Studies Towards the Synthesis of Peptide-Oligonucleotide Conjugates

Abstract

We describe a peptide fragment, solid-phase coupling strategy for synthesis of peptide-oligonucleotide conjugates. Model conjugates contained a hydrophobic tetrapeptide, a hydrophobic influenza virus fusion nonapeptide, or a basic octapeptide of the HIV-1 Tat protein coupled to either dT₁₂ or a 16-mer anti-Tat oligodeoxyribonucleotide. Conjugation yields were improved by removal of internucleotide 2-cyanoethyl groups prior to peptide coupling and by use of a C12 spacer between peptide and oligonucleotide.     

Synthesis of Nucleopeptide-Oligonucleotide Conjugates

Abstract

Two nucleopeptides (NPs) were synthesized on the base of δ-ornithine peptides by modification of the α-amino ornithine functions with pyrimidyl-1- and purinyl-9-acetic acids or with pyrimidyl-1- and purinyl-9-alanines. NPs were prepared on solid polymer bearing photolinker. Conjugates with the 16-mer oligonucleotide complementary to the env AUG codon region of the Friend murine leukemia virus were prepared.     

Synthesis of Paclitaxel-BGL Conjugates

Four kinds of symmetrically branched oligoglyceryl trimeric (BGL003)-paclitaxel conjugates and a corresponding heptameric (BGL007) conjugate were synthesized. Molecular weights of all the compounds were less than two times that of paclitaxel. The anti-tumor activity of the most water-soluble BGL003 conjugate was examined and found to be preserved in spite of the chemical modification that is displacement of the N3'-debenzoyl residue with the BGL003 succinyl residue.     

Synthesis of Circular Oligonucleotide Conjugates

Abstract

A new approach to the non-template synthesis of circular oligodeoxyribonucleotides containing flexible non-nucleotidic linkers has been developed. Using this technique a set of circular molecules representing triple helix forming, antisense and guanosine tetrad containing oligonucleotides has been obtained.     

肽缀合反义寡核苷酸的合成和性能

反义寡核苷酸可作为基因表达的抑制剂和潜在的治疗药物,但多种类型的寡核苷酸为聚阴离子化合物,难以跨过细胞膜.已知包括融合肽、信号肽在内的多种生物活性多肽具有跨膜与核定位能力.讨论了反义寡核苷酸-肽缀合物的合成和生物活性.     

薯蓣皂甙元ELISA定量分析方法的建立Ⅰ-薯蓣皂甙元全抗原的合成

建立薯蓣皂甙元的ELISA定量分析方法必须先合成薯蓣皂甙元的全抗原。试验利用薯蓣皂甙元3位上的-OH,在DMAP的催化下,薯蓣皂甙元与丁二酸酐反应,生成薯蓣皂甙元丁二酸单酯,用MSI、R1、H NMR1、3CNMR等方法对产物结构进行了表征。用混合酸酐法制备薯蓣皂甙元与牛血清白蛋白的结合物(DG-HS-BSA),碳二亚胺法制备薯蓣皂甙元与卵清蛋白的结合物(DG-HS-OVA),经TNBS测定,每分子结合物连接的薯蓣皂甙元分子数分别为28.0和8.8。     

Synthesis of Oligonucleotide Conjugates with the Aid of N-Chloroacetamidohexyl Phosphoramidite Reagent

Abstract

A novel phosphoramidite building block derived from N-chloroacetyl-6-aminohexanol is attached at the 5′-terminus on the last step of oligonucleotide synthesis. Postsynthetic treatment of support-bound modified oligonucleotides with a variety of amines and mercaptanes affords oligonucleotide conjugates in a high yield.     

Design and Synthesis of Heterocyclic Carboxamides as Natural Nucleic Acid Base Mimics

Abstract

A series of heterocyclic carboxamides have been designed as mimics for the natural nucleic acid bases. The nucleosides 1-(2′-deoxy-β-d-ribofuranosyl)imidazole-4-carboxamide (1), 1-(2′ -deoxy-β-d-ribofuranosyl)pyrazole-3-carboxamide (2), and 1-(2′ -deoxy-β-d-ribofuranosyl)pyrrole-3-carboxamide (3) were synthesized and their structures confirmed by spectroscopic and analytical means.

     

Synthesis of N-Peptide-6-Amino-d-Luciferin Conjugates with Optimized Fragment Condensation Strategy

International Journal of Peptide Research and Therapeutics - The synthesis of peptide-luciferin conjugates has a pivotal role in the development of bioluminescent detection systems that are based...     

Conjugates of 2',3'-didehydro-3'-deoxythymidine with thymogen. Synthesis and anti-HIV activity

An effective synthesis of thymogen was developed. Conjugates of 2',3'-didehydro-3'-deoxythymidine (nucleoside d4T) with thymogen were prepared in which the nucleoside hydroxyl group was linked to the thymogen carboxyl group of either tryprophan or glutamic acid residues. It was shown that the anti-HIV activity of the d4T-thymogene conjugate with the tryptophan linkage was comparable to that of d4T, whereas its cytotoxicity was nil. The d4T-tryptophan conjugate also displayed high anti-HIV activity.     

Conjugates of catecholamines. VII. Synthesis and beta-adrenergic activity of peptide catecholamine conjugates

A series of novel catecholamine derivatives has been prepared in which one of the N-methyl substituents of isoproterenol has been extended by a spacer consisting of a chain of four methylenes which terminates with an amide linkage to a peptide, the point of attachment being via the aromatic amino group of p-aminophenylalanine. In one of the derivatives, two catecholamines are attached to the same peptide in this manner. The peptides, which range in size from three to eight amino acid residues and contain phenylalanine, glycine, and L-alpha-amino-delta-hydroxyvaleric acid, were synthesized via stepwise and fragment condensation techniques. The beta-adrenergic agonist activities of the derivatives were evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells.     

Tri-N-Boc-Tetraazamacrocycle-Nucleoside Conjugates: Synthesis and anti-HIV activities

Abstract

As far as linear N-Boc-polyamines conjugates elicited remarkable anti-HIV activity, the synthesis and anti-HIV properties of cyclic N-Boc-polyamines conjugates such as tetraazamacrocycle-nucleoside were studied. These new conjugates include an ester linkage between the two moieties. They were synthesized using Benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate coupling reagent, in the case of N-alkyl polyazamacrocycle derivatives, or through direct condensation of the acyl chloride derivative with nucleoside in the case of N-acyl polyazamacrocycle compounds. None of the new conjugates presented anti-HIV activity greater than that of the corresponding parent nucleosides.     

Synthesis and Analytical Characterization of RNA-Polyethylene Glycol Conjugates

Abstract

Polyethylene glycols with degrees of polymerization from 5 to more than 100 were incorporated into synthetic oligoribonucleotides by automated solid phase synthesis at 3′-terminal, 5′-terminal and internal positions. The conjugates were characterized by chromatographic, electrophoretic and mass-spectrometric methods. The influence of coupling site, polymer size and number of coupled polymers per oligonucleotide on the molecular properties of the conjugates is investigated.     

Synthesis and Hybridization Characteristics of Oligodeoxynucleotide-Alkaline Phosphatase Conjugates

Abstract

Modified oligodeoxynucleotides, 20 to 30 bases in length and containing “linker arm” bases, are chemically synthesized, then attached covalently to alkaline phosphatase in a 1:1 conjugate through a 19 atom spacer. Such conjugates hybridize rapidly and selectively to complementary sequences similar to unmodified oligomers, and allow colorimetrlc and fluorogenic detection of hybrids.     

Study on the Methods for Synthesis of GM-CSF Conjugates with Alendronic Acid

Russian Journal of Bioorganic Chemistry - In order to develop a target drug we studied the process of conjugation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and...     

Carboxamides combining favorable olfactory properties with insect repellency

By a simple methodology, we have synthesized 68 carboxamides, with structural analogy to the most efficient mosquitoes repellent DEET (N,N-diethyl-m-toluamide, 9). Eight of them have very promising olfactory profiles. In addition, 34 carboxamides have been tested for their repellency properties against three breeds of cockroach; six of them are excellent in this domain. Two of these, the 2-ethyl-N-isopropyl-N-methylbutanamide and N,N-diallyl-2-ethylbutanamide combine both the positive aspects, and are thus very good candidates for use in functional perfumery, and more particularly in home-care formulations.     

Synthesis of Novel DNA Analoues Containing Aminomethylphosphonate Internucleoside Linkages

Abstract

Modified oligodeoxyribounucleotides with asminomethylphonate bonds between nucleoside residues were prepared and investigated for their hybridization properties toward DNA and RNA.     

Synthesis and Antiviral Activity of Betulonic Acid Amides and Conjugates with Amino Acids

Betulonic acid amides with aliphatic and heterocyclic amines and with L-amino acids were synthesized by the acid chloride method. Betulonic acid amide and L-methionine derivatives of betulonic acid and its 3-oxime effectively inhibit the influenza A virus. Betulonic acid octadecylamide is active against the herpes simplex Type 1 virus. The conjugate of betulonic acid 3-oxime with L-methionine is also active toward HIV-1. The tested compounds mainly show no activity toward the ECHO6 virus, which is devoid of a coat.     

Synthesis of Novel Pyrazole-Oxindole Conjugates with Cytotoxicity in Human Cancer Cells via Apoptosis

A novel series of pyrazole-oxindole conjugates were prepared and characterized as potential cytotoxic agents by FT-IR, NMR and HR-MS. The cytotoxic activity of these compounds was tested in the Jurkat acute T cell leukemia, CEM acute lymphoblastic leukemia, MCF10 A mammary epithelial and MDA-MB 231 triple negative breast cancer cell lines. Among the tested conjugates, 5-methyl-3-((3-(1-phenyl)-3-(p-tolyl)-1H-pyrazol-4-yl)methylene)indolin-2-one 6h emerged as the most cytotoxic with a CC₅₀ of 4.36+/−0.2 μM against Jurkat cells. The mechanism of cell death induced by 6h was investigated through the Annexin V-FITC assay via flow cytometry. Reactive oxygen species (ROS) accumulation, mitochondrial health and the cell cycle progression were also evaluated in cells exposed to 6h . Results demonstrated that 6h induces apoptosis in a dose-response manner, without generating ROS and/or altering mitochondrial health. In addition, 6h disrupted the cell cycle distribution causing an increase in DNA fragmentation (Sub G0-G1), and an arrest in the G0-G1 phase. Taken together, the 6h compound revealed a strong potential as an antineoplastic agent evidenced by its cytotoxicity in leukemia cells, the activation of apoptosis and restriction of the cell cycle progression.