Substituted adamantylphthalimides: Synthesis,antiviral and antiproliferative activity

In this study, three groups of adamantylphthalimides, bearing different substituents at the phthalimide moiety, N-(4′-R²)phthalimidoadamantanes ( 1 – 7 ), 3-[N-(4′-R²)phthalimido]-1-adamantanols ( 8 – 10 ), and 3-[N-(4′-R²)phthalimido]adamantane-1-carboxylic acids ( 11 – 15 ), were synthesized and screened against tumor cells and viruses. The most potent compounds are not substituted at the adamantane and bear an OH or NH₂ substituent at the phthalimide (compounds 3 and 5 ). The antiproliferative activities of compounds 3 and 5 are in the micromolar range, much higher than the one of thalidomide. A minor antiviral activity against cytomegalovirus and varicella-zoster virus was found for compounds 3 and 5 , but these compounds lacked selectivity. The results presented are important for the rational design of the next-generation compounds with anticancer and antiviral activities.     

The involvement of glutamatergic transmission in the mechanism of movement disorders induced by reversive rotation of white mice

The ability of the selective non-competitive NMDA receptor blocker MK-801 and a series of new glutamate antagonists—the adamantane derivatives IEM-1754 and IEM-1857 and phencyclidine (IEM-1925)—to prevent movement disorders induced by reversive rotation in mice was studied. I.p. MK-801 at a dose of 0.15 ml and IEM-1754 at a dose of 5.0 mg/kg prevented the development of akinesia in response to reversive rotation, as effectively as scopolamine, a known agent which provides effective prophylaxis for movement diseases. IEM-1857, the quaternary analog of IEM-1754, was not effective. IEM-1925 significantly increased the responses of mice to reversive rotation, possibly because of its high activity in relation to other subtypes of glutamate receptors. These data provide evidence for the involvement of glutamatergic transmission in the mechanism of movement disorders of vestibular origin. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 85, No. 4, pp. 497–501, May, 1999.     

In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes

Aim:

To investigate the binding mode of synthesized adamantly derivatives inside of cholinesterase enzymes using molecular docking simulations.

Methods:

A series of hybrid compounds containing adamantane and hydrazide moieties was designed and synthesized. Their inhibitory activities against acetylcholinesterase (AChE) and (butyrylcholinesterase) BChE were assessed in vitro. The binding mode of the compounds inside cholinesterase enzymes was investigated using Surflex-Dock package of Sybyl7.3 software.

Results:

A total of 26 adamantyl derivatives were synthesized. Among them, adamantane-1-carboxylic acid hydrazide had an almost equal inhibitory activity towards both enzymes, whereas 10 other compounds exhibited moderate inhibitory activity against BChE. The molecular docking studies demonstrated that hydrophobic interactions between the compounds and their surrounding residues in the active site played predominant roles, while hydrophilic interactions were also found. When the compounds were docked inside each enzyme, they exhibited stronger interactions with BChE over AChE, possibly due to the larger active site of BChE. The binding affinities of the compounds for BChE and AChE estimated were in agreement with the experimental data.

Conclusion:

The new adamantly derivatives selectively inhibit BChE with respect to AChE, thus making them good candidates for testing the hypothesis that BChE inhibitors would be more efficient and better tolerated than AChE inhibitors in the treatment of Alzheimer''s disease.     

Study of auto- and heteroreceptor components of the presynaptic dopamine reuptake modulation in the mechanism of the in vitro action of the novel antiparkinsonian drug hemantane

The effect of Hemantane, a new 2-aminoadamantane derivative (N-adamant-2-ylhexamethylenimine hydrochloride) with antiparkinsonian activity on [³H]-dopamine ([³H]-DA) uptake and binding by D1, D2, and D3 dopamine and NMDA glutamate receptors was studied in comparison with the clinically used drug Amantadine. The method of radioligand binding to rat striatal membrane preparations was used. Both drugs, when used within a concentration range of 10^?11 to 10^?3 M did not affect the[G-³H]-SCH23390 and [G-³H]-Spiperone binding by D1 and D2 receptors. However, at micromolar concentrations (>10^?5 M), Hemantane and Amantadine inhibited the binding of the D3 receptor ligand 7-OH-[G-³H]-DPAT with IC₅₀ values of 39 and 360 μM, respectively; i.e., Hemantane is almost one order of magnitude more efficient. Both preparations exhibited a similar effect on NMDA receptors: the semiinhibition constants IC₅₀ were 5.5 μM for Hemantane and 4 μM for Amantadine. Hemantane and Amantadine were shown to reproducibly inhibit the reuptake of [³H]-dopamine at concentrations of 100–500 μM. The study of inhibition kinetics demonstrated the noncompetitive character of the action: Hemantane decreased the B _max value from 9.0 (control) to 5.1 pmol of [³H]-DA per min/mg of protein (p < 0.05), whereas K _m value remained constant (0.5 μM), which is characteristic of the noncompetitive type of inhibition. The (±)CPP and MK-801 antagonists of NMDA receptors inhibited the reuptake of [³H]-DA with IC₅₀ of 6 and 38 μM, respectively; NMDA (1, 10, and 100 μM) had no effect; and quisqualate, an agonist of nonNMDA receptors, moderately (?37%, p < 0.05) inhibited dopamine transport at 100 μM. These data seem to indicate that the mechanism of increase of dopaminergic transfer under the action of adamantane derivatives could involve noncompetitive inhibition of dopamine transport.     

甲型H1N1流感病毒的分子特征

当前新型甲型H1N1流感病毒的暴发,引起全球的关注。本文对甲型H1N1流感病毒的分类地位、结构特征、基因复制、蛋白功能进行介绍,说明新型甲型H1N1流感病毒是甲型流感病毒通过抗原漂移和抗原转换所产生的,对奥塞米韦(达菲)敏感,但对金刚烷胺有抗药性。     

Coexistence of two adamantane binding sites in the influenza A M2 ion channel

The influenza A virus contains a proton-selective ion channel (M2) that is the target of the adamantane family of drug inhibitors. Two recently published studies relating to adamantane binding of the M2 ion channel using X-ray crystallography and solution NMR have reignited interest in the potential use of adamantanes in combating the spread of influenza A. However, these two studies propose different binding sites for the adamantane drugs with the X-ray M2/amantadine structure favoring an ion channel pore-binding model and the solution NMR M2/rimantadine structure suggesting the existence of a lipid-facing binding pocket. We conducted a series of surface plasmon resonance (SPR) experiments designed to accurately measure the affinity of amantadine and rimantadine to M2 ion channels embedded in 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC) liposomes. We find that this class of drug is capable of binding M2 with two different affinities in the order of 10⁻⁴ and 10⁻⁷ M, suggesting that both proposed binding sites are feasible. Furthermore, by examining drug binding to M2 mutant constructs (V27A, S31N, and D44A), it was possible to probe the location of the two binding sites. We show that a high-affinity binding site corresponds to the M2 ion channel pore whereas the secondary, low-affinity binding site can be attributed to the lipid face of the pore. These SPR results are in excellent agreement with the most recent solid-state NMR study of amantadine-bound M2 in lipid bilayers and provide independent support that the ion channel pore-binding site is responsible for the pharmacological activity elicited by the adamantane drugs.     

基于碱性磷酸酶-金刚烷体系的化学发光酶免疫分析法对磺胺对甲氧嘧啶的测定

目的用碱性磷酸酶（ALP）-金刚烷（AMPPD）体系,建立化学发光酶免疫分析定量检测磺胺对甲氧嘧啶（SMD）的方法。方法利用重氮化偶联法标记ALP,在优化的实验条件下抗体包被浓度为5.0μg.mL-1,酶标记物工作液稀释度为1∶10,每孔加待测样品或标准品50μL和酶标记物50μL,在37℃下反应l h,洗涤后每孔加发光底物100μL,避光反应25 min后在发光检测仪下检测发光计数。结果该方法检测限为28.0 pg.mL-1,批内变异系数为13.5%~14.6%,批间变异系数为16.1%~17.5%。标准曲线回归方程为Y=-0.021 5X＋5.172 6（r=0.996 1）,线性范围为50~10 000 pg.mL-1。结论首次运用ALP-AMPPD发光体系的化学发光酶免疫分析法实现了对SMD残留的快速检测。     

Mannich bases of 1,2,4‐triazole‐3‐thione containing adamantane moiety: Synthesis,preliminary anticancer evaluation,and molecular modeling studies

A series of 18 novel N‐Mannich bases derived from 5‐adamantyl‐1,2,4‐triazole‐3‐thione was synthesized and characterized using NMR spectroscopy and X‐ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL‐60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC‐5 compared to cancer cells. The effects of compounds 5b , 5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase‐dependent apoptosis, while the anti‐angiogenic effects of 5b , 5e, and 5j have been confirmed in EA.hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.     

Effect of antiparkinsonian drug himantane on the content of dopamine transporter DAT protein in rat striatum and cultured heochromocytoma PC-12 cells

We studied the effects of antiparkinsonian drug himantane (acute and subchronic administration) on the content of dopamine transporter protein DAT in rat striatum ex vivo and on the content of DTA in cultured PC-12 cells (10⁻⁵–10⁻⁷ M, the preparation was added to the incubation medium once or 7 times). The preparation significantly reduced the content of DAT protein both ex vivo and in vitro. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 3, pp. 300–303, March, 2008     

金刚乙胺盐酸盐的制备工艺改进

报道了以金刚烷为起始原料，经1－溴代金刚烷、1－金刚烷甲基酮等中间体，再与盐酸羟胺反应，然后催化加氢反应，制得金刚乙胺盐酸盐，总收率为53．6％。