Synthesis and antinociceptive-antimicrobial activities of some new amide derivatives of 3,5-di/-and 1,3,5-trimethylpyrazoles

Some N-(3,5-di-/1,3,5-trimethylpyrazole-4-yl)-4-substitutedbenzamide derivatives were prepared as possible antiociceptive-antimicrobial agents. New amide derivatives (3–12) were synthesized by reacting 4-amino-3,5-di and 1,3,5-trimethylpyrazoles with 4-substitutedbenzoyl chlorides. Hotplate and tail-immersion tests were used for the determination of the antinociceptive activity. Morphine, was used as a standard test drug. All compounds were administered at a dose of 100 mg/kg ip and some of them had significant antinociceptive activity in both tests. Compound 10 (N-(1,3,5-trimethylpyrazole-4-yl)-4-bromobenzamide), was the most active one in both tests among the compounds. The antinociceptive activity of the compounds 10, 11 (N-(1,3,5-trimethylpyrazole-4-yl)-4-chlorobenzamide), and 12 (N-(1,3,5-trimethylpyrazole-4-yl)-4-fluorobenzamide), started at 30 minutes and continued up to 150 minutes in the hotplate test. Also compounds were tested for their in vitro antimicrobial activity, but exhibited weak antibacterial activity.     

Irreversible,Tight-Binding Inhibition of Adenosine Deaminase by Coformycins: Inhibitor Structural Features That Contribute to the Mode of Enzyme Inhibition

Abstract

Coformycin analogues 1–6 were synthesized and biochemically screened against adenosine deaminase in order to assess the relative contributions of N-4, N-6, and the N-3 sugar moiety to the mode of enzyme inhibition. Our results indicate that N-4 plays a relatively greater role than N-6 in enzyme tight-binding, and that a benzyl group can substitute for the sugar moiety at N-3. The absence of a sugar or benzyl group at N-3, however, leads to loss of activity. The hydroxyl group at C-8, while crucial for activity, does not alone confer the tight-binding characteristics to coformycins.     

The Derivatives of Phosphorothioate Oligonucleotides

Abstract

Derivatives of phosphorothioate oligonucleotide analogues bearing alkylating N-methyl-4-(N-2-chloroethyl)-N-methylamino)benzylamine or stabilizing complementary complexes N-(2-hydroxyethyl)phenazinium residues at the 3′-terminal phosphate group were synthesized and investigated.     

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.     

Dietary omega-6/omega-3 fatty acids and risk of prostate cancer; Is there any potential interaction by organophosphate insecticides among the agricultural health study population

BackgroundIn the United States (US), the average annual increase in the incidence of prostate cancer (PCa) has been 0.5% between 2013 and 2017. Although some modifiable factors have been identified as the risk factors for PCa, the effect of lower ratio of omega-6 to omega-3 fatty acids intake (N-6/N-3) remains unknown. Previous studies of the Agricultural Health Study (AHS) reported a significant positive association between PCa and selected organophosphate pesticides (OPs) including terbufos and fonofos.ObjectiveThe aim of this study was to evaluate the association between N-6/N-3 and PCa and any interaction between N-6/N-3 and 2 selected OPs (i.e., terbufos and fonofos) exposure.Design and ParticipantsThis case-control study, nested within a prospective cohort study, was conducted on a subgroup of the AHS population (1193 PCa cases and 14,872 controls) who returned their dietary questionnaire between 1999 and 2003Main Outcome MeasuresPCa was coded based on the International Classification of Diseases of Oncology (ICD-O-3) definitions and obtained from the statewide cancer registries of Iowa (2003–2017) and North Carolina (2003–2014).Statistical AnalysisMultivariate logistic regression analysis was applied to obtain the odds ratios adjusted (aORs) for age at dietary assessment (years), race/ethnicity (white, African American, other), physical activity (hours/week), smoking (yes/no), terbufos (yes/no), fonofos (yes/no), diabetes, lycopene intake (milligrams/day), family history of PCa, and the interaction of N-6/N-3 with age, terbufos and fonofos. Pesticide exposure was assessed by self-administrated questionnaires collecting data on ever/never use of mentioned pesticides during lifetime as a yes/no variable. Assessing the P value for the interaction between pesticides and N-6/N-3, we used the continuous variable of “intensity adjusted cumulative exposure” to terbufos and fonofos. This exposure score was based on duration, intensity and frequency of exposure. We also conducted a stratified regression analysis by quartiles of age.ResultsRelative to the highest N-6/N-3 quartile, the lowest quartile was significantly associated with a decreased risk of PCa (aOR=0.61, 95% CI: 0.41–0.90), and quartile-specific aORs decreased toward the lowest quartile (P_trend=<0.01). Based on the age-stratified analysis, the protective effect was only significant for the lowest quartile of N-6/N-3 among those aged between 48 and 55 years old (aORs=0.97, 95% CI, 0.45–0.55). Among those who were exposed to terbufos (ever exposure reported as yes in the self-report questionnaires), lower quartiles of N-6/N-3 were protective albeit nonsignificant (aORs: 0.86, 0.92, 0.91 in quartiles 1,2, and 3, respectively). No meaningful findings were observed for fonofos and N-6/N-3 interaction.ConclusionFindings showed that lower N-6/N-3 may decrease risk of PCa among farmers. However, no significant interaction was found between selected organophosphate pesticides and N-6/N-3.     

Synthesis of New 1,2,3-Triazole Acyclonucleoside Analogues of ACV and HBG

Abstract

1,3-dipolar cycloaddition of. N-9/N-1-propargylpurine/pyrimidine to the corresponding azido-compounds 9–10 produces acyclonucleoside analogues 13a-h, 14a-h in which the 4-methyl-1,2,3-triazole is used as spacer arm.     

The Novel 6–(N-Pyrrolyl)purine Acyclic Nucleosides: 1H and 13C NMR and X-ray Structural Study†

Abstract

Synthesis of the novel nucleoside analogues containing exocyclic pyrrolo moiety and acyclic side chains attached to the purine ring at N-9 and N-7 is described. The site of alkylation was determined by ¹H and ¹³C NMR on the basis of chemical shifts, C-H coupling constants and connectivity in NOESY and HETCOR spectra. The N-9 substitution of 7 was proved by its X-ray crystallographic analysis.

     

Coronary Vasoactivity of Novel N6-Substituted Adenosines

Abstract

Previous studies of the structure-coronary vasoactivity relationships of adenosines substituted at N-6 identified certain simple alkyl and aralkyl groups that can promote activity and others that reduce activity. The present study shows that such alkyl and aryl moieties, when combined in an N-6 substituent, can contribute additively to coronary vasoactivity.     

A New Simple Synthesis of N-2-Methylguanosine and Its Analogues Via Derivatives of 4-Desmethylwyosine (Nucleosides and Nucleotides. Part 631)

Abstract

Guanosine and 2′-deoxyguanosine have been converted into the corresponding N-2-methyl and N-2-ethyl derivatives in a simple, three-step procedure by N-5-alkylation of N-4-desmethylwyosines (4,5) and subsequent deprotection with N-bromosuccinimide.     

Synthesis of the Sulfonylpyrimidine Derivatives as a New Type of Sulfonylcycloureas

Abstract

The synthesis of several novel N-1 and N-1,NH-4-disulfonylpyrimidine derivatives are described.     

Arylamidation of Purine Nucleosides by 2-Acetylalkoxy- Aminofluorene - an Intramolecular Approach to the Synthesis of Nucleoside - Carcinogen Adducts

Abstract

Arylamidation of the guanosine ring at position C-8 by the carcinogen N-2acetylalkoxyaminofluorene was achieved using an intramolecular approach.     

Quantitative Parametrs of Cooperative Interactions of the Oligodeoxyribonucleotides on the Complementary Template

Abstract

The cooperative interactions of oligonucleotides on the complementary template were studied using the quantitative analysis of the template alkylation with the oligonucleotides bearing covalently attached 4-[N-(2-chloroethyl)-N-methylamino]benzyl group at 5′-end. The influence of the mismatched nucleotides and the stabilizing N-(2-hydroxyethyl)phenazinium group at the 5′- and 3′-ends of the oligonucleotides on the parameters of cooperativity was evaluated.     

Synthesis of cyclobutane nucleoside analogues 3: Preparation of carbocyclic derivatives of oxetanocin

Abstract

A synthesis of cyclobutene nucleoside analogs in which the nucleobase is tethered by a methylene group is described. The coupling of 6-chloropurine with 3-hydroxymethyl-cyclobutanone proceeds via its triflate to give both N-7 and N-9 regioisomers with relative yields corresponding to the calculated charge distribution of the 6-chloropurinyl anion. The stereoselective reduction of the N-alkylated ketones yielded quantitatively one stereoisomer in each case. The structural assignments were based on spectroscopic data and single crystal X-ray diffraction. Attempts to photoexcite the N-7 and N-9 ketones in order to promote ring-expansion did not ensue. Preliminary evidence suggests a photodecarbonylation to cyclopropanes took place.     

SYNTHESIS AND ANTI-HIV ACTIVITY OF NEW MODIFIED 1,2,3-TRIAZOLE ACYCLONUCLEOSIDES

The synthesis of 1,2,3-triazole acyclonucleosides 7a-h via 1,3-dipolar cycloaddition of N-9/N-1-propargylpurine/pyrimidine 2a-h with azido-pseudo-sugar 4 is described and none of them had anti-HIV activity.     

Synthesis of Novel Thiopurine Pyranonucleosides: Evaluation of Their Bioactivity

We report the synthesis of novel thiopurine pyranonucleosides. Direct coupling of silylated 6-mercaptopurine and 6-thioguanine with the appropriate pyranoses 1a–e via Vorbrüggen nucleosidation, gave the N-9 linked mercaptopurine 2a–e and thioguanine 4a–e nucleosides, while their N-7 substituted congeners 10a–e and 7a–e, were obtained through condensation of the same acetates with 6-chloro and 2-amino-6-chloropurines, followed by subsequent thionation. Nucleosides 3a–e, 5a–e, 8a–e, and 11a–e were evaluated for their cytostatic activity in three different tumor cell proliferative assays.     

Indole carboxamides inhibit bovine testes hyaluronidase at pH 7.0 and indole acetamides activate the enzyme at pH 3.5 by different mechanisms

Hyaluronidases are enzymes controlling many crucial physiological processes. Imbalanced enzymatic activity is connected with severe diseases. Because there is limited availability of drugs modulating hyaluronidase activity, the search for hyaluronidase interacting compounds is getting more and more important. A series of fifteen indole carboxamides and acetamides were synthesized and tested on inhibition of bovine testes hyaluronidase. In vitro assays were performed using stains-all at pH 7 and the Morgan-Elson reaction at pH 3.5. At neutral pH, the most active inhibitory compound was N-(Pyridin-4yl)-[5-bromo-1-(4-fluorobenzyl)indole-3-yl]carboxamide (20) with an IC₅₀ value of 46 μM. Surprisingly, inhibition of all compounds was completely abolished by a decrease in pH. At pH 3.5 the activity of the enzyme was increased up to 134% by compound N-(4,6-Dimethylpyridin-2yl)-(1-ethylindole-3-yl)acetamide (24) at a concentration of 100 μM. The known activating effect of bovine serum albumine (BSA) on hyaluronidase activity was verified in the assay and compared to the effect of compound 24. Structure-activity relationships are discussed and a model is proposed, which explains the increase in activity at pH 3.5 by bonding of the protonated form of N-(4,6-Dimethylpyridin-2yl)-(1-ethylindole-3-yl)acetamide (24) to hyaluronic acid. The bonding results in an elongated form of the substrate with easier enzymatic access.     

Synthesis,Protonation Behavior,Conformational Analysis,and Regioselective Enzymatic Acylation of the Novel Diamino Analogue of (E)-5-(2-Bromovinyl)-2′-deoxyuridine (BVDU)

Abstract

(E)-3′,5′-Diamino-5-(2-bromovinyl)-2′,3′,5′-trideoxyuridine (5), the diamino analogue of BVDU (1), was synthesized from BVDU. The protonation behavior of 5 has been studied by means of pH-metric measurements and NMR spectroscopy. This study allows the determination of the basicity constants and the stepwise protonation sites. Thus, the main species at physiological pH is the monoprotonated form. The conformational analysis of this nucleoside analogue was also carried out through ¹H NMR spectroscopy. In addition, a convenient synthesis of N-3′ and N-5′ acylated derivatives was developed by regioselective enzymatic acylation. Thus, Candida antarctica lipase B (CAL-B) selectively acylated the 5′-amino group, thus furnishing nucleosides 8. On the other hand, immobilized Pseudomonas cepacia lipase (PSL-C) exhibited the opposite selectivity, conferring acylation at the 3′-amino group, thus affording derivatives 9.     

Synthesis of Alkenyl Acyclonucleosides Derivatives of 5-Halogenouracil as Antiviral and Antitumoral Agents

Abstract

Alkenyl acyclonucleosides derivatives of 5-halogenouracil have been synthesized via Michael addition reaction. These compounds were treated by allylbromide, propargylbromide or ethylbromoacetate to give the corresponding N-1,N-3-disubstituted 5-halogenouracil.     

Phosphonylalkoxyalkyl and Phosphonylalkyl Derivatives of Heterocyclic Bases

Abstract

This review describes chemical syntheses of acyclic nucleotide analogs containing various types of phosphonate grouping, with an emphasis on preparative methods for N-(3-hydroxy-2-phosphonylmethoxypropyl) and N-(2-phosphonylmethoxyethyl) derivatives of purine and pyrimidine bases.     

Ligand structures of synthetic deoxa-pyranosylamines with raucaffricine and strictosidine glucosidases provide structural insights into their binding and inhibitory behaviours

Abstract

Insight into the structure and inhibition mechanism of O-β-d-glucosidases by deoxa-pyranosylamine type inhibitors is provided by X-ray analysis of complexes between raucaffricine and strictosidine glucosidases and N-(cyclohexylmethyl)-, N-(cyclohexyl)- and N-(bromobenzyl)-β-d-gluco-1,5-deoxa-pyranosylamine. All inhibitors anchored exclusively in the catalytic active site by competition with appropriate enzyme substrates. Thus facilitated prospective elucidation of the binding networks with residues located at <3.9?Å distance will enable the development of potent inhibitors suitable for the production of valuable alkaloid glucosides, raucaffricine and strictosidine, by means of synthesis in Rauvolfia serpentina cell suspension cultures.