Regiocontrolled General Synthesis of Branch-Type 2′-5′-Linked Oligoadenylates

Abstract

2′-5′-Linked oligoadenylates (2-5As) having a nucleotide branch at the 3′ position have been synthesized in a general, regiodefined manner.     

Synthesis and Binding Properties of a Homopyrimidine 2′,5′-Linked Xylose Nucleic Acid (2′,5′-XNA)

Abstract

The synthesis and hybridization properties of pyrimidine 2′,5′-RNA and 2′,5′-Xylose Nucleic Acid (2′,5′-XNA) are described.     

Synthesis and Antiviral Activity Assay of Novel (E)-3′,5′-Diamino-5-(2-bromovinyl)-2′,3′,5′-trideoxyuridine

Abstract

(E)-3′,5′-diamino-5-(2-bromovinyl)-2′,3′,5′-trideoxyuridine (5), the diamino analogue of BVDU (1), was synthesized from BVDU. In contrast with BVDU, compound 5 did not show activity against herpes simplex virus or varicella-zoster virus.     

A Direct and Efficient Synthesis of 5′-Deoxy-2′, 3′-

Abstract

A direct and efficient synthesis of 5′-deoxy-2′,3′-O-isopropylideneinosine, 7, from readily available inosine is described. An example of a potentially general synthesis of N -substituted-5′-deoxyadenosines from 7 is also described.     

Structure of 2′,5′-Linked Tetraribonucleotide Loops: A Novel RNA Motif

Abstract

We report on the three dimensional structure of an RNA hairpin containing a 2′,5′-linked tetraribonucleotide loop, namely, 5′-rGGAC(UUCG)GUCC-3′ (where UUCG = U_2′p5′U_2′p5′C_2′p5′G_2′p5′). We show that the 2′,5′-linked RNA loop adopts a conformation that is quite different from that previously observed for the native 3′,5′-linked RNA loop. The 2′,5′- RNA loop is stabilized by (a) U:G wobble base pairing, with both bases in the anti conformation, (b) extensive base stacking, and (c) sugar–base contacts, all of which contribute to the extra stability of this hairpin structure.     

A general method for phospholipid polar head spin labeling: Synthesis of diphosphatidylglycerol-2-(2′,2′,5′,5′-tetramethylpyrroline-N-oxide) carboxylate

The synthesis of a highly reactive side-branched pyrroline-N-oxyl stable free radical, 2,2,5,5-tetramethylpyrroline-N-oxide-3-carbonyl chloride, versatile for polar head labeling of many phospholipid classes, is presented. As an example of applicability, the synthesis of diphosphatidylglycerol-2-(2′,2′,5′,5′-tetramethylpyrroline-N-oxide) carboxylate is reported.     

Synthesis and Properties of Novel 5′-Linked Oligos

Abstract

We have synthesized normal and phosphorothioate oligos with 5′-linked groups, using either a phosphoramidite with the linked group attached or a mercaptopropanol linker. These linked oligos have been studied for cellular uptake as fluorescent labels, and for inhibition of gene expression in a cell free expression system, and in several other biological systems.     

Synthesis of (±)-Methyl 5-(1′,2′-Epoxy-2′,6′-dimethylcyclohexyl)-3-methyl-(2Z,4E)-2,4-pentadienoate

The effect of tripropyltin chloride (TPT) on transport systems in E. coli was investigated. The inhibition on uptakes of ¹⁴C-l-leucine, l-proline, adenine and methyl-(α-d-gluco)pyrano-side (α-methylglucoside) by TPT was examined. The active uptake of l-leucine which utilized ATP molecule as an energy source was 100% inhibited at the concentration of 10 µg/ml TPT. On the other hand, the uptake of l-proline which was generated by an “energied” membrane state of the cells was inhibited only 40% at the same concentration of TPT. α-Methylglucoside uptake was scarcely inhibited. Adenine uptake was intensely inhibited at 20 µg/ml TPT. The effect of the delayed addition of TPT on transport systems was also examined. l-Leucine incorporated into cells was completely released from cells by TPT. Leucine binding protein (LBP) was prepared from E. coli cells and the effect of TPT on LBP activity was examined. TPT scarcely inhibited LBP activity.     

Synthesis and Properties of 2′4′- and 3′-5′-Linked Ribodinucleoside Monophosphates Containing 2-Aminoadenosine and Uridine

Abstract

Self complementary diribonucleoside monophosphates containing 2-aminoadenosine (n²A) and uridine (U) residues, (2′-5′) n²ApU (1), (3′-5′) n²ApU (2), (2′-5′) Upn²A (3) and (3′-5′) Upn²A (4), were synthesized by condensation of suitably protected nucleoside and nucleotide units using dicyclohexylcarbodiimide (DCC). The dimers, (3) and (41, were also obtained from uridine 2′,3′-cyclic phosphate and unprotected 2-aminoadenosine using 2,4,6-triisopropylbenzenesulfonyl chloride (TPS-Cl) as the condensing agent. The conformational properties of these dimers were examined by UV, CD and NMR spectroscopy. The results reveal that the 2′-5′ isomers take a stacked conformation, which contains a larger base-base overlap and is more stable against thermal perturbation with respect to the 3′-5′ isomers. The n²ApU isomers have more stacked structure than the Upn²A isomers.     

Synthesis of 2′,3′-Dideoxyribavirin

Abstract

A synthesis of 1-(2,3-dideoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′,3′-dideoxyribavirin, ddR) is described. Glycosylation of the sodium salt of 1,2,4-triazole-3-carbonitrile (5) with 1-chloro-2-deoxy-3,5-di-0-p-toluoyl-α-D-erythro-pentofuranose (1) gave exclusively the corresponding N-1 glycosyl derivative with β-anomeric configuration (6), which on ammonolysis provided a convenient synthesis of 2′-deoxyribavirin (7). Similar glycosylation of the sodium salt of methyl 1,2,4-triazole-3-carboxylate (2) with 1 gave a mixture of corresponding N-1 and N-2 glycosyl derivatives (3) and (4), respectively. Ammonolysis of 3 furnished yet another route to 7. A four-step deoxygenation procedure using imidazolylthiocarbonylation of the 3′-hydroxy group of 5′-0-toluoyl derivative (9a) gave ddR (11). The structure of 11 was proven by single crystal X-ray studies. In a preliminary in vitro study ddR was found to be inactive against HIV retrovirus.     

A Short Synthesis of 2′,3′-Didehydro-3′-deoxythymidine

Abstract

Reaction of sodium metal in HMPA-THF with 2,3′-anhydrothymidine la, results in an elimination to give the 2′,3′-unsaturated nucleoside 3a, This process was utilized in a synthesis of the antiviral drug D4T from thymidine.     

Synthesis of 1,2-diacyloxypropyl-3-(1′,2′-diacyl-sn-glycero)-phosphonate

The total synthesis of 1,2-diacyloxypropyl-3-(1′,2′-diacyl-sn-glycero)phosphonate is described. The 1,2-dipalmitoyloxypropyl phosphonic acid was prepared by an Arbusov reaction of 1,2-diacylglycerol bromohydrin with trimethyl phosphite; the final product was obtained by a coupling reaction involving the diacyloxypropyl-3-phosphonic acid and 1,2-dipalmitoyl-sn-glycerol, catalysed by tri-isopropylbenzene sulfonyl chloride. The resulting synthetic product was characterised by elemental analysis, phosphono-phosphorus determinations and IR spectroscopy.     

Synthesis of 2-(2′-Hydroxy-2′, 2′-diphenylethyl)-8-hydroxy-quinoline and Its Biological Activity

2-(2′-Hydroxy-2′,2′-diphenylethyl)-8-hydroxyquinoline was prepared via Grignard reaction involving the activated methyl group in position 2. This compound inhibited the action of the phenol oxidase prepared from prepupae of housefly. In a dipping test of the final instar larvae of housefly, it showed some inhibitory effects on the metamorphosis.     

A New 5′-Protecting Group for Use in Solid-Phase Synthesis of Oligoribonucleotides

Abstract

The 2-(2,4-dinitrobenzenesulphenyloxymethyl)benzoyl (DNBSB) group is proposed as a protecting group for the 5′-position of nucleosides. The DNBSB group may be removed under mild non-acidic conditions and may have potential in solid-phase synthesis of oligoribo- and oligodeoxyribonucleotides.     

A Convenient Synthesis of 9-(5′-DEOXY-β-D-Allofuranosyl)-Adenine (5′-Homoadenosine)

Abstract

The synthesis of 5′-homoadenosine, a chain extended analogue of adenosine, has been developed by coupling the appropriately protected deoxyallofuranose derivative with adenine.     

Synthesis of 1-O-(2′,4′-Dichlorophenoxyacetyl)-d-glucopyranose

1-O-Glucosyl esters of 2,4-dichlorophenoxyacetic acid (2,4-D) were easily prepared from 4,6-O-benzylideneglucose. The configuration of 1-O-ester linkage was affected by pH at the end of the reaction, that is, β-type was a major product at a neutral or acidic condition and α-type at an alkaline condition. Both of the anomers showed the same biological activities as sodium salt of 2,4-D.     

A Simple Synthesis of N4 -(6-Aminohexyl)-2′-Deoxy-5′-O-(4,4′-Dimethoxytrityl)Cytidine

Abstract

The title compound was synthesized by a transamination reaction between N⁴ -benzoyl-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)cytidine and hexane-1,6-diamine in the presence of 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD).     

Synthesis and biological evaluation of 2-substituted-4-(3′,4′,5′-trimethoxyphenyl)-5-aryl thiazoles as anticancer agents

Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH₃ > Me ? N(CH₃)₂. The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1–2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC₅₀ values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.