encoded and particularly nonencoded chiral alpha-, beta-, and gamma-amino acids available today. Although these have been extensively exploited in peptide science, the community of organic chemistry has only used this source of diversity in a quite focused and targeted manner. The properties and behavior of peptides as functional molecules in biology are well documented and based on the ability of peptides to adapt a range of discrete conformers at a minimal entropic penalty and therefore ideally fitting their endogenous targets. The development of new organic reactions and chemistries that in a general and quantitative way transform peptides into new functional molecules, preferably on solid support, is a source of completely new classes of molecules with important and advantageous functional properties. The peptide diversity and the ability to perform chemistry on solid support add tremendously to the combinatorial scope of such reactions in pharmaceutical and materials screening scenario. In recent years, the need for "click" reactions to shape complex molecular architecture has been realized mainly with a basis in the world of peptides and DNA, and in polymer chemistry where connection of highly functionalized biologically active substances or property bearing fragments are assembled as molecular LEGO using quantitative and orthogonal click chemistries. In this article, three such new reactions originating in the Carlsberg Laboratory over the last decade taking advantage of organic transformations in the peptide framework is presented. Initially, the click reaction between azide and terminal alkynes catalyzed by Cu(1) (CuAAC-reaction) is described. This CuAAC "click" reaction was observed first at Carlsberg Laboratory in reactions of azido acid chlorides with alkynes on solid support. Second, the Electrophilic Aromatic Substitution Cyclization-Intramolecular Click-Cascade (EASCy-ICC) reaction will be presented. This quantitative stereo-selective cascade reaction provides a highly diverse set of interesting novel scaffolds from peptides. Finally, we describe the preparation of solid phase peptide phosphine- and carbene-based green catalysts (organozymes), which upon complex formation with transition metal perform with high turnovers under aqueous conditions. These catalysts thrive from the peptide folding and diversity, while phosphines and carbenes in the backbone provide for bidental complex formation with transition metals in a format providing an excellent entry into combinatorial catalyst chemistry.
Subject(s)
Models, Molecular , Organic Chemicals , Peptides/chemistry , Caspase 8/chemistry , Methane/analogs & derivatives , Methane/chemistry , Molecular Structure , Organic Chemicals/chemistry , Peptides/classificationABSTRACT
A short synthetic strategy for preparation of the conduritols is described. The key step employs a zinc-mediated fragmentation of protected methyl 5-deoxy-5-iodo-d-pentofuranosides followed by an allylation of the intermediate aldehyde in the same pot. The allylation is performed with 3-bromopropenyl benzoate and occurs with good diastereoselectivity. An amino group can be introduced in the product by trapping the intermediate aldehyde as the imine prior to the allylation. The functionalised 1,7-octadienes, thus obtained, are converted into protected conduritols by ring-closing olefin metathesis.
Subject(s)
Cyclohexanols/chemical synthesis , Pentoses/chemistry , Cyclization , Cyclohexanols/chemistry , Molecular StructureABSTRACT
A new protocol for the synthesis of vicinal amino alcohols is described. The method employs a Barbier-type reaction between an imine and 3-benzoyloxyallyl bromide in the presence of zinc metal. The addition products are debenzoylated to afford amino alcohols in good yields and with diastereomeric ratios greater than 85:15 in favor of the anti isomer. A Hammett study has been performed which strongly indicates that the allylation does not follow a radical mechanism, but instead an organometallic reagent is formed which subsequently reacts with the imine. A computational study based on this mechanism reproduces the observed diastereoselectivity with high accuracy, but only when a sufficiently large portion of the substrate is included.
ABSTRACT
Enzymatic modifications of split and mix libraries were followed by "pulling down" onto a 2-dimensional DNA microarray, via PNA tagging; this allowed complete library interrogation of all members of the split and mix library.
Subject(s)
Combinatorial Chemistry Techniques/methods , Oligonucleotide Array Sequence Analysis , Peptide Nucleic Acids , Molecular Structure , Peptide Hydrolases/chemistry , Proto-Oncogene Proteins c-abl/chemistry , Solutions/chemistryABSTRACT
We have synthesized four conformationally restricted bicyclic 2'-spiro nucleosides via 2'-C-allyl nucleosides as key intermediates. The ribo-configured 2'-spironucleosides 9b and 14b were obtained by a convergent strategy starting from 2-ketofuranose 1 whereas the arabino-configured 2'-spironucleosides 21 and 27 were obtained by a linear strategy with a 2'-ketouridine derivative as starting material. The furanose ring of 9b/14b adopts N-type conformations whereas the furanose ring of 21/27 exists as an N<==>S equilibrium. These compounds showed no anti-HIV-1 activity or cytotoxicity. Incorporation of the four 2'-spironucleosides (as monomers X4 and X5) into oligodeoxynucleotides was accomplished using the phosphoramidite approach on an automated DNA synthesizer. Irrespective of monomeric configuration, hybridization studies revealed that these 2'-spironucleotide monomers (X4 and X5) induce decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes. Molecular modelling indicated that steric constraints are a possible reason for the lowered binding affinities of the modified oligodeoxynucleotides towards complementary single-stranded DNA and single-stranded RNA complements.
Subject(s)
Anti-HIV Agents/chemical synthesis , Oligodeoxyribonucleotides/chemistry , Anti-HIV Agents/chemistry , Arabinonucleosides/chemical synthesis , Arabinonucleosides/chemistry , DNA/chemistry , Models, Chemical , Models, Molecular , Molecular Conformation , Oligodeoxyribonucleotides/chemical synthesis , RNA/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistryABSTRACT
Four conformationally restricted bicyclic 2'-spiro nucleosides were synthesised and incorporated into oligonucleotides. These spiro nucleotides induced decreased duplex thermostabilities.
Subject(s)
Arabinonucleosides/chemical synthesis , DNA/chemistry , Oligodeoxyribonucleotides/chemical synthesis , Spiro Compounds , Arabinonucleosides/chemistry , Base Sequence , Molecular Conformation , Nucleic Acid Denaturation , Oligodeoxyribonucleotides/chemistry , RNA/chemistry , ThermodynamicsABSTRACT
Synthesis of the novel alpha-L-ribofuranosyl phosphoramidite derivative was accomplished via the alpha-L-ribofuranosyl thymine nucleoside. Amidite was used in automated syntheses of chimeric oligonucleotides composed of mixtures of the novel alpha-L-RNA nucleotide monomer ((alphaL)T, alpha-L-ribo configured RNA), and DNA, LNA (T(L), locked nucleic acid) or alpha-L-LNA ((alphaL)T(L), alpha-L-ribo configured locked nucleic acid) nucleotide monomers. For alpha-L-RNA/DNA and alpha-L-RNA/alpha-L-LNA chimeras, RNA-selective hybridization was obtained, for alpha-L-RNA/alpha-L-LNA chimera we found increased binding affinity compared to the corresponding DNA:RNA reference duplex. In addition, alpha-L-RNA/alpha-L-LNA chimera displayed significant stabilization towards 3'-exonucleolytic degradation. These results indicate that alpha-L-RNA/alpha-L-LNA chimeras deserve further evaluation as antisense molecules.
