Synthesis,anticancer activity,and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system

Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N⁶-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N⁶-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N⁶-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N⁶ and no attachment at N-1, or a combined C-10 at N⁶ and a CH₂Ph at N-1. Any alkyl chain shorter or longer than C-10 at N⁶ with a CH₂Ph attached at N-1, would result in decrease of biological 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.     

SYNTHESIS OF 5-ALKENYLATED D4T ANALOGUES VIA THE Pd-CATALYZED CROSS-COUPLING REACTION

The target compounds 5-[N-(6-amino-hexyl)-acrylamide]-2′,3′-didehydro-2′,3′-dideoxy-uridine (12) and 5-{N-[5-(methoxycarbonyl)-pentyl]-acrylamide}-2′,3′-didehydro-2′,3′-dideoxy-uridine (15) were prepared by the palladium acetate-triphenylphosphine-catalyzed reaction of the 5′-O-acetyl-5-iodo-d4T analogue (3). These compounds 12 and 15 can be used to prepare nucleotide probes carrying fluorescent labels and were nevertheless screened for their anti-HIV activity. The biological data demonstrated that none of them were active against HIV-1.     

New AZT Analogues Having 5′-Alkylsulfonyl Groups: Synthesis and Anti-HIV Activity

New derivatives of azidothymidine (AZT) substituted by alkyl and alkylsulphonyl groups at N-3 and C-5′, respectively, have been synthesized. The new synthesized derivatives showed remarkable anti-HIV-1 and HIV-2 activity in MT-4 cells. Compounds 8 and 10 have IC₅₀ values of 0.83 and 0.31 μg/mL against HIV-1 with therapeutic index of 83 and 403, respectively, and IC₅₀ values of 0.93 and 0.29 μg/mL against HIV-2 with therapeutic index of 74 and 431, respectively. This means that compounds 8 and 10 were cytotoxic to MT-4 cells at CC₅₀ of 69.2 μg/mL and 125 μg/mL, respectively.     

Design,synthesis and preliminary structure–activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives

In order to study the structure–activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4?a–8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC₅₀ value: 0.85?μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.     

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 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.     

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 BIOLOGICAL ACTIVITY OF CYCLIC ADP-CARBOCYCLIC-RIBOSE ANALOGS: STRUCTURE-ACTIVITY RELATIONSHIP AND CONFORMATIONAL ANALYSIS OF N-1-CARBOCYCLIC-RIBOSE MOIETY

Several cyclic ADP-carbocyclic-ribose analogs 3–10 modified in the N-1-carbocyclic-ribose moiety were synthesized. Their Ca²⁺-releasing activity was estimated in sea urchin eggs to show that the 3″-deoxy analog 6 shows 5 times more potent activity than cADPcR, but the 2″,3″-didieoxy-2″,3″-unsunsaturated analog 3 has very weak activity. We also calculated their stable conformation and found that 3 and 6 were significantly different in their stable conformation.     

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.     

除臭微生物的筛选复配及其在堆肥中的应用

【目的】从沼渣和硫铁矿场土壤中分离可以去除氨氮和硫化物的微生物,并筛选复配后应用于堆肥中,以减少畜牧业粪便处理时臭气的释放量,改善工作环境。【方法】利用选择培养基分别筛选除氨和除硫的微生物,并进行16SrRNA基因序列分析鉴定,挑选效果较好的菌株进行组合,复配出微生物除臭剂将其应用于粪便堆肥中,通过检测现场氨气和硫化氢浓度初步评估其除臭效果。【结果】分离出了12株除氨微生物和5株除硫微生物,挑选出5株效果较好的菌株分别标记为N-2、N-5、N-6、N-11和S-3。复配实验表明菌株N-5+N-6+N-11+S-3组成的微生物除臭剂效果最佳,对NH4+-N和S2–去除率最高,分别为82.46%和84.84%。同时,堆肥应用实验证明微生物除臭剂具有除臭功效,尤其是在堆肥前期,在第7天翻堆的过程中氨气和硫化氢释放量相对于对照组减少了62.84%和53.12%。堆肥结束,与对照组相比,微生物除臭剂组氨氮含量低于对照组33.62%。【结论】本研究获得的微生物除臭剂有效降低了畜禽粪便堆肥过程中恶臭气体的释放,在改善畜牧业粪便堆肥处理环境方面具有较大的应用潜力。     

Synthesis and antitumor activity of tetrahydrocarbazole hybridized with dithioate derivatives

Abstract

The present study reported the synthesis of tetrahydrocarbazoles hybridized with dithioate derivatives. Three series were synthesized namely alkyl dithiocarbonates (4a–d), heterocyclic dithiocarbamates (6a–g) and dialkyl dithiocarbamate (7). The synthesized compounds were tested in vitro on human breast adenocarcinoma cell line (MCF7) and the human colon tumor cell line (HCT116). Most of the synthesized compounds exploited potent antitumor activity, especially compound 6f [4-chlorophenylpiperazine derivative], which showed cytotoxic activity against MCF7 superior to doxorubicin with IC₅₀ value of 7.24?nM/mL.     

SYNTHESIS AND IN VITRO ANTIVIRAL ACTIVITY EVALUATION OF 9-(2-AZIDO-2,3-DIDEOXY-β-D-THREO-PENTOFURANOSYL)ADENINE DERIVATIVES

9-(2-Azido-2,3-dideoxy-β-D-threo-pentofuranosyl)adenine derivatives (1a–e) containing a lipophilic function at the N-6 position in the purine ring were prepared and evaluated for their antiviral activity. The compounds 1a–e turned out to be inactive as antiviral agents.     

Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns

The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.     

Synthesis and Liposome Formation of New Synthetic Perfluoroalkylated Cationic Lipids Derived from N-[[2-(F-Alkyl)Ethylthio]Methyl (Or Propyl] N'(2-Dimethylaminoethyl) Ureas

Abstract

The synthesis of new urea intermediates was performed from 3′-[2-(F-alkyl)ethylthio]alkyl isocyanates. The quatemization of N-[[2-(F-alkyl)ethyl-thio]methyl (or propyl)] N'-(2-dimethylaminoethyl)ureas by 1-bromoalkanes or 2-(F-hexyl) ethylbromoacetamide allowed to obtain perfluoroalkylated cationic double-chain amphiphiles. Their ability to form liposomes was investigated and discussed according to their molecular structure.     

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 the Pink Bollworm Sex Pheromone, 7-cis, 11-cis-Hexadecadienyl Acetate and Its 11-trans Isomer

Four types of amino acid related compounds were examined on their plant growth-regulating activity. These compounds were N-acylamino acids (N-acyl), N-alkylamino acids (N-alkyl), amino acid higher alkyl esters (ester) and amino acid higher alkyl amides (amide). Every compound, when the number of carbon atoms of the acyl or alkyl radical was 10 to 12, was most effective in inhibiting the root and shoot elongation of rice plant (Oryza sativa L.) in Petri dish. Ester and amide were much more effective than N-acyl and N-alkyl. Ester and amide also showed herbicidal activity against barnyardgrass (Echinochloa crusgalli) grown in pot filled with paddy soil and irrigated, especially, lauryl dl-valinate-HCl being most effective.     

Synthesis of some N-[4-(benzothiazole-2yl) phenyl]-2-aryloxyacetamide derivatives and their anticancer activities

In this study, some N-[4-(Benzothiazole-2-yl) phenyl]-2-aryloxyacetamide derivatives were prepared by reacting N-[4-(benzothiazole-2yl)phenyl]-2-chloroacetamide and different substituent phenol or thiophenol derivatives. The anticancer activities of the compounds obtained were investigated. It was observed that some of the compounds, namely 25 and 38, showed notable anticancer activity.     

Design and Synthesis of Regioisomeric Analogues of a Specific Anti-HIV-1 Agent 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Abstract

Regioisomeric analogues of the anti-HIV-1 lead 1-[(2-hydroxy-ethoxy)methyl]-6-(phenylthio)thymine (1: HEPT) have been synthesized. These compounds, having an ethoxymethyl side chain at C-5 and an ethyl group at the N-1 position of the uracil ring, also possess activity against HIV-1.     

Novel Acyclic Analogues of Purine Nucleosides: 2,3-Dihydroxy-1-Methoxypropyl and 3-Hydroxy-1-Methoxypropyl Derivatives

Abstract

Novel purine nucleoside analogues in which the N-9 ribosyl moiety is replaced by a 2,3-dihydroxy-1-methoxypropyl or 3-hydroxy-1-methoxypropyl substituent and their N-7 substituted isomers have been synthesized and tested for antiviral activity.