Synthesis and serotonin receptor binding properties of 5-substituted 3-(1′,2′,5′,6′-tetrahydropyridin-3′-yl) indoles

A semi-rigid 5-hydroxytryptamine (5-HT) analogue, RU28253 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-3′-yl) indole], is a potent 5-HT₁ and 5-HT₂ agonist. It is isomeric to RU24969 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-4′-yl) indole], a conformationally restricted 5-HT homologue, which has been extensively used in the study and classification of 5-HT receptors. A series of RU28253 derivatives with diverse substituents on indole 5-position were synthesized and their dissociation constants determined at the 5-HT₁ and 5-HT₂ receptors.     

Enzymatic alcoholysis of 3′,5′-di-O-acetyl-2′-deoxynucleosides

Candida antarctica-B (CAL-B) lipase-catalysed alcoholysis of a set of 3′,5′-di-O-acetyl-2′-deoxynucleosides (1a–e) gave the corresponding 3′-O-acetyl-2′-deoxy-nucleosides (2a–e) in yields ranging from 50 to 96%. The alcohol employed in the biotransformation affected the rate of the enzymatic reaction and the yield of the 3′-O-acetylated product, but in all cases only this regioisomer was formed. The obtained results are in agreement with the regioselectivity displayed by CAL-B lipase in previously reported biotransformations of nucleosides. CAL-B catalysed alcoholysis of 2′,3′,5′-tri-O-acetyl-cytidine and 4-N-acetyl-2′,3′,5′-tri-O-acetylcytidine was also studied, affording with the same regioselectivity the corresponding free 5′-hydroxyl nucleosides.     

The synthesis of 2,1′-anhydro-,2,1′:3,6-dianhydro-, and 2,1′:3,6: 3′,6′-trianhydro-sucrose

1′-O-Mesyl-6,6′-di-O-tritylsucrose and the corresponding 1′-O-tosyl derivative were prepared from 6,6′-di-O-tritylsucrose by selective sulphonylation. Both sulphonates underwent intramolecular cyclisation reactions, to give 2,1′-anhydrosucrose in high yields rather than the isomeric 1′,4′-anhydride. Sequential benzoylation, detritylation, and mesylation of the 2,1′-anhydride afforded 2,1′-anhydro-6,6′-di-O-mesylsucrose tetrabenzoate which, in the presence of base, gave 2,1′:3,6:3′,6′-trianhydrosucrose that was not identical with the product previously claimed to have this structure. Several derivatives of 2,1′-anhydrosucrose were prepared possessing different functional groups at either the 6,6′- or 4,6′-positions. Dimolar mesitylene-sulphonylation of 3,3′,4′6′-tetra-O-acetylsucrose gave the 6,1′-disulphonate, which, in the presence of alkali, gave 2,1′:3,6-dianhydrosucrose, which was transformed into the 2,1′:3,6:3′,6′-trianhydride by sequential bromination at C-6′ (carbon tetrabromide-triphenylphosphine) and base-catalysed cyclisation. Treatment of 3,3′,4′,6′-tetra-O-benzoylsucrose with sulphuryl chloride furnished the 4,6,1′-trichloro derivative, which, on alkaline hydrolysis, was converted into 2,1′:3,6-dianhydro-4-chloro-4-deoxy-galacto-sucrose.     

Synthesis of (+/−)–1′-Aza-carbocyclic-pyrimidine-2′,3′-dideoxynucleoside analogues as potential anti-HIV agents

1′-Aza-carbocyclic-2′, 3′-dideoxyuridine, 3′-deoxythymidine and 2′, 3′-dideoxycytidine were synthesized from 1-aminopyrrolidine intermediate 13 and evaluated as anti-HIV agents in MT-4 cells.     

Synthesis of 3-methylpseudouridine and 2′-deoxy-3-methyl-pseudouridine

The first chemical synthesis of 3-methyl-ψ-uridine (5) and its 2′-deoxy analogue (9) has been achieved. ψ-Uridine was trimethylsilylated and the crude product was treated with acetyl chloride, to give the 1-acetyl derivative (3). Crude 3 was methylated with dimethoxymethyldimethylamine and then saponified, to give crystalline 5 in 82% overall yield. Treatment of 5 with 1,3-dichloro-1,1,3,3-tetraiso-propyldisiloxane afforded the 3′,5′-protected product, which was converted into the 2′-O-[(imidazol-1-yl)thiocarbonyl] derivative 7. Reduction of 7 with tributyltin hydride followed by deblocking of the product gave crystalline 2′-deoxy-3-methyl-ψ-uridine (9) in 35% yield from 5.     

Effects of electronic structure on chiral induction in outer-sphere electron transfer reactions of complexes with the C3 symmetric ligand, 1,4,7-triazacyclononane-1,4,7-tris[2′(R)-2′-propionate](-3)

The ligand 1,4,7-triazacyclononane-1,4,7-tris[2′(R)-2′-propionate](-3)((R)-tacntp³⁻), binds stereospecifically to transition metal ions. The structures of the complexes [Cr((R)-tacntp)]·NaBr and [Fe((R)-tacntp)]·H₂O have been determined by X-ray crystallography. Both complexes have the Λ-configuration but the conformation of the chelate rings in Λ-[Cr((R)-tacntp)] is (λ,λ,λ) with a geometry close to octahedral while in Λ-[Fe((R)-tacntp)] it is (δ,δ,δ) and the geometry is closer to that of a trigonal prism. Chiral induction in the electron transfer reactions of Λ-[Co((R)-tacntp)], Λ-[Fe((R)-tacntp)] and Λ-[Mn((R)-tacntp)] with [Co((RR,SS)-chxn)₃]²⁺ has been investigated. All three reactions are outer-sphere and four isomeric [Co((RR,SS)-chxn)₃]³⁺ products are identified in each case. The oxidants Λ-[Fe((R)-tacntp)] and Λ-[Mn((R)-tacntp)] show very similar selectivities, quite different from those of Λ-[Co((R)-tacntp)]. Reasons for this behavior are discussed.     

Stereoselective synthesis of 3′-C-methylene- and 2′-methyl-3′-C-methylene-3′-deoxythymidine

Stereoselective synthesis of 3′-C-methylene- and 2′-methyl-3′-C-methylene-3′-deoxythymidine is described, the key reaction being the formation of 3-C-methylene function by catalytic isomerization of a chiral epoxyalcohol, prepared from commercially available 3-methyl-2-butenal and 3-methyl-2-pentenal.     

Furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives as potential inhibitors of inflammatory factors in sepsis

Synthesis and anti-inflammatory effects of certain furo[3′,2′:3,4]naphtho[1,2-d]imidazole derivatives 12–18 were studied. These compounds were synthesized from naphtho[1,2-b]furan-4,5-dione (10) which in turn was prepared from the known 2-hydoxy-1,4-naphthoquinone (7) in a one pot reaction. Furo[3′,2′:3,4]naphtho[1,2-d]imidazole (12) was inactive (IC₅₀ value of >30 μM) while its 5-phenyl derivative 13, with an IC₅₀ value of 16.3 and 11.4 μM against lysozyme and β-glucuronidase release, respectively, was comparable to the positive trifluoperazine. The same potency was observed for 5-furan derivative 16 with an IC₅₀ value of 19.5 and 11.3 μM against lysozyme and β-glucuronidase release, respectively. An electron-withdrawing NO₂ substituted on 5-phenyl or 5-furanyl group led to the devoid of activity as in the cases of 14 and 17. Among them, compound 15 exhibited significant inhibitory effects, with an IC₅₀ value of 7.4 and 5.0 μM against lysozyme and β-glucuronidase release, respectively.For the LPS-induced NO production, the phenyl derivatives 12–15 were inactive while the nitrofuran counterparts 17 and 18 suppress LPS-induced NO production significantly, with an IC₅₀ value of 1.5 and 1.3 μM, respectively, which are more active than that of the positive 1400 W. Compounds 16–18 were capable of inhibiting LPS-induced iNOS protein expression at a dose-dependent manner in which compound 18, with an IC₅₀ of 0.52 μM in the inhibition of iNOS expression, is approximately fivefold more potent than that of the positive 1400 W. In the CLP rat animal model, compound 18 was found to be more active than the positive hydrocortisone in the inhibition of the iNOS mRNA expression in rat lung tissue. The sepsis-induced PGE2 production in rat serum decreased 150% by the pretreatment of 18 in a dose of 10 mg/kg.     

Carbocyclic phosphonate analogs of 2′,3′-dideoxyadenosine-5′-monophosphate as substrates of 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetate

Several carbocyclic phosphonate analogs of 2′,3′-dideoxyadenosine-5′-monophosphate (ddAMP) were pyrophosphorylated by E. coli 5-phosphoribosyl-1-pyrophosphate (PRPP) synthetase in the presence of PRPP. Structure-activity relationships are discussed.     

Dinuclear sulfide–thiolate complexes [Pt2(μ-S)(μ-SR)(PPh3)4] as cationic metalloligands

The cationic monoalkylated derivatives of the well-known metalloligand [Pt₂(μ-S)₂(PPh₃)₄], viz. [Pt₂(μ-S)(μ-SR)(PPh₃)₄]⁺ (R = n-Bu, CH₂Ph) are themselves able to act as metalloligands towards the Ph₃PAu⁺ and R′Hg⁺ (R′ = Ph or ferrocenyl) fragments, by reaction with Ph₃PAuCl or R′HgCl, respectively. The resulting dicationic products [Pt₂(μ-SR)(μ-SAuPPh₃)(PPh₃)₄]²⁺ and [Pt₂(μ-SR)(μ-SHgR′)(PPh₃)₄]²⁺ are readily isolated as their hexafluorophosphate salts, and have been fully characterised by spectroscopic techniques and an X-ray structure determination on [Pt₂(μ-SR)(μ-SHgFc)(PPh₃)₄](PF₆)₂.     

Regulation of DNA synthesis by guanosine-5′-diphosphate, cyclic guanosine-3′,5′-monophosphate, and cyclic adenosine-3′,5′-monophosphate in mouse lymphoid cells

The effect of various adenine and guanine nucleotides and nucleosides on DNA synthesis was studied in various types of mouse lymphoid cells. Two out of the ten compounds tested, namely guanosine-5′-diphosphate (GDP) and cyclic guanosine-3′,5′-monophosphate (cGMP) increased the thymidine incorporation into the DNA of the spleen cells and counteracted completely or partially the inhibitory action of cyclic adenosine-3′,5′-monophosphate (cAMP) on spleen cells stimulated by various B or T cell mitogens. GDP seems to act preferentially on thymus cells while cGMP acts better on bone marrow cells. The possible significance of the results for the mechanism of the mitogenic signal is discussed.     

3′-Fluoro-3′-deoxyribonucleoside 5′-triphosphates: Synthesis and use as terminators of RNA biosynthesis

3′-Fluoro-3′-deoxy-uridine, -cytidine, -adenosine and -guanosine have been synthesized by glycosylation of the corresponding silylated bases with 1-O-acetyl-2,5-di-O-benzoyl-3-fluoro-3-deoxy-D-ribofuranose in the presence of Friedel-Crafts catalysts and were converted to the 5′- triphosphates, NTP(3′-F). It was shown that NTP(3′-F) are terminators of RNA synthesis catalyzed by DNA-dependent RNA polymerase from E. coli and may thus serve as tools for DNA sequencing.     

Localization of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in human erythrocyte membranes

The location of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in human erythrocyte membranes was determined. This was accomplished by comparing the enzyme's accessibility with that of glyceraldehyde-3-phosphate dehydrogenase (cytoplasmic surface marker) and acetylcholinesterase (external marker) in sealed and unsealed ghosts and normal and inverted membrane vesicles. The results showed that 2′,3′-cyclic nucleotide 3′-phosphodiesterase, like glyceraldehyde-3-phosphate dehydrogenase, meets several criteria for an inner (cytoplasmic) membrane location: (1) the enzyme was accessible to substrate in unsealed ghosts and inside-out vesicles but not in sealed or right-side-out vesicles, (2) latent activity in sealed ghosts could be exposed with detergent (Triton X-100), (3) activity in unsealed ghosts was gradually sequestered during resealing and could be re-exposed with detergent, and (4) the enzyme was susceptible to trypsin proteolysis only in unsealed ghosts. These results demonstrate that the active site of 2′,3′-cyclic nucleotide 3′-phosphodiesterase faces the cytoplasm of erythrocytes and that the enzyme may not span the lipid bilayer of the membrane. The localization of the phosphodiesterase on the inner membrane surface of erythrocytes suggests that the similar enzyme of myelin may be embedded within the major dense line of the compact lamellae.     

Synthesis and evaluation of 4′-5′-dehydro-5′-fluoroaristeromycins as S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitors

4′,5′-Dehydro-5′-fluoro analogs of aristeromycin were synthesized and shown to be potent inhibitors of recombinant rat liver AdoHcy hydrolase.     

Inhibition of replicative DNA synthesis in nuclei of Strongylocentrotus intermedium urchin embryo by 2′,3′-dideoxy-3′-aminonucleoside 5′-triphosphates

2′,3′-Dideoxy-3′-aminonucleoside 5′-triphosphates have been shown to be inhibitors of replicative DNA synthesis in isolated nuclei of sea urchin embryo. These compounds inhibit the Okazaki fragment synthesis. The effect of 2′,3′-dideoxy-3′-aminothymidine 5′-triphosphate and arabinothymidine 5′-triphosphate is reversible when adding the corresponding substrate for DNA synthesis, 2′-deoxythymidine 5′-triphosphate.     

Alkene rotation in [Ru(η-C5H5) (L2) (η-alkene][CF3SO3] with L2 = iPr- or pTol-diazabutadiene. X-ray crystal structure of [Ru(η-C5H5(pTol-DAB) (η-ethene][CF3SO3]

Reaction of RuCl(η⁵-C₅H₅(pTol-DAB) with AgOTf (OTf = CF₃SO₃) in CH₂Cl₂ or THF and subsequent addition of L′ (L′ = ethene (a), dimethyl fumarate (b), fumaronitrile (c) or CO (d) led to the ionic complexes [Ru(η⁵-C₅H₅)(pTol-DAB)(L′)][OTf] 2a, 2b and 2d and [Ru(η⁵-C₅H₅)(pTol-DAB)(fumarontrile-N)][OTf] 5c. With the use of resonance Raman spectroscopy, the intense absorption bands of the complexes have been assigned to MLCT transitions to the iPr-DAB ligand. The X-ray structure determination of [Ru(η⁵-C₅H₅)(pTol-DAB)(η²-ethene)][CF₃SO₃] (2a) has been carried out. Crystal data for 2a: monoclinic, space group P2₁/n with A = 10.840(1), b = 16.639(1), C = 14.463(2) Å, β = 109.6(1)°, V = 2465.6(5) ų, Z = 4. Complex 2a has a piano stool structure, with the Cp ring η⁵-bonded, the pTol-DAB ligand σN, σN′ bonded (Ru-N distances 2.052(4) and 2.055(4) Å), and the ethene η²-bonded to the ruthenium center (Ru-C distances 2.217(9) and 2.206(8) Å). The C = C bond of the ethene is almost coplanar with the plane of the Cp ring, and the angle between the plane of the Cp ring and the double of the ethene is 1.8(0.2)°. The reaction of [RuCl(η⁵-C₅H₅)(PPh)₃ with AgOTf and ligands L′ = a and d led to [Ru(η⁵-C₅H₅)(PPh₃)₂(L′)]OTf] (3a) and (3d), respectively. By variable temperature NMR spectroscopy the rottional barrier of ethene (a), dimethyl fumarate (b and fumaronitrile (c) in complexes [Ru(η⁵-C₅H₅)(L₂)(η²-alkene][OTf] with L₂ = iPr-DAB (a, 1b, 1c), pTol-DAB (2a, 2b) and L = PPh₃ (3a) was determined. For 1a, 1b and 2b the barrier is 41.5±0.5, 62±1 and 59±1 kJ mol⁻¹, respectively. The intermediate exchange could not be reached for 1c, and the ΔG^# was estimated to be at least 61 kJ mol⁻. For 2a and 3a the slow exchange could not be reached. The rotational barrier for 2a was estimated to be 40 kJ mol⁻. The rotational barier for methyl propiolate (HC≡CC(O)OCH₃) (k) in complex [Ru(η⁵-C₅H₅)(iPr-DAB) η²-HC≡CC(O)OCH₃)][OTf] (1k) is 45.3±0.2 kJ mol⁻¹. The collected data show that the barrier of rotational of the alkene in complexes 1a, 2a, 1b, 2b and 1c does not correlate with the strength of the metal-alkene interaction in the ground state.     

Synthesis and anti-HIV activity of 3′-deoxy-3′-(N-hydroxyamino) analogues of nucleosides

3′-Deoxy analogues of thymidine and uridine bearing a 3′-N-alkyl-(or N-aralkyl) -N-hydroxyamino group either on the or the β face of the furanose ring have been prepared. One of these (13), exhibited a moderate anti-HIV activity.     

Phospholipid metabolism and lysosomal enzyme secretion by leukocytes Effects of dibutyryl cyclic adenosine 3′ : 5′-monophosphate and ATP

The effects of dibutyryl cyclic adenosine 3′ : 5′-monophosphate and ATP on isotope incorporation into phospholipids and the release of β-glucuronidase into the extracellular medium were studied in polymorphonuclear leukocytes from guinea pig peritoneal exudates. Exogenous dibutyryl cyclic adenosine 3′ : 5′-monophosphate (0.1–1.0 mM) reduced β-glucoronidase release induced by cytochalasin B in the absence of inert particles. It selectively inhibited ³²P_i incorporation into phosphatidic acid and the phosphoinositides and the incorporation of myo-[2-³H]inositol into the phosphoinositides. Added ATP (0.1–1.0 mM), but not other nucleotides, was found to potentiate β-glucuronidase release provoked by cytochasin B, but it impaired the labeling of the phosphoinositides by myo-[2-³H]inositol. The mechanism of the inhibition of the isotope incorporation into these acidic phospholipids by the two nucleotides has not been defined. Dibutyryl cyclic adenosine 3′ : 5′-monophosphate at 2–4 mM concentration was not found to appreciably alter the incorporation of [γ-³²P]ATP into phosphatidic acid, phosphatidylinositol, diphosphoinositide, and triphosphoinositide.     

2′,3′-Dideoxy-3′-aminonucleoside 5′-triphosphates inhibit the repair of DNA in rat liver chromatin

2′,3′-Dideoxy-3′-aminonucleoside 5′-triphosphates are shown to be strong inhibitors of repair DNA synthesis in γ-irradiated rat liver chromatin. The activity of these compounds is comparable with that of the most effective inhibitor of the DNA polymerase β-catalyzed repair DNA synthesis.     

Chiral carbocylic nucleosides: The synthesis and antiviral activity of 4′-hydroxy and 4′-fluorocarbocyclic - 2′- deoxyguanosines

The chiral carbocyclic nucleosides 2 and 3 were prepared from aristeromycin. The 4′-hydroxy compound 2 displays good antiviral activity against HSV-1 and HSV-2 with low toxicity.