RNA Modified Uridines. V. An Improved Synthesis of 3-[3-(S)-Amino-3-carboxypropyl]uridine (acp3U) and Its 5′-Phosphate

Abstract

The condensation of 2′,3′-0-isopropylideneuridine sodium salt 3 with benzyl 2-(S)-benzyloxycarbonylamino-4-iodobutyrate 2a derived from L-homoserine, followed by the deprotection of 4a in mild conditions gives the title nucleoside 1a in 68% yield. The syntheses of acp³U 3R-epimer 1b and of acp³U 5′-phosphate 6 are also described.     

The tRNA “WOBBLE POSITION” Uridines. III.1 the Synthesis of 5-[S-Methoxycarbonyl (Hydroxy)Methyl] Uridine and its 2-Thio Analogue

Abstract

The diastereoisomers 2a, 2b and their 2-thio analogues 4a and 4b were obtained by three-step transformation of uridine and 2-thiouridine, respectively. The absolute configuration at C-5¹ in 2a and 2b was established by CD, while for 4a and 4b the configurational assignment was based on the chemical correlation. The acids 1 and 3 were obtained by alkaline hydrolysis of 2a and 4a, respectively.     

Synthesis and Biological Evaluation of 4-Amino-1-β-D-Ribofuranosylpyrrolo[3,2-c]Pyriding (3-Deazatubercidin)

Abstract

4-Amino-1-β-D-ribofuranosylpyrrolo[3,2-c]pyridine (3-deazatubercidin) has been synthesized in four steps by glycosylation of the anion of the 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine with 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dimethylsily 1-α-D-ribofuranose. 3-Deaza-tubercidin was found devoid of antitumor activity in vitro.     

Synthesis and Biological Activity of the Novel Adenosine Analogs; 3-Amino-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole and 3-Amino-1-methyl-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole

Abstract

Chemical modification of the 4-nitrile group in 5-amino-1-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile (1) afforded 5-amino-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzyl-β-D-ribofuran osyl)pyrazole (3). The methylation of 3, via a three step procedure, gave 5-methylamino-4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzyl-β-D-ribofuranosyl)pyrazole (3a). The mononuclear heterocyclic rearrangement (m.h.r) of 3 and 3a, provided a convenient route to the novel azapentalene adenosine analogs 3-amino-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole (6) and 3-amino-1-methyl-6-(β-D-ribofuranosyl)pyrazolo[3,4-c]pyrazole (6a), respectively. Compound 6 exhibited no cytotoxicity when screened in vitro against either mouse L1210 leukemic cells or human foreskin fibroblasts. Nor was it active against human cytomegalovirus. Compound 6a was designed and prepared to investigate the possibility that the lack of biological activity of 6 might be due to annular tautomerization limiting the ability of 6 to serve as a substrate for the activating enzyme adenosine kinase. This hypothesis was neither supported nor disproved by the results, as compound 6a was also inactive in both the antiproliferative and antiviral test systems.     

Polydeoxyaminohexopyranosylnucleosides. Synthesis of 1-(2,3,4-Trideoxy-3-nitro-β-D-erythro- and threo-hexopyranosyl)-uracils from Uridine

Abstract

The first synthesis of nitro-multideoxy-sugar containing nucleosides was achieved. 1-(4,6-O-Benzylidene-3-deoxy-3-nitro-β-D-glucopyranosyl)uracil (3) was converted in 75% yield into 1-(4,6-O-benzylidene-2,3-dideoxy-3-nitro-arabinohexopyranosyl)uracil (7) by acetylation followed by NaBH₄ reduction in methanol. De-O-benzylidenation with CF₃CO₂H afforded crystalline 1-(2,3-dideoxy-3-nitro-β-D-arabinohexopyranosyl)uracil (S) was obtained in 87% yield. Raney Ni reduction of 8 afforded the corresponding 3′-amino-nucleoside 9. Acetylation of 8 followed by NaBH₄ treatment afforded an 8:1 mixture from which 1-(2,3,4-trideoxy-3-nitro-β-D-threohexopyranosyl)-uracil (14) was obtained in pure crystalline form. After Raney Ni reduction of the mixture, 1-(3-amino-2,3,4-trideoxy-β-d-threo-hexopyranosyl)uracil (16) and its erythro epimer 21 were isolated. 1-(4,6-O-Benzylidene-2,3-dideoxy-3-nitro-β-d-lyxohexopyranosyl)uracil (24) was prepared in 72% yield from 1-(4,6-O-benzylidene-3-deoxy-3-nitro-β-d-galactopyranosyl)uracil (4) by acetylation and subsequent reduction with NaBH₄. De-O-benzylid-enation of 23 afforded 1-(2,3,4-trideoxy-3-nitro-β-d-lyxohexopyranosyl)uracil (25) in 83% yield. Schmidt-Rutz reaction of 25 followed by NaBH₄ reduction afforded a mixture of threo and elythro isomers of 2′,3′,4′-trideoxy-3′-nitro-hexopyranosyluracil, from which pure 16 and 21 were obtained.

     

Synthesis and X-Ray Crystal Structure of 3-Amino-1-β-D-Ribofuranosyl-s-Triazolo[5, 1-c]-s-Triazole

Abstract

The first chemical synthesis of 3-amino-1-β-D-ribofuranosyl-s-triazolo[5,1-c]-s-triazole (6) is described. Direct glycosylation of 3-amino-5(7)H-s-triazolo[5,1-c]-s-triazole (2) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (3) in the presence of TMS-triflate gave 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-s-triazolo[5, 1-c]-s-triazole (4) which, on ammonolysis, gave 6. The absolute structure of 6 is determined by X-ray diffraction techniques employing Mo Kα radiation. The structure is solved by direct methods and refined to the R value of 0.044 by using a full-matrix least-squares method. The sugar of 6 has a ³T₂ configuration. The torsion angles about the C5′–C4′ bond are both gauche and the torsion angle about the glycosidic bond is in the anti range. Each azole ring of the aglycon is planar and the dihedral angle between the planes of the rings is 3.6°.     

Enzymatic Deamination of (±)-2-Methyl- and (S)-2,2-Dimethyl-1-aminocyclopropane-1-carboxylic Acid

The effects of drinking deaerated water on serum biochemical values, and on the concentrations of short-chain fatty acids (SCFAs) derived from bacterial fermentation in the colon were examined in rats. Drinking deaearted water decreased the levels of serum alkaline phosphatase (SAP) and serum urea nitrogen (SUN), and increased the serum potassium (SK) and serum phosphorus (SP) levels. Although the concentration of propionic acid in the cecum was decreased by drinking deaerated water, the concentrations of isobutyric, valeric, and isovaleric acids in the cecum were increased.     

Synthesis and Biological Activity of 4-Amino-1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazin-7-one

Abstract

The Lewis acid catalyzed ribosylation of 5(4)-cyano-4(5)-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-imidazole (2) with 1-O-acetyl-2,3,5-tri-O-benzoyl-B-D-ribose gave only 4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(2,3,5-tri-O-benzoy 1-B-D-ribofuranosyl)imidazole-5-carbonitrile (3). Treatment of 3 with methanolic ammonia gave 4-(5-methyl-1,2,4-oxadiazol-3-yl)-1-(6-D-ribofuranosyl)imidazole-5-carbonitrile (4). Treatment of 4 with hydrogen peroxide in ammonia gave -(5-methyl-1,2,4-oxadiazol-3-yl)-1-(B-D-ribofuranosyl)imidazole-5-carboxamide (5). When 5 was treated with sodium hydride in dimthyl-sulfoxide a rearrangement (mononuclear heterocyclic rearrangement, m.h.r.) occurred to give a modest 17% yield of 4-acetamido-1-(B-D ribofuranosyl)imidazo[4,5-d]pyridazin-7-one (6). Treatment of 6 with aqueous ammonia gave4-amino-l-(B-D-ribofuranosyl)imidazo[4,5-d]pyridazin-7-one (1). The synthesis of compound 1 using the m.h.r. for the preparation of a single regioisomer of the imidazo[4,5-d]pyridazin-7-one ring system, has demonstrated the potential of this methodology. Neither compound 5 nor 6 affected the growth or replication of human foreskin fibroblasts (HFF cells) or human cytomegalovirus (HCMV). In contrast, compound 1 inhibited the replication of HCMV (IC₅₀=29 μM) but produced visual cytotoxicity in uninfected HFF cells (IC₅₀=70μM). Compound 1 also inhibited the proliferation of L1210 murine leukemic cells (IC₅₀=25μM), whereas the precursors 4 and 6 did not.     

Reaction of Azide Ion with 1-(2,3-Anhydrolyxofuranosyl)Uracil. Isolation of 1-(2-Amino-2-deoxy-β-D-Xylo-Furanosyl)uracil and 1-(3-Amino-3-deoxy-β-D-arabinofuranosyl)uracil

Abstract

The reaction of the 2′,3′-lyxoepoxide (1) with ammonium azide gives two products; namely, the 3′-arabino azide (2a) and in low yield 2′-xylo azide (3a). After debenzoylation and reduction the resulting mixture of amines was resolved by chromatography on a weak cation exchanger, Amberlite IRC-50, and afforded crystalline 1-(3-amino-3-deoxy-β-D-arabinofuranosyl)uracil (2c) and 1-(2-amino-2-deoxy-β-D-xylofuranosyl)uracil (3c) in the ratio of 4:1.     

Synthesis and Properties of Modified Oligodeoxyribonucleotides Containing 9-(2-Amino-2-deoxy-β-D-arabinofuranosyl)adenine

Abstract

The synthesis of modified oligodeoxyribonucleotides# This publication is dedicated to Professor Tsujiaki Hata, who made a valuable contribution to the chemistry of nucleosides and nucleotides. containing 2′-amino-2′-deoxyarabinoadenosine residues (aAⁿ) was carried out by means of the standard phosphoramidite chemistry. A high reactivity of such compounds to electrophilic reagents was shown. The cross-link formation between 2′-amino group of aAⁿ and carboxyl function introduced into complementary strands occurs with 55% yield. The aAⁿ residues was shown to induce the increased resistance of modified oligomers towards the enzymatic cleavage and provide the insignificant destabilization of DNA duplexes.

     

Phylogenetic relationships of true butterflies (Lepidoptera: Papilionoidea) inferred from COI, 16S rRNA and EF-1α sequences

The molecular phylogenetic relationships among true butterfly families (superfamily Papilionoidea) have been a matter of substantial controversy; this debate has led to several competing hypotheses. Two of the most compelling of those hypotheses involve the relationships of (Nymphalidae + Lycaenidae) + (Pieridae + Papilionidae) and (((Nymphalidae + Lycaenidae) + Pieridae) + Papilionidae). In this study, approximately 3,500 nucleotide sequences from cytochrome oxidase subunit I (COI), 16S ribosomal RNA (16S rRNA), and elongation factor-1 alpha (EF-1α) were sequenced from 83 species belonging to four true butterfly families, along with those of three outgroup species belonging to three lepidopteran superfamilies. These sequences were subjected to phylogenetic reconstruction via Bayesian Inference (BI), Maximum Likelihood (ML), and Maximum Parsimony (MP) algorithms. The monophyletic Pieridae and monophyletic Papilionidae evidenced good recovery in all analyses, but in some analyses, the monophylies of the Lycaenidae and Nymphalidae were hampered by the inclusion of single species of the lycaenid subfamily Miletinae and the nymphalid subfamily Danainae. Excluding those singletons, all phylogenetic analyses among the four true butterfly families clearly identified the Nymphalidae as the sister to the Lycaenidae and identified this group as a sister to the Pieridae, with the Papilionidae identified as the most basal linage to the true butterfly, thus supporting the hypothesis: (Papilionidae + (Pieridae + (Nymphalidae + Lycaenidae))).     

Antagonists of 5-HT₆ receptors. Substituted 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines-Synthesis and 'structure-activity' relationship

Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT(6) receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT(2B) blocking activity (IC(50)=6.16 μM as compared with IC(50)=1.8 nM for 5-HT(6) receptors) and very low hERG potassium channel blocking potency (IC(50)=54.2 μM). The linear analog, 11, is less favorable as while showing no binding to the 5-HT(2B) receptor at concentrations of up to 10 μM, it exhibits quite a high potency to block the hERG channel (IC(50)=0.5 μM).     

Synthesis and characterization of [Pt(COD)Cl(NO3)] and [Pt(COD)(NO3)2] and the use of [Pt(COD)Clx(NO3)2−x] in the preparation of cis[Pt(PPh3)2Clx(NO3)2−x] (x=0, 1, 2) and [Pt(PPh3)3L](NO3) (L=Cl,NO3)

[Pt(COD)Cl₂] (COD=1,5-cyclooctadiene) is a versatile starting material for the synthesis of Pt(II) compounds. The preparations of the new compounds [Pt(COD)Cl(NO₃)], [Pt(COD)(NO₃)₂] and [Pt(PPh₃)₃(NO₃)](NO₃) and also of the known compounds cis[Pt(PPh₃)₂Cl₂], cis [Pt(PPh₃)₂Cl(NO₃)], cis[Pt(PPh₃)₂(NO₃)₂] and [Pt(PPh₃)₃Cl](NO₃)are reported. The compounds are characterized by elemental analysis, ³¹P{¹H} NMR spectroscopy and IR spectroscopy.     

Quercetin 3-O-[6″-(3-hydroxy-3-methylglutaroyl)-β-galactoside] from blackberries

Quercetin 3-[6″-(3-hydroxy-3-methylglutaroyl)-galactoside] was isolated and identified from blackberries.     

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Regulates the Stability and Function of GluA1 α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) Receptor in Neurons

The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor abundantly expressed in neurons. Increasing evidence demonstrates that LRP1 regulates synaptic integrity and function at the post synapses, at least partially by regulating glutamate receptors. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are critical ionotropic glutamate receptors consisting of homotetramer or heterotetramer of GluA1-4 subunits and play an essential role in synaptic transmission and synaptic plasticity. Our previous work has shown that neuronal deletion of the Lrp1 gene in mice leads to decreased level of GluA1 and reduced long-term potentiation. To understand the underlying mechanism, we investigated the cellular and functional consequences of LRP1 deletion in primary neurons. Here, we show that LRP1 interacts with and regulates the cellular distribution and turnover of GluA1. LRP1 knockdown in mouse primary neurons led to accelerated turnover and decreased cell surface distribution of GluA1, which correspond to decreased phosphorylation of GluA1 at S845 and S831 sites. Decreased LRP1 expression also attenuated AMPA-evoked calcium influx and reduced GluA1-regulated neurite outgrowth and filopodia density. Our results reveal a novel mechanism by which LRP1 controls synaptic integrity and function, specifically by regulating GluA1 trafficking, phosphorylation and turnover. They further demonstrate that LRP1-GluA1 pathway may hold promises as a therapeutic target for restoring synaptic functions in neurodegenerative diseases.     

2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: Design and synthesis of a potent and isoform selective PKC-ζ inhibitor

The inhibition of PKC-ζ has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-ζ). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH₂ derivative. The analog displays good selectivity over other PKC isoforms (α, βII, γ, δ, ε, μ, θ, η and ι/λ) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).     

Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,a potent and orally active neuropeptide Y Y5 receptor antagonist

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.     

Synthesis and evaluation of (S,S)-N,N′-bis-[3-(2,2′,6,6′-tetramethylbenzhydryloxy)-2-hydroxy-propyl]-ethylenediamine (S2824) analogs with anti-tuberculosis activity

In order to identify new and potent candidate drugs to treat tuberculosis, a library of compounds was screened, and (S,S)-N,N′-bis-[3-(2,2′,6,6′-tetramethylbenzhydryloxy)-2-hydroxy-propyl]-ethylenediamine (S2824) was identified as a hit in the screen. This research discusses our efforts to synthesize and test 30 analogs of this hit for activity against Mycobacterium tuberculosis. Two compounds with homopiperazine ring possess high in vitro activity against drug sensitive and resistant M. tuberculosis with MICs 0.78–3.13 μg/mL (or 1.22–4.88 μM).     

Tumour-specific cytotoxicity and structure–activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones

A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3–7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC₅₀ and CC₅₀ values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells.