N6-Alkylthiomethyl and N6-Arylthiomethyl Derivatives of Adenosine and Their Cytokinin Activity

Five new derivatives of adenosine, N⁶-[(1-methylethyl)thiomethyl]-(1), N⁶-methyithiomethyl-(2), N⁶-phenylthiomethyl-(3), N⁶-[(3-amino-3-carboxypropyl)thiomethyl]-(4), and N⁶-[(2-amino-2-carboxyethyl)thiomethyl]adenosine (5), were synthesized and their cytokinin activity was tested in the Amaranthus betacyanin assay and the soybean callus growth.

1, 2, and 3 were active in the former assay and all five compounds were active in the latter assay. The activities of the compounds were, however, weaker than those of the reference derivatives, in which Sulfides were replaced by methylenes, N⁶-isopentyl-, N⁶-n-propyl-, N⁶-benzyl-, and N⁶-(5-amino-5-carboxypentyl)adenosine. This fact indicates that the sulfide structure introduced into the N⁶-side chains had the effect of reducing cytokinin activity.     

Ribosylation of the Base Residue of Inosine Derivatives by Phase-Transfer Catalysis

Abstract

Reaction of 2′,3′,5′-O-silylated inosine derivative 1 with 2, 3-O-isopropylidene-5-O-tritylribosyl chloride (3) in a two-phase (CH₂Cl₂-aq. NaOH) system in the presence of Bu₄NBr gave three products, i. e., 6-O-α-, 6-O-β-, and N ¹-β-isomers of glycosides 4, 5a, and 5b. A similar PTC reaction of 1 with 2, 3, 5-tri-O-benzylribosyl bromide (9) gave four regio- and stereo-isomers involving the N¹-β-glycoside 10. Reaction of 1 with 2, 3, 5-tri-O-benzoylribosyl bromide (11) afforded three products involving the desired N¹-β-glycoside 12b, which could be deprotected to give N ¹-ribosylinosine (15b) as a useful intermediate for the synthesis of cIDPR.

     

Synthesis of novel selenium containing sulfa drugs and their antibacterial activities

Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyri-do[3′,2′:4,5]selenolo[3,2-d]pyrimidines,7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4′,5′:4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-substituted sulfamoyl)phenyl]-1,11-dihydro 11-oxo-4-methylpyrimido[4′,5′:4,5]selenolo[2,3-b]quinolines is reported. 4-Amino-N-pyrimidine-2-ylbenzene sulfonamide (a), 4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzene sulfonamide (b), N-[(4-aminophenyl)sulfonyl] acetamide (c) with N-ethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and selenolo quinoline derivatives respectively were obtained starting from 1-amino-N ⁴-substituted sulfanilamides. Spectroscopic data (IR, ¹H NMR, ¹³C NMR and Mass spectral) confirmed the structure of the newly synthesized compounds. Substituted pyrimidines, pyridazines and quinolines were screened for antibacterial activity against gram-positive and gram-negative bacteria. Selenolo derivative of N-[(4-aminophenyl)sulfonyl] acetamide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested organisms. Selenolo[3,2-d]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococcus aureus and Escherichia coli. Compounds selenolo[2,3-c]pyridazine (substitutent b), selenolo[2,3-b]quinoline(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the synthesized seleno pyridazines has a considerable antimicrobial activity against the tested organisms. The minimum inhibitory concentration (MIC) of the most active compound-3-[4-(N-acetyl sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3′,2′:4,5]selenolo [3,2-d]pyrimidine was 10 mg ml⁻¹.     

Synthesis of the Oligoribonucleotides Incorporating 8-Oxo-Guanosine and Evaluation of their Base Pairing Properties

6-O-7-N-Bis(diphenylcarbamoyl)-2-N-phenoxyacetyl-5′-O-dimethoxytrityl-2′-O-{[(triisopropyl- silyl)oxy]methyl}-8-oxoguanosine-3′-yl-β-cyanoethyl-N,N-diisopropylphosphoramidite (5) was synt- hesized as a new phosphoramidite precursor unit for the synthesis of RNA. Compound 5 was successfully incorporated into the middle of the RNA sequences, and the synthesized RNAs were identified by MALDI-TOF mass measurements. Their properties were evaluated for formation of the RNA duplex and RNA/DNA heteroduplex. ORNs 1 and 4 containing 8-oxo-G can form base pairs with rC or dC in an anti conformation, while it can also interact with rA or dA in a syn conformation in the RNA duplex or RNA/DNA heteroduplex. The described synthetic method is therefore a useful procedure for the synthesis of ORN containing 8-oxo-G and contributes to the study of 8-oxo-G in RNA.     

Facile Synthesis of N-(1-Alkenyl) Derivatives of 2,4-Pyrimidinediones

Abstract

N-(1-alkenyl) derivatives of 2,4-pyrimidinediones (6–9) were prepared in a one pot synthesis from aldehydes and the nucleobases using trimethylsilyl trifluoromethanesulfonate (TfOTMS) as coupling reagent. Presilylation of the above nucleobases, and N ⁶-benzoyladenine, with excess N,O-bis(trimethylsilyl)acetamide (BSA) followed by addition of one mol eq. TfOTMS yielded the N-(1-trimethylsilyloxyalkyl) derivatives 1–5.     

Improved Targeting of the Flanks of a DNA Stem Using α-Oligodeoxynucleotides.-The Enhanced Effect of an Intercalator

Abstract

2′-Deoxy-5′-0-(4,4′-dimethoxytrityl)-5-methyl-N ⁴-(1-pyrenylmethyl)-α-cytidine (5) was prepared by reaction of 1-pyrenylmethylamine with an appropriate protected 4-(l,2,4-triazolyl)-α-thymidine derivative 3 which was synthesized from 5-O-DMT protected α-thymidine 1. Aminolysis of 3 afforded 3′-O-acetyl-2′-deoxy-5′-O-(4,4′-dimethoxytrityl)-5-methyl-α-cytidine (8). Benzoylation of 8 and removal of acetyl afforded N ⁴-benzoyl-2-deoxy-5–0-(4,4′-dimethoxytrityl)-5-methyl-α-cytidine (10). The amidites of compounds 5and 10 were prepared and used in α-oligonucleotide synthesis. DNA three-way junction (TWJ) is stabilized when an α-ODN is used for targeting the dangling flanks of the stem in a DNA hairpin. Further stabilization of the TWJ is observed when 5 is inserted into the α-ODN at the junction region.

     

Asymmetric hydrogenation of dehydrodipeptides bearing different protecting groups

Summary.  N-[(Z)-N-Benzoyl- or N-boc-(2-fluorophenyl)dehydroalanyl]-(R)- or (S)-phenyl-alanines 1,2,5 and 6 were hydrogenated in the presence of chiral and achiral rhodium complexes. The optical induction is compared to the results obtained using the corresponding esters as substrates. Received November 11, 2001 Accepted January 15, 2002     

Synthesis and bioactivity of 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-xylopyranosyl-1,3,4-oxa(thia)diazol-2-amines

A series of new N′-[N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)thiocarbamoyl]-2-[(1-aryl-1H-tetrazol-5-yl)sulfanyl]acetohydrazides 5a–5e were synthesized rapidly in high yields from 2-(1-aryl-1H-tetrazol-5-ylsulfanyl)acetohydrazides 3a–3e and 2,3,4-tri-O-acetyl-β-d-xylopyranosyl isothiocyanate 4, then 5a–5e were converted to a series of new 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-oxadiazole-2-amines 6a–6e and 5-(1-aryl-1H-tetrazol-5-ylsulfanylmethyl)-N-(2,3,4-tri-O-acetyl-β-d-xylopyranosyl)-1,3,4-thiadiazole-2-amines 7a–7e, respectively under mercuric acetate/alcohol system or acetic anhydride/phosphoric acid system, then deacetylated in the solution of CH₃ONa/CH₃OH. All of the novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The structures of compounds 2e, 3e, 5a and 5c have been determined by X-ray diffraction analysis. Some of the synthesized compounds displayed PTP1B inhibition and microorganism inhibition.     

Insights into biological activity of ureidoamides with primaquine and amino acid moieties

Primaquine (PQ) ureidoamides 5a–f were screened for antimicrobial, biofilm eradication and antioxidative activities. Susceptibility of the tested microbial species towards tested compounds showed species- and compound-dependent activity. N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]-4-methylpentanamide (5a) and 2-(4-chlorophenyl)-N-(diphenylmethyl)-2-[({4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamoyl)amino]acetamide (5d) showed antibacterial activity against S. aureus strains (MIC?=?6.5?µg/ml). Further, compounds 5c and 5d had weak antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. None of the tested compounds showed a wide spectrum of antifungal activity. In contrast, most of the compounds exerted strong activity in a biofilm eradication assay against E. coli, P. aeruginosa and Candida albicans, comparable to or even higher than gentamycin, amphotericin B or parent PQ. The most active compounds were 5a and 5b. Tested compounds were inactive against biofilm formation by C. parapsylosis, Enterococcus faecalis, C. tropicalis and C. krusei. Compounds 5b–f significantly inhibited lipid peroxidation (80–99%), whereas compound 5c presented interesting LOX inhibition.     

Synthesis of Hydantoin Nucleosides with Naphthylmethylene Substituents in the 5-Position

Abstract

(Z)-5-(Naphthylmethylene)-2-thiohydantoin derivatives (3a,b,12a-d) were prepared directly fiom condensations of 2-thiohydantoin derivatives (1,l la,b) with naphthaldehydes. Bisglycosylation took place on reaction of (Z)-5-(naphthylmethylene)- 2-thiohydantoin derivatives (3a,b) with glycosyl halides (4a,b) under alkaline conditions. The bisglycosilated hydantoins produced N₃ glycosylated hydantoins on treatment with ammonia in methanol. (Z)-5-(2-Naphthylmethylene)-2-(benzylidene E-hydrazono)hydantoin (9a) and (Z)-5-(2-naphthylmethylene)-2-(polyhydroxyalkylidene E-hydrazono)hydantoins (9b,c) were prepared fiom the reaction of (Z)-5-(2-naphthyylmethylene)-2- methylmercaptohydantoin (7) with benzylidene E-hydrazone (8a) and monosaccharide E-hydrazones (8b,c). S-Glycosylation also took place when N₃ substituted hydantoins were reacted. The hydantoin nucleosides were tested for their potential activity against HTV and HSV.     

An Improved Synthesis of N6-(6-Aminohexyl)FAD

Abstract

We report an improved synthesis of N ⁶-(6-aminohexyl)FAD (1) using an efficient one-pot conversion of inosine to the N-trifluoroacetyl protected N ⁶-(6-aminohexyl)adenosine 3. The 5′-O-phosphorylated AMP derivative 4, activated as the imidazolide, was coupled with commercial sodium riboflavin phosphate by using 18-crown-6 in DMF.     

Novel achiral titanocene anti-cancer drugs synthesised from bis-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-dimethylamino fulvene and lithiated heterocyclic compounds

Abstract From the carbolithiation of 6-bis-N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl₄ resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC₅₀-values obtained were of 240, and 270 μM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC₅₀-value of 36 μM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC₅₀ = 5.5 μM) and almost ten times less cytotoxic than cisplatin, which showed an IC₅₀-value of 3.3 μM, when tested on the LLC-PK cell line. Graphical abstract Bis-(bis- (N,N-dimethylamino)-2-(N′-methylpyrrolyl)methylcyclopentadienyl) titanium (IV) dichloride, {η⁵-C₅H₄-CH[N(CH₃)₂]₂[C₅H₃NCH₃]}₂TiCl₂ was synthesised starting from 6-bis-(N,N-dimethylamino) fulvene and 2-N-methylpyrrolyl lithium. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Interaction of (2′ -5′) and (3′ -5′) Linked 2-Aminoadenylyl-3-aminoadenosines with Polyuridylic Acid

Abstract

2′-5′ and 3′-5′ linked 2-aminoadenylyl-2-aminoadenosines [(2′-5′)n²Apn²A (1) and (3′-5′)n²Apn²A (2)] were synthesized by condensation of 5′-O-monomethoxytrityl-N ² N ⁶-dibenzoyl-2-aminoadenosine and N ²,N ⁶,2′,3′-O-tetrabenzoyl-2-aminoadenosine 5′-phosphate using dicyclohexylcarbodiimide (DCC). The conformational properties of these dimers 1 and 2 were examined by UV, NMR and CD spectroscopy. The results reveal that the 2′-5′-isomer 1 takes a stacked conformation, which contains a larger base-base overlap and is more stable against thermal perturbation with respect to the 3′-5′-isomer 2. Interactions of 1 and 2 with polyuridylic acid (Poly (U)) were also examined by Tm, mixing curves, UV and CD spectra. Both the dinucleoside isomers 1 and 2 formed a complex of 1 : 2 stoichiometry with poly(U), which was much more stable than that of the corresponding ApA isomer     

Synthesis and Conformational Analysis of A Novel Type of Spin Labelled Bicyclonucleoside Based on A Tetrahydrofurano[2,3-c]Pyrrolidine Sugar Skeleton

Abstract

Bicyclonucleosides bearing a 5-deoxy-5-N-hydroxyamino-3,N ⁵-(1,1-ethano)-β-o-furanosyl sugar moiety (15–18) have been prepared by glycosidation of the corresponding bicyclosugars obtained via an intramolecular reverse Cope elimination. The configuration of the asymmetric carbon of the 1,1-ethano bridge is the most important factor directing the conformation of the N-hydroxypyrrolidine ring and its invertomers ratio as shown by variable temperature H NMR experiments.     

Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC₅₀ = 5.67 μm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC₅₀ = 6.1 μm) and oral (IC₅₀ = 4.17 μm) cancers. These compounds could be of use in designing new anti-cancer agents.     

8-Aza-1-deazapurine Nucleosides as Antiviral Agents

Abstract

2′,3′-Dideoxy-8-aza-1-deazaadenosine (21) and its α-anomer (20) were synthesized via glycosylation of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridi-ne with 2,3-dideoxy-5-O-[(1, 1)-dimethylethyl)diphenylsilyl]-D-glycero-o-pen-tofuranosyl chloride. The reaction gave a mixture of α- and β-anomers of N³-, N⁴- and N¹-glycosylated regioisorners (12–15). The α- and β-anomers of the N⁴-glycosylated isomer 26 and 27 were also synthesized through the glycosylation of 8-aza-1-deazaadenine with 1-acetoxy-2,3-dideoxy-5-O-f(1,1-di-methylethyl)dimethylsilyl]-D-glycero-pentouranose. These dideoxynucleo-sides and a series of previously synthesized 8-aza-1-deazapurine nucleosidcs were tested for activity against several DNA and RNA viruses, HIV-1 included. The α- and β-anomers of 7-chloro-3-(2-deoxy-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (3a and 4) showed activities against Sb-1 and Coxs viruses. The α- and β-anomers of 2′,3′-dideoxy-8-aza-1-deazaadenosine (20 and 21) were found active as inhibitors of adenosine deaminase.     

Synthesis and Anti-HIV Activity of 5-Fluorocytallene: N-Dimethylaminomethylene as a Facilitating Group in Acetylene → Allene Isomerization

Abstract

The synthesis and biological activity of 5-fluorocytallene (3a) is described. 5-Fluorocytosine (4) was alkylated with 1-benzoyloxy-4-bromo-2-butyne (5) to give N¹-(4-benzoyloxy-2-butyn-1-yl)-5-fluorocytosine (6). Debenzoylation led to N¹-(4-hydroxy-2-butyn-1-yl)-5-fluorocytosine (7a). The latter compound was transformed to the N⁴-dimethylaminomethylene derivative 8 which was isomerized in situ to the corresponding allene 9. Deprotection afforded 5-fluorocytallene (3a). Compound 3a suppressed the infectivity and replication of both laboratory and primary HIV-1 strains in vitro at nontoxic concentrations.     

Palladium-Mediated Coupling Reactions of an Aminosubstituted Heterocycle. Direct Synthesis of C-Nucleosides Related to Adenosine

Abstract

C-Nucleosides of the pyrazolo[1, 5-a]-1, 3, 5-triazine aglycon system have been prepared by palladium-mediated coupling of 8-iodopyrazolo[1, 5-a]-1, 3, 5-triazines. 4-(N, N-Diisobutyloxycarbonyl)amino-8-iodopyrazolo[1, 5-a]-1, 3, 5-triazine and the furanoid glycal 1, 4-anhydro-2-deoxy-3-O[(1, 1 dimethylethyl)diphenylsilyl]-D-erythro-pent-1-enitol coupled in the presence of catalytic palladium(0) to yield, after desilylation of the intermediate silyl enol ether, a C-glycoside analog of adenosine.     

Isobutyl Amides from Pepper (Piper nigrum L.)

Four isobutyl amides were isolated from the fruits of white pepper (Piper nigrum L.) and identified to be N-isobutyl-13-(3,4-methylenedioxyphenyl)-2E,4E,12E-tridecatrienamide (3, guineensine), N-isobutyl-2E,4E,8Z-eicosatrienamide (5), N-isobutyl-2E,4E-octadecadienamide (6) and N-isobutyl-2E,4E-decadienamide (7, pellitorine).