Nucleosides,LVIII1 Synthesis of Base - Modified Oligonucleotides Containing 6- and 7-Aryl Lumazines

Abstract

6-Phenyl-, 7-phenyl-, 6-(4-biphenyl)- 7-(4-biphenyl)lumazine N-1-2-deoxy-β-D-ribofuranosides were synthesized, then converted into the corresponding 5′-O-dimethoxytrityl-3′-O-(β-cyanoethyl, N,N-diisopropyl)phosphoramidites and incorporated into different positions of self-complementary oligonucleotides. The influence of modifications on the melting temparature of the resulting duplexes was studied.

     

Synthesis of Potential Pyrimidine Derivatives via Suzuki Cross-Coupling Reaction as HIV and Kinesin Eg5 Inhibitors

A series of 4-amino-5-((4-chlorophenyl)diazenyl)-6-(alkylamino)-1-methylpyrimidin-2-one deri- vatives 7–16 were prepared by nucleophilic displacement of 6-chloro-pyrimidine 6 by various amines. 4-Amino-5-((aryl-4-yl)diazenyl)-6-aryl-1-methylpyrimidin-2-one analogs 19–27, as well as 4-amino-5-((aryl-[1,1′-biphenyl]-4-yl)diazenyl)-6-aryl-1-methylpyrimidin-2-one 29–31 and 4-amino-6-aryl-1-methylpyrimidin-2-one 34–34, were synthesized via Suzuki cross-coupling reaction, using Pd(PPh₃)₄ as a catalyst and arylboronic acids as reagents. All compounds were evaluated for their antiviral activity against the replication of HIV-1 and HIV-2 in MT-4. Compounds 6, 16, 27, and 29 showed a 50% effective concentration of >2.15, >3.03, >2.29, and >1.63 μM, respectively, but no selectivity was observed (selectivity index < 1). Two of the newly synthesized pyrimidines 12 and 29 exhibited moderate kinesin Eg5 inhibition.     

Transglycosylation Reactions of 6-Thioguanine Acyclonucleosides

Abstract

9-(2-Acetoxyethoxy)methyl-N²-acetyl-6-thioguanine (2) undergoes two different transglycosylation reactions: i) the 7 ? 9 isomerization, which gives the respective 7-regioisomer (3) as the major product, ii) the 9 ? S⁶ glycosyl migration, which leads to a 9,S⁶-disubstituted product (4). S⁶-Methylation completely stopped the reversibility of transglycosylation.     

Substituent — Directed Aralkylation and Alkylation Reactions of the Tricyclic Analogues of Acyclovir and Guanosine

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine (6-R-TACV)¹ 1 partly directs aralkylation reactions into unusual positions: N-4 to give 3 and C-7 to give N-5, 7-disubstituted or N-4, 7-disubstituted derivatives. In the case of alkylation the effect is limited to aryl substituent and position N-4. Replacement of acyclic moiety of 1 with a ribosyl one like in 7 prevents N-4 substitution. Cleavage of the third ring of 3b to give 3-benzylacyclovir 10 is an example of a new short route to 3-aralkyl-9-substituted guanines.     

Synthesis and Fluorescent Properties of 6-(4-Biphenylyl)-3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine Analogues of Acyclovir and Ganciclovir

Abstract

Tricyclic (T) analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2) carrying the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system [i.e., 6-(4-BrPh)TACV, 5 and 6-(4-BrPh)TGCV, 6] were transformed into 6-[(4′-R²)-4-biphenylyl] derivatives of TACV (7–9) and TGCV (10–12) by Suzuki cross coupling with 4-substituted phenylboronic acids. Compound 11 (R² = CH₂OH) showed a high (～1000) selectivity index against herpes simplex virus type 1 (HSV-1) together with advantageous fluorescence properties (emission in visible region, little overlap with absorption and moderate intensity).     

Stereoselective Approach to the Z-Isomers of Methylenecyclopropane Analogues of Nucleosides: A New Synthesis of Antiviral Synguanol

Stereoselective synthesis of antiviral synguanol (1) is described. Reaction of 6-benzyloxy-2-(dimethylaminomethyleneamino)purine (10) with ethyl (cis,trans)-2-chloro-2-(chloromethyl) cyclopropane-1-carboxylate (2c) under the conditions of alkylation-elimination gave (Z)-6- benzyloxy-2-formylamino-9-[(2-carbethoxycyclopropylidene)methyl]purine (11) but no E,N⁹-isomer. Minor amounts of (Z)-6-benzyloxy-2-formylamino-7-[(2-carbethoxy-cyclopropylidene)methyl]purine (13) were also obtained. Hydrolysis of compounds 11 and 13 in 80% acetic acid afforded (Z)-9-[2-(carbethoxycyclopropylidene)methyl]guanine (14) and (Z)-7-[2-(carbethoxy- cyclopropylidene)methyl]guanine (15). Reduction of 14 furnished synguanol (1). Reaction of N⁴-acetylcytosine (7) with ester 2c led to (Z,E)-1-(2-carbethoxycyclopropropylidenemethyl)cytosine (8, Z/E ratio 6.1:1). Basicity of purine base, lower reactivity of alkylation intermediates as well as interaction of the purine N³ or cytosine O² atoms with the carbonyl group of ester moiety seem to be essential for the observed high stereoselectivity of the alkylation-elimination. The Z-selectivity is interpreted in terms of E1cB mechanism leading to a transitory “cyclic” cyclopropenes which undergo a cyclopropene-methylenecyclopropane rearrangement.     

Design,synthesis and evaluation of some 1,3,5-triazinyl urea and thiourea derivatives as antimicrobial agents

In an effort to establish new candidates with improved antimicrobial activities we report here the synthesis and in vitro biological evaluation of various series of compounds (5a-j) and (7a-j) which were evaluated against two Gram positive (S. aureus, B. subtilis), two Gram negative (S. typhosa, E. coli) strains and a yeast-like fungi (C. albicans) using the micro-dilution procedure. Among the synthesized compounds 2-(cyclohexyl amino)-4-(3,4-dimethoxy phenyl ethyl thioureido)-6-(2-chloro phenyl ureido) s-triazine (7e) and 2-(cyclohexyl amino)-4-(3,4-dimethoxy phenyl ethyl thioureido)-6-(4-chloro phenyl ureido) s-triazine (7g) proved to be effective with MIC (0.019 mg ML^?1) against S. typhosa & E. coli respectively.     

Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph₃P/Py/NH₄OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N¹-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Synthesis of new N,N′-bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides and evaluation of their cytotoxicity against human hepatoma and breast cancer cells

Abstract

N,N′-Bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides were synthesized by the reaction of 2 mols of 1-aryl-3-(piperidine-1-yl)-1-propanone hydrochlorides with 1?mol of hydrazine hydrate. Aryl part was C₆H₅ (P1), 4-CH₃C₆H₄ (P2), 4-CH₃OC₆H₄ (P3), 4-HOC₆H₄ (P4), 4-ClC₆H₄ (P5), 3-CH₃OC₆H₄ (P6), 4-FC₆H₄ (P7) and 4-BrC₆H₄ (P8). Except P1, all compounds were reported for the first time. The chemical structures were confirmed by UV, ¹H NMR, ¹³C NMR and HRMS spectra. P1, P2, P7 and P8 against human hepatoma (Huh7) cells and P1, P2, P4, P5, P6, P7 and P8 against breast cancer (T47D) cells have shown cytotoxicity. P1, P2 and P7 had more potent cytotoxicity against Huh7 cells than the reference compound 5-FU, whereas only P2 was more potent than the 5-FU against T47D cells. Representative compound P7 inhibited the mitochondrial respiration at 144, 264 and 424?µM concentrations dose-dependantly in liver homogenates. The results suggest that P1, P2, P7 and P8 may serve as model compounds for further synthetic studies.     

Synthesis of Base Substituted 2-Hydroxy-3-(purin-9-yl)-propanoic Acids and 4-(Purin-9-yl)-3-butenoic Acids

Abstract

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N⁶-substituted adenines (5a–5c) and 2,6-diaminopurines (5d–5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8–10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

Two-Electron Aromatics with Classical and Non-Classical Homobridges

Bishomotriborirane anions with a B-H-B bridge, 7, have been synthesized by a) protonation and b) methylation of bishomodianions, 3, as well as by c) hydride addition to 1,2,4-triboracyclopentanes, 15. Compounds 7 were characterized by ¹H, ¹³C and ¹¹B NMR spectroscopy and X-ray diffraction analyses. The suggested mechanism for the formation of 7 is supported by MP4SDTQ/6-311++G**//MP2(fc)/6-31+G* computations on [C₂B₃H₈]^- model compounds. Classical 1,2-dibora-4-borata-cyclopentane intermediates 16 undergo an intramolecular hydrogen shift to the B-B unit in their envelope conformation to give intermediates 17, which easily isomerize to 7. Relative energies for the parent compounds, 16u, 17u, 7u and the transition structures, TS-16/17u and TS-7/17u are predicted to be 30.7, 14.5, 0.0, 32.6 and 23.5 kcal mol^-1, respectively. The terms classical and non-classical homobridges are suggested for methylene and hydrogen bridges in 7 and in related compounds on the grounds of common building principles. The strength of homoaromaticity in 7u was estimated to be at least 23.5 kcal mol^-1, neglecting the much higher strain in 7u compared to TS-7/17u without a 3c2e bond.Electronic Supplementary Material available.     

Design,Synthesis, and Anti-Tumor Activity of 4′-Thionucleosides as Potent and Selective Agonists at the Human A3 Adenosine Receptor

On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A₃ adenosine receptor, its 4′-thioadenosine derivatives were efficiently synthesized starting from D-gulonic γ -lactone. Among compounds tested, 2-chloro-N ⁶-(3-iodobenzyl)- and 2-chloro-N ⁶-methyl-4′ -thioadenosine-5′ -methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K _i = 0.38 nM and 0.28 nM, respectively) at the human A₃AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.     

Synthesis and Evaluation of Antimicrobial Activity of Some Pyrimidine Glycosides

Reaction of ethyl 4-thioxo-3,4-dihydropyrimidine-5-carboxylate derivatives 1a,b and ethyl 4-oxo-3,4-dihydropyrimidine-5-carboxylate 1c with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in KOH or TEA afforded ethyl 2-aryl-4-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosylthio or/ oxy)-6-methylpyrimidine-5-carboxylate 6a-c. The glucosides 6a and 6b were obtained by the reaction of 1a and 1b with peracetylated glucose3 under MW irradiation. Mercuration of 1a followed by reaction with acetobromoglucose gave the same product 6a. The reaction of 1a-c with peracetylated ribose 4 under MW irradiation gave ethyl 2-aryl-4-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosylthio)-6-methylpyrimidine-5-carboxylate 8a–c. The deprotection of 6a–c and 8a–c in the presence of methanol and TEA/H₂O afforded the deprotected products 7a–c and 9a–c. The structure were confirmed by using ¹H and ¹³CNMR spectra. Selected members of these compounds were screened for antimicrobial activity.     

Photodimerizations of hydroxy- and benzoylated 4-azachalcones and quantum chemical investigation of the reactions

Photodimerization reactions of compounds 4–6 gave four new cyclobutane-containing compounds (7–9) with full control over the stereochemistry at the four stereogenic centers. These new cyclobutane-containing compounds had β-truxinic (7a), δ-truxinic (7b and 9), and ε-truxillic (8) structures. However, o-, m-, and p-hydroxy 4-azachalcones (1–3) did not give photochemical cyclization products under any conditions (in solvent or in their solid or molten states). Experimental data suggested the possibility of frontier orbital control over stereochemical behavior, so some theoretical calculations were performed. Full geometrical optimization of compounds 1–9 was performed via DFT B3LYP/6-31⁺G**, and their electronic structures were also investigated. The geometries of the singlet and triplet states were initially optimized by density functional theory (DFT) and the configuration interaction singles (CIS) B3LYP/3-21⁺G** level. An additional calculation was performed for the triplet state using the ground-state geometry. The possible photochemical dimerization products of compounds 7–9 (a–g) and the intrinsic reaction coordinates (IRCs) of the reactions of compounds 4–6 were calculated theoretically by the DFT/3-21⁺G** method. The configurations (reactant, transition state, product, and reaction pathway) corresponding to the stationary points (minima or saddle points) were determined. The intrinsic reaction coordinates were followed to verify the energy profiles that connect each TS to the appropriate local minimum. The dimeric products expected from the calculations coincided with the dimers produced experimentally.     

An Efficient Synthesis Of Acyclic N7- and N9-Adenine Nucleosides Via Alkylation With Secondary Carbon Electrophiles to Introduce Versatile Functional Groups At the C-1 Position of Acyclic Moiety

The introduction of versatile functional groups, allyl and ester, at the C-1 position of the acyclic chain in acyclic adenine nucleosides was achieved for the first time directly by alkylation of adenine and N⁶-protected adenine. Thus, the C-1′-substituted N⁹-adenine acyclic nucleoside, adenine-9-yl-pent-4-enoic acid ethyl ester (11), was prepared by direct alkylation of adenine with 2-bromopent-4-enoic acid ethyl ester (6), while the corresponding N⁷-regioisomer, 2-[6, (dimethylaminomethyleneamino)-purin-7-yl]-pent-4-enoic acid ethyl ester (10), was obtained in one step by the coupling of N,N-dimethyl-N′- (9H-purin-6-yl)-formamidine (9) with 2-bromopent-4-enoic acid ethyl ester (6). The functional groups, ester and allyl, were converted to the desired hydroxymethyl and hydroxyethyl groups, and subsequently to phosphonomethyl derivatives and corresponding pyrophosphorylphosphonates.     

SYNTHESIS AND CHARACTERIZATION OF NUCLEOSIDE DERIVATIVES,N-(BENZOYL)-N-(DEOXYGUANOSIN-8-YL)-4-AMINOBIPHENYL AND N-(2′-DEOXYGUANOSIN-8-YL)-4-AMINOBIPHENYL VIA α-PHENYL-N-(4-BIPHENYL)NITRONE

ABSTRACT

Lead tetraacetate (LTA) oxidation of α-Phenyl-N-(4-biphenyl)nitrone (8) to give a new ultimate carcinogen, N-acetoxy-N-benzoyl-4-aminobiphenyl (9) which was reacted with deoxyguanosine (dG) at pH 6.9 to give nucleoside derivative, N-(benzoyl)-N-(deoxyguanosin-8-yl)-4-aminobiphenyl (10). Following debenzoylation with sodium carbonate-methanol leads to N-(2′-deoxyguanosin-8-yl)-4-aminobiphenyl (11).     

Synthesis of “Reversed” Methylenecyclopropane Analogues of Antiviral Phosphonates

Synthesis of “reversed” methylenecyclopropane analogues of nucleoside phosphonates 6a,7a, 6b, and 7b is described. 1-Bromo-1-bromomethylcyclopropane 8 was converted to the bromocyclopropyl phosphonate 9 by Michaelis-Arbuzov reaction with triisopropyl phosphite. Base-catalyzed β-elimination and deacetylation gave the key Z- and E-hydroxymethylcyclopropyl phosphonates 10 and 11 separated by chromatography. The Mitsunobu type of alkylation of 10 or 11 with adenine or 2-amino-6-chloropurine afforded phosphonates 12a, 12b, 13a, and 13b. Acid hydrolysis furnished the adenine and guanine analogues 6a, 7a, 6b, and 7b. The E and Z configuration was assigned on the basis of NOE experiments with phosphonates 6b and 7b. All Z- and E-isomers were also distinguished by different chemical shifts of CH₂O or CH₂N (H₄ or H_4′). Significant differences of the chemical shifts of the cyclopropane C_3(3’) carbons and coupling constants ³J_P,C2(2’) or ³J_P,C3(3’) selective for the Z- or E-isomers were also noted. Phosphonates 6a, 7a, 6b, and 7b are devoid of significant antiviral activity.     

SECO C-NUCLEOSIDE ANALOGS OF THE 1,2,4-TRIAZOLE

The seco C-nucleosides 3-(1,2,3,4,5-penta-O-acetyl-D-gluco- and D-galacto-pentitol-1-yl)-1H-1,2,4-triazoles (6 and 7) were obtained in one pot by deamination and dethiolation of 4-amino-3-(D-gluco- and D-galacto-pentitol-1-yl)-5-mercapto-1,2,4-triazoles (1 and 2), respectively, using sodium nitrite in orthophosphoric acid and subsequent acetylation. The structures were confirmed by using ¹H, ¹³C and 2D NMR spectra, DQFCOSY, HMQC and HMBC experiments. The favored conformational structures were deduced from the vicinal coupling constants of the protons.     

Nucleosides Having Quinolone Derivatives as Nitrogenated Base: Regiospecific and Stereospecific Ribosylation of 3-Carbethoxy-1,4-dihydro-4-oxoquinolines

Abstract

Ribosylation reactions of previously silylated 3-carbethoxy-8-methyl-1,4-dihydro-4-oxoquinoline (6a) and 3-carbethoxy-6-methyl-1,4-dihydro-4-oxoquinoline (6b) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (7), under Lewis acid catalysis, were studied. The method using hexamethyldisilazane (HMDS)/trimethylchlorosilane (TMCS) mixture for silylation and anhydrous stannic chloride as catalyst for ribosylation failed to give any nucleoside product. On the other hand, the protected nucleoside 3-carbethoxy-6-methyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,4-dihydro-4-oxoquinoline (8b) was obtained in good yields using bis(trimethylsilyl)trifluoroacetamide (BSTFA) containing 1% of TMCS and the same catalyst. Compound 8b was more easily isolated in higher yields with an improvement of the later method by replacing stannic chloride with trimethylsilyl trifluoromethanesulfonate (TMSOTf).

De-O-benzoylation of 8b with methanolic sodium hydroxide solution afforded the free riboside 3-carbomethoxy-6-methyl-1-β-D-ribofuranosyl-1,4-dihydro-4-oxoquinoline (9b). The structures of the obtained products were confirmed by their LTV, MS, IR, ¹H and ¹³C-NMR data.     

Synthesis and Antibacterial Activity Evaluation of Biphenyl and Dibenzofuran Derivatives as Potential Antimicrobial Agents against Antibiotic-Resistant Bacteria

The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, a series of biphenyl and dibenzofuran derivatives were designed and synthesized by Suzuki-coupling and demethylation reactions in moderate to excellent yields (51–94% yield). Eleven compounds exhibited potent antibacterial activities against the prevalent antibiotic-resistant Gram-positive and Gram-negative pathogens, among which compounds 4′-(trifluoromethyl)-[1,1′-biphenyl]-3,4,5-triol (6i) and 5-(9H-carbazol-2-yl) benzene-1,2,3-triol (6m) showed the most potent inhibitory activities against methicillin-resistant Staphylococcus aureus and multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 3.13 and 6.25 μg/mL, respectively. Compounds 3′,5′-dimethyl-[1,1′-biphenyl]-3,4,4′,5-tetraol (6e), 4′-fluoro-[1,1′-biphenyl]-3,4,5-triol (6g), and 4′-(trifluoromethyl)-[1,1′-biphenyl]-3,4,5-triol (6i) showed comparable inhibitory activities with ciprofloxacin to Gram-negative bacterium carbapenems-resistant Acinetobacter baumannii. Study of the structure–activity relationship indicated that a strong electron-withdrawing group on the A ring and hydroxyl groups on the B ring of biphenyls were beneficial to their antibacterial activities, and for benzo-heterocycles, N-heterocycle exhibited optimal antibacterial activity. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.