Synthesis and characterization of radioiodinated MD-230254: a new ligand for potential imaging of monoamine oxidase B activity by single photon emission computed tomography

A series of iodinated analogues of MD-230254 was synthesized and evaluated for inhibitory potency and selectivity toward monoamine oxidase B (MAO-B). Among them, 5-[4-(2-iodobenzyloxy)phenyl]-3-(cyanoethyl)-1,3,4-oxadiazole-2(3H)one (2-IBPO) was found to have high inhibitory potency and selectivity toward MAO-B (IC50=2.0 nM, MAO-A/MAO-B >50000). Analysis of the inhibition kinetics indicated that 2-IBPO acts in a two-step mechanism as a competitive, slow, and tight-binding inhibitor of MAO-B with a Ki value of 2.4 nM and an overall Ki* value at an equilibrium of 3.8 nM. The new radioligand for MAO-B, [125I]2-IBPO was conveniently synthesized from a tributylstannyl precursor by an iododestannylation reaction using sodium [125I]iodide and hydrogen peroxide with high radiochemical yield. The in vivo tissue distribution studies of [125I]2-IBPO demonstrated its high initial uptake and prolonged retention in the brain. A selective interaction of [125I]2-IBPO with MAO-B was confirmed by the pretreatment experiment with well known MAO specific inhibitors, l-deprenyl, Ro-16-6491, clorgyline, and Ro-41-1049. These very desirable characteristics of [125I]2-IBPO suggested that a 123I-labeled counterpart, [123I]2-IBPO, would have great potential in in vivo studies of MAO-B in the human brain with single photon emission computed tomography (SPECT).     

Synthesis and evaluation of iodinated benzamide derivatives as selective and reversible monoamine oxidase B inhibitors.

A new series of iodinated analogues of N-(2-aminoethyl)benzamide was synthesized and evaluated for inhibitory potency and specificity toward monoamine oxidase type-B (MAO-B). Among them, N-(2-aminoethyl)-2-chloro-4-iodobenzamide hydrochloride (2d) showed high inhibitory potency and selectivity against MAO-B. The type of MAO-B inhibition by 2d was non-competitive and the inhibition constant (Ki) was 0.80 microM. Strong and selective in vivo MAO-B inhibition by 2d was also confirmed. The brain MAO-B inhibition by 2d was reversible and the enzyme activity completely returned to the control value 24 h after administration. Compound 2d was, therefore, considered to be a candidate for advanced development as a radioiodinated ligand that may be useful for functional MAO-B studies in the living brain using single photon emission computer tomography.     

N-[2-(4-吗啉基)乙基]苯甲酰胺类单胺氧化酶抑制剂的合成及其生物活性研究

以取代苯甲酸为原料,经缩合反应制得N-(2-溴乙基)苯甲酰胺类化合物(4a~4i);4a~4i经N-烷基化反应合成N-[2-(4-吗啉基)乙基]苯甲酰胺类化合物(1a~1i),其结构经~1H NMR,~(13)C NMR,MS和元素分析表征。并对其生物活性进行了初步实验。实验结果表明:1a~1i对单胺氧化酶(MAO-A)有良好的抑制作用,其中1a最好,当IC50=3.652μmol·L~(-1)时,SI=42.32。     

Concise,efficient and highly selective asymmetric synthesis of (+)-(3S,4R)-cisapride

A concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2″′-methoxy-4″′-amino-5″′-chlorobenzamido)piperidine} from commercially available starting materials has been developed. The key step of this synthesis employs the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-[N-3′-(4″-fluorophenoxy)propyl-N-allylamino]pent-2-enoate and in situ enolate oxidation with (?)-camphorsulfonyloxaziridine to set the (3S,4R)-configuration found within the piperidine ring of the product. This synthesis proceeds in 9 steps from commercially available 1-(4′-fluorophenoxy)-3-bromopropane with an overall yield of 19%.     

Preparation and characterization of modified 3-aminopropylsilyl silica phases with 1,8-naphthalic anhydrides in HPLC

Modified 3-aminopropylsilyl silica stationary phases with 1,8-naphthalic anhydrides [3-(1,8-naphthalimido)propyl (NAIP), 3-(4-amino-1,8-naphthalimido)propyl (4A-NAIP), 3-(3-nitro-1,8-naphthalimido)propyl (3N-NAIP), and 3-(4-nitro-1,8-naphthalimido)propyl modified silyl silica gel (4N-NAIP)] are prepared in a single reaction. Chromatographic properties of these phases are characterized using various solutes including monosubstituted benzenes, alkyl benzenes, and polycyclic aromatic hydrocarbons (PAHs) in high-performance liquid chromatography. Even though the retention in these NAIPs is mainly based on the reversed-phase mode, 3N- and 4N-NAIP show a remarkable recognition toward aromatic hydrocarbons, which is attributed to their strong pi-pi interaction. Furthermore, the recognition ability is according to the molecular planarity and non-linearity of PAHs. Subsequently, 3N- and 4N-NAIP has a distinct selectivity from octadecyl silica and, therefore, will be a valuable alternative for a separation or a solid-phase extraction of aromatic compounds.     

Synthesis and nematicidal activities of 1,2,3-benzotriazin-4-one containing 4,5-dihydrothiazole-2-thiol derivatives against Meloidogyne incognita

Abstract

A series of novel 1,2,3-benzotriazin-4-one derivatives containing 4,5-dihydrothiazole-2-thiol were synthesized and characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. The bioassay results showed that compounds 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-7-methoxybenzo[d][1–3]triazin-4(3H)-one, 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-6-nitrobenzo[d][1–3]triazin-4(3H)-one, 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita at the concentration of 10.0?mg L^?1 in vivo. Compound 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one showed excellent nematicidal activity with inhibition 68.3% at a concentration of 1.0?mg L^?1. It suggested that the structure of 1,2,3-benzotriazin-4-one containing 4,5-dihydro-thiazole-2-thiol could be optimized further.     

Synthesis and antiarrhythmic activity of 2,2-dialkyl-1'-(N-substituted aminoalkyl)-spiro-(chroman-4,4'-imidazolidine)-2',5'-diones.

A novel series of 2,2-dialkyl-1'-(N-substituted aminoalkyl)-spiro-[chroman-4,4' -imidazolidine]-2',5'-diones was synthesized and evaluated for antiarrhythmic activity in chloroform- or/and aconitine-induced ventricular arrhythmia in mice. Among these compounds, (-)-6-chloro-2,2-dimethyl-1'-[3-(4-hydroxypiperidino)propyl] -spiro-[chroman-4,4'-imidazolidine]-2',5' -dione was found to be more effective than reference agents and was selected for further development.     

An unexpected cyclization discovered during the synthesis of 8-substituted purines from a 4,5-diaminopyrimidine

Attempted conversion of 4-chloro-5-(N-4-bromobutanoyl)amino-6-phenethylaminopyrimidine (2) to 6-chloro-8-[1-(3-bromo)propyl]-9-phenethylpurine (1) under standard cyclization conditions did not give the targeted product. Instead, an unexpected cyclization occurred to give 6-chloro-5-[1-(3-hydroxy)propyl]-9-phenethylpurine (3), which can be viewed as a hydrolysis product of the resulting halide. The cyclization reaction was optimized and compound 3 was prepared in excellent yield. A mechanism involving transient generation of a spiro-tetrahydrofuran is also proposed.     

Investigation of nitrogen- and sulfur-containing heterocycles

The corresponding N-(3-pyridyl)hydroxamic acid derivatives were obtained by reductive desulfuration of [2-(ethoxycarbonylmethylthio)-6-chloro-3-pyridyl]hydroxamic acid amide, benzylamide, and morpholide. The amides were synthesized by reaction of [2-(ethoxycarbonylmethylthio)-6-chloro-3-pyridyl]hydroxamic acid ester with diethylaminoethylamine and pyrrolidine. Heating of the ester and morpholide of [2-(ethoxycarbonylmethylthio)-6-chloro-3-pyridyl]hydroxamic acid with H₂SO₄ gives 2-chloropyrido[2,3-b] [1,4]thiazin-6-one.See [1] for communication XXVI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 676–678, May, 1973.     

15N-labeled ionic probe attachment mass spectrometry of carbon clusters

An ionization method that uses metal-complex-based ionization probes, malonic acid 3-[2,6-bis(4,4-dimethyloxazolin-2-yl)pyridin-4-yloxy]propyl ethyl ester (EM-TMpybox) and potassium N-{3-[2,6-bis(4,4-dimethyloxazolin-2-yl)pyridine-4-yloxy]propyl} aminoacetate (Sar-TMpybox), was developed for isotope ratio analysis and the effective ionization of unsubstituted carbon clusters. The preparation of Sar-TMpybox and EM-TMpybox and their applications in cold-spray ionization mass spectrometry are reported. A probe applicable to a substituted fullerene is also demonstrated.     

Synthesis and evaluation of novel N-substituted-6-methoxynaphthalene-2-carboxamides as potential chemosensitizing agents for cancer

A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 microg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 microg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.     

Synthesis and pharmacological evaluation of 2-(1-alkylpiperidin-4-yl)-n-[(1r)-1-(4-fluorophenyl)-2-methylpropyl]acetamide Derivatives as Novel Antihypertensive Agents

We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca(2+) channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca(2+) channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca(2+) channels over L-type Ca(2+) channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca(2+) channels over L-type Ca(2+) channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.     

Synthesis of 1,3-Bis[3-X-2-(X-acetoxy)propyl]-6-methyl- 1,2,3,4-tetrahydropyrimidine-2,4-diones

A procedure was developed for synthesizing nitrogen-and-sulfur-containing pyrimidine derivatives by reactions of 1,3-bis(3-chloro-2-hydroxypropyl)-6-methyluracil with 1-butanethiol and chloroacetyl chloride, followed by treatment of the resulting 1,3-bis[3-chloro-2-(chloroacetoxy)propyl]-6-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione with 1-butanethiol, morpholine, and piperidine. Oxidation of the sulfur-containing products with NaIO₄ gave the corresponding sulfoxides.     

Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors IV. A series of new derivatives containing a spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one skeleton

In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (-)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1'-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC(50)=2 nM, with high selectivity for FXa over thrombin and trypsin.     

Enantiomer separation by reversed-phase liquid chromatography with novel hydrophobic phases composed of chiral cationic surfactants

This paper describes enantiomer separation using four kinds of chiral stationary phases (CSPs) where quaternary ammonium surfactants containing L-valine diamide moieties into long alkyl chains were bound to silicagel supports by reversed phase liquid chromatography. Our aim was to examine hydrogen bonding association of the chiral moiety in hydrophobic phase brought about by aggregation of the micelle-forming surfactants on the surface. The following CSPs were thus derived from the vinyl-terminated chiral surfactants via hydrosilylation: CSP 1 from N-[3-(10-undecenoyl-L-valylamino)propyl]-N,N,N-trimethylammonium bromide, CSP 2 from N-[6-(10-undecenoyl-L-valylamino)hexyl]-N,N,N-trimethyl-ammonium bromide, CSP 3 from N-[3-(10-undecenoyl-L-valylamino)propyl]-N-octadecanyl-N,N-dimethyl-ammonium bromide and CSP 4 from N-[6-(10-undecenoyl-L-valylamino)hexyl]-N-octadecanyl-N,N-dimethylammonium bromide. The degree of hydrophobicity in the interfacial phase was observed by measuring pyrene fluorescence in aqueous media including an organic modifier. Retention of racemic N-acylleucine isopropyl esters was highest in CSP 4, followed by 3, 2, and 1. Largest alpha values toward enantiomer separation were observed for CSP 4 where the chiral moieties were kept through a hexamethylene unit apart from the polar head groups and to which another long alkyl chain was attached, as compared with those for CSP 4. In CSP 4, the chiral moiety to interact with enantiomeric solutes should be buried into the interfacial phase deeply in more extent than CSP 3. In a similar manner, CSP 2 has more effective for enantiomer separation than CSP 1. The interfacial phase of these CSPs was easily exposed to the bulk phase because of the affinity between the bulk phase and the polar head groups as well as their electrostatic repulsion. However, degree of the enantiomer separation can be controlled by the depth of the chiral moiety in the hydrophobic interfacial phase.     

Synthesis,cytotoxic, and carbonic anhydrase inhibitory effects of new 2-(3-(4-methoxyphenyl)-5-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazole derivatives

2-(3-[4-Methoxyphenyl]-5-aryl-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazoles ( 1b-7b ) were synthesized for the first time except 1b , and spectral methods such as ¹H NMR, ¹³C NMR and HRMS were utilized to illuminate the chemical structures of the synthesized compounds. Phenyl ( 1b ), 2-methoxyphenyl ( 2b ), 4-methoxyphenyl ( 3b ), 4-methoxy-3-hydroxyphenyl ( 4b ), 2,5-dimethoxyphenyl ( 5b ), 3,4,5-trimethoxyphenyl ( 6b ), or thiophene-2-yl ( 7b ) was used as a aryl part. The inhibitory effects of the compounds were evaluated toward human carbonic anhydrase I and II enzymes (hCA I and hCA II). In vitro cytotoxic effects of the compounds against human oral squamous carcinomas and human normal oral cells were carried out via MTT. The compounds ( 1b-7b ) had Ki values of 36.87 ± 11.62-66.24 ± 2.99 μM (hCA I) and 22.66 ± 1.41-89.95 ± 6.25 μM (hCA II). Compounds 1b (Ki = 36.87 ± 11.62 μM) toward hCA I, 6b (Ki = 22.66 ± 1.41 μM) toward hCA II had significant enzyme inhibitory potency. Compound 6b had the highest tumor selectivity (TS = 29.3) and potency selectivity expression (PSE = 272.3) values. Therefore, compounds 1b and 6b with CAs inhibition effect and compound 6b with the cytotoxicity may be forwarded to further studies as potent compounds.     

Discovery of a novel acyl-CoA: cholesterol acyltransferase inhibitor: the synthesis, biological evaluation, and reduced adrenal toxicity of (4-phenylcoumarin)acetanilide derivatives with a carboxylic acid moiety

As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.     

Increasing 5-lipoxygenase inhibitory activities by oxidative conversion of o-methoxyphenols to catechols using a Cu2(+)-ascorbic acid-O2 system

Several complicated o-methoxyphenols were oxidized with high selectivity to catechols by a Cu2(+)-ascorbic acid-O2 system. In this way, the RBL-1 5-lipoxygenase inhibitory activities of o-methoxyphenols were greatly increased. [6]-Norgingerol (4), a novel compound derived from [6]-gingerol (3), shows promise as a lead compound for new drugs because of its high inhibitory potency (IC50 = 5.0 x 10(-8) M).     

Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide derivatives

A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC(50) = 1.4 μM) compared with sorafenib (IC(50) = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC(50) = 22.6 μM).     

Aromatic substitution by N-arylhydroxylamines—II : Generation of nitrenes from arylhydroxylamines and N-benzenesulfonylhydroxylamines and phosphorous pentoxide

Substitution of benzene by N-benzene- and N-(4-methylbenzenesulfonyl)hydroxylamines occurs in the presence of phosphorous pentoxide whereas N-methyl-N-benzenesulfonylhydroxylamine gave no substitution product under the same conditions. When N-(4-methylbenzenesulfonyl)hydroxylamine was treated with phosphorous pentoxide in pyridine, N-(4-methylbenzenesulfonimido)pyridinium ylide was formed. Nitrene intermediates are postulated to account for these products. Similarly carbazole was formed from 2-hydroxylamino[1,1′-biphenyl] and phosphorous pentoxide but with phosphorous pentachloride, 3- and 3-chloro-2-amino[1,1′-biphenyls] were formed, most likely via a nitrenium ion intermediate.