Synthesis of<Emphasis Type="Italic">N</Emphasis>-phenylphthalimide Derivatives as α-Glucosidase Inhibitors

Sixteen N-phenylphthalimide derivatives were synthesized and their ability to inhibit alpha-glucosidase was investigated. N-(2,4-dinitrophenyl)phthalimide was a potent inhibitor of yeast alpha-glucosidase (IC50; 0.158 +/- 0.005 mM) and maltase (IC50; 0.051 +/- 0.008 mM), whereas it did not inhibit sucrase. From a Lineweaver-Burk plot of alpha-glucosidase kinetics, N-(2,4-dichlorophenyl)phthalimide was found to be a competitive inhibitor of yeast alpha-glucosidase. These results indicate that N-(2,4-dinitrophenyl)phthalimide could be a representative of a new group of alpha-glucosidase inhibitors.     

Synthesis and pharmacological properties of alkylammonium salts of <Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>′-malonyl-<Emphasis Type="Italic">bis</Emphasis>-<Emphasis Type="Italic">p</Emphasis>-aminobenzoic acid

A series of ammonium salts of N,N′-malonyl-bis-p-aminobenzoic acid with some alkylamines have been obtained. It is established that these compounds possess hypotensive, antiarrhythmic, and anticoagulative activities depending on the structure of the alkylamine constituents.     

Synthesis of novel <Emphasis Type="Italic">N</Emphasis>-acyl-<Emphasis Type="Italic">β</Emphasis>-<Emphasis Type="SmallCaps">d</Emphasis>-glucopyranosylamines and ureas as potential lead cytostatic agents

Novel classes of acetylated and fully deprotected N-acyl-β-d-glucopyranosylamines and ureas have been synthesized and biologically evaluated. Acylation of the per-O-acetylated β-d-glucopyranosylurea (5), easily prepared via its corresponding phosphinimine derivative, by zinc chloride catalyzed reaction of the corresponding acyl chlorides RCOCl (a–f) gave the protected N-acyl-β-d-glucopyranosylureas (6a–f), in acceptable-to-moderate yields. Subsequent deacetylation of analogues 6a–f under Zemplén conditions afforded the fully deprotected derivatives 7a,b,d,e,f, while the desired urea 7c was formed after treatment of 6c with dibutyltin oxide. All protected and unprotected compounds were examined for their cytotoxic activity in different L1210, CEM and HeLa tumor cell lines and were also evaluated against a broad panel of DΝΑ and RNA viruses. Derivative 7c exhibited cytostatic activity against the three evaluated tumor cell lines (IC₅₀ 9–24 μΜ) and might be the basis for the synthesis of structure-related derivatives with improved cytostatic potential. Only analogue 6f weakly but significantly inhibited the replication of parainfluenza-3 virus, Sindbis virus and Coxsackie virus B4 in cell cultures at concentrations of 45–58 μM.     

Synthesis and hypnotic activities of <Emphasis Type="Italic">N</Emphasis>-Cbz-α-aminoglutarimidooxy carboxylate derivatives

Typical hypnotic drugs, such as barbitals and glutethimide, have a cyclic imide (-CO-NH-CO-) moiety. The N-Cbz-alpha-aminoglutarimidooxy carboxylate derivatives, which we previously showed exhibit moderate anticonvulsant activities, also have a cyclic imide (-CO-N-CO-) moiety. This structural similarity prompted us to examine the hypnotic activities of the N-Cbz-alpha-aminoglutarimidooxy carboxylate derivatives, and we describe their moderate hypnotic activities here.     

<Emphasis Type="Italic">N</Emphasis>-4-iodophenyl-<Emphasis Type="Italic">N</Emphasis>′-2-chloroethylurea,a novel potential anticancer agent with colon-specific accumulation: radioiodination and comparative in vivo biodistribution profiles

In a search for more selective anticancer drugs, we have designed nitrogen mustard and nitrosourea conjugates leading to a series of N-4-aryl-N′-2-chloroethylureas (CEUs). The iodinated derivative N-4-iodophenyl-N′-2-chloroethylurea (4-ICEU) has demonstrated significant antineoplastic and antiangiogenic potency in preclinical evaluations. In this study, 4-ICEU was radiolabelled with [¹²⁵I]iodide in order to carry out a comparative study of its in vivo behavior profile. 4-[¹²⁵I]-ICEU was synthesized by direct electrophilic radioiodination with 80% radiochemical yield and 97% radiopurity. Three different routes of administration (intraperitoneal (ip), intravenous (iv) and intratumoral (it)) were tested in mice bearing subcutaneously implanted CT-26 murine colon carcinoma. The results clearly established that 4-ICEU was more stable to biotransformation than previously studied CEUs congeners. It was readily bioavailable and reached the CT-26 colorectal tumor regardless of the route of administration. Additionally, the colon mucosa was an important target tissue where 4-ICEU accumulated and remained largely untransformed. In conclusion, these results justify further investigations for developing 4-ICEU as a new chemotherapeutic agent for colorectal cancer.     

Lignan and neolignan glucosides,and tachioside 2′-<Emphasis Type="Italic">O</Emphasis>-4″-<Emphasis Type="Italic">O</Emphasis>-methylgallate from the leaves of <Emphasis Type="Italic">Glochidion rubrum</Emphasis>

Thirteen compounds (1–13) were isolated from a MeOH extract of leaves of Glochidion rubrum. The structures of four new compounds were elucidated to be (−)-isolariciresinol 2a-O-β-d-glucopyranoside (1), (7R,8S)- and (7R,8R)-4,7,9,9′-tetrahydroxy-3,3′-dimethoxy-8-O-4′-neolignan 7-O-β-d-glucopyranosides (2 and 3, respectively), and tachioside 2′-O-4″-O-methylgallate (4) on detailed inspection of one- and two-dimensional NMR spectral data.     

The interaction of host genetic factors and <Emphasis Type="Italic">Helicobacter</Emphasis> <Emphasis Type="Italic">pylori</Emphasis> infection

Helicobacter pylori plays an important role in the development of atrophic gastritis that represents the most recognized pathway in multistep gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of Helicobacter pylori infection. As to bacterial virulence factors, a high proportion of Japanese strains are cagA⁺vacAs1. The CagA protein is injected from attached Helicobacter pylori into gastric epithelial cells and the CagA-SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. Host cytokine gene polymorphisms and a frequent single nucleotide polymorphism in the PTPN11 gene that encodes SHP-2 may associate with gastric atrophy among Helicobacter pylori-infected subjects. Prevention of gastric cancer requires the development of better screening strategies for determining eradication candidates and further improvement of treatments of Helicobacter pylori infection. Received 6 August 2006; accepted 21 August 2006     

Synthesis of phenylazonaphtol-β-<Emphasis Type="SmallCaps">D</Emphasis>-<Emphasis Type="Italic">O</Emphasis>-glycosides,evaluation as substrates for beta-glycosidase activity and molecular studies

Background

Phenylazonaphtol-β-D-O-glycosides are alternative substrates for the detection of enzymatic activity of β-glycosidases which are involved in various important processes. These azoic compounds are currently exploited as prodrugs for colonic disease due the presence of β-glycosidase activity in the gut flora and therefore allowing the release of the drug at the specific site.

Results

Phenylazonaphtol-β-D-O-glucoside 3a and galactoside 3b were prepared via diazonium salt conditions under weak acidic conditions which do not compromise the O-glycosidic bond stability, by coupling reaction between 2-naphtol sodium salt with aminoglycosides 1a and 1b. The resulting phenylazonaphtol glycosides 2a and 2b were deprotected affording the phenylazonaphtol glycosides 3a and 3b in quantitative yield. The galactoside glycoside 3b was assayed as substrate for in vitro β-galactosidase enzymatic activity showing strong absorbance after releasing of the azoic chromophore. Also, docking studies were performed to determine the best pose as well as the interactions between the ligand and the residues located at the active site.

Conclusions

The methodology developed for synthesizing the phenylazonaphtol glycosides described proved to be convenient for generating azoic functionalities in the presence of glycosidic bonds and the glycosides suitable as alternative substrates and potentially useful prodrugs in the treatment of colonic diseases.

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Components of convolvulin from <Emphasis Type="Italic">Quamoclit</Emphasis> × <Emphasis Type="Italic">multifida</Emphasis>

Alkaline hydrolysis of the ether-insoluble resin glycoside (convolvulin) fraction of the seeds of Quamoclit × multifida (syn. Q. sloteri House, Convolvulaceae), a hybrid between Q. pennat and Q. coccinea, gave three new glycosidic acids (maltifidinic acids C, D, and E) along with three known glycosidic acids (quamoclinic acids B, C, and D) and four organic acids (2S-methylbutyric, tiglic, 2R,3R-nilic, and 7S-hydroxydecanoic acids). The structures of the new glycosidic acids were characterized on the basis of spectroscopic data as well as chemical evidence.     

<Emphasis Type="Italic">Buddlejol</Emphasis>, a new α-chymotrypsin inhibitor from <Emphasis Type="Italic">Buddleja asiatica</Emphasis>

Buddlejol (1), a new sterol, has been isolated from the ethyl acetate soluble fraction of the antispasmodic plant Buddleja asiatica along with stigmasterol (2), lignoceric acid (3), taraxerol (4) and α-amyrin (5), respectively. The structure of Buddlejol (1) was established as (24S)-stigmast-5,22-diene-7β-ethoxy-3β-ol by spectral analysis and comparison with closely related structures. Buddlejol revealed to be a competitive inhibitor of chymotrypsin with the Ki value of 10.60 µM as indicated by Lineweaver–Burk and Dixon plots and their re-plots against its chymotrypsin inhibition assay, while the other compounds showed less inhibitory potential. The bioassay-guided isolation was stimulated by the preliminary cytotoxic screening of various fractions of B. asiatica.     

Side Effects of Interferon-<Emphasis Type="Italic">α</Emphasis> Therapy

Aim

Interferon-α (IFN-α) has been extensively explored for its efficacy in various disease conditions and is currently used as a standard treatment in several of these. Its use is accompanied by a wide variety of possible side effects. These side-effects may hamper reaching and maintaining the dose needed for maximal therapeutic effect while their occurrence can outweigh clinical benefit of IFN-α treatment. This review addresses the toxicity profile of IFN-α, the presumed pathophysiology of the different side effects and the strategies to handle these.

Methods

Computerized searches were used and cross-references of articles and books were checked.

Results

Adverse effects due to IFN-α have been described in almost every organ system. Many side-effects are clearly dose-dependent. Taken together, occurrence of flu-like symptoms, hematological toxicity, elevated transaminases, nausea, fatigue, and psychiatric sequelae are the most frequently encountered. Although insight in the mechanisms accounting for IFN-α-related toxicities has improved in recent years, much remains to be elucidated. Guidelines on the management of these untoward sequelae are mostly based on clinical experience, while many side-effects can only be adequately handled by dose adjustment or cessation of treatment.

Conclusion

Further research on the mechanisms underlying both therapeutic effects and adverse events is warranted. Hopefully, this will lead to better identification of those patients who are likely to benefit from treatment without experiencing severe toxicities.

     

Structure–activity relationship study of secondary metabolites from <Emphasis Type="Italic">Mesua beccariana</Emphasis>, <Emphasis Type="Italic">Mesua ferrea</Emphasis> and <Emphasis Type="Italic">Mesua congestiflora</Emphasis> for anti-cholinesterase activity

Our search for potential anti-acetylcholinesterase (AChE) inhibitors for treatment of Alzheimer’s disease has led to the discovery of two bioactive compounds, α-mangostin (11) and congestiflorone acetate (13). This discovery was achieved from a preliminary screening of the anti-AChE activity on the extracts of three Mesua species namely M. ferrea, M. beccariana and M. congestiflora using Ellman’s method. The pure metabolites, 1–12 which were isolated from the Mesua species, along with a synthetic derivative, compound 13 were then evaluated for their activities in order to identify the compounds that correspond to the enzyme inhibitory activities. Compounds 11 and 13 were found to give significant anti-AChE activities with IC₅₀ values of 17.51 and 20.25 µM.     

A glycerol α-<Emphasis Type="SmallCaps">d</Emphasis>-glucuronide and a megastigmane glycoside from the leaves of <Emphasis Type="Italic">Guettarda</Emphasis><Emphasis Type="Italic">speciosa</Emphasis> L.

From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Guettarda speciosa L., two new compounds (1, 2) were isolated together with six known compounds. Spectroscopic analysis of 1 and 2 established their structures to be derivatives of a glycerol α-glucuronide and a megastigmane glycoside, respectively. HPLC analysis of the hydrolyzate of 1 confirmed the presence of d-glucuronic acid in the structure, and the modified Mosher’s method established the absolute structure of 2.     

High incidence of acute promyelocytic leukemia specifically induced by <Emphasis Type="Italic">N</Emphasis>-nitroso-<Emphasis Type="Italic">N</Emphasis>-methylurea (NMU) in Sprague–Dawley rats

Carcinogenic agents such as N-methyl-N-nitrosourea can cause tumors. The aims of the present study were to evaluate and classify a subtype of AML (acute myeloid leukemia) that was induced by NMU. According to previous publications, NMU induces not only mammary cancer but also leukemia in Sprague–Dawley (S-D) rats. However, the subtype of leukemia involved in NMU-treated rats is unknown. We found that both organ weight and relative organ weights were significantly higher in NMU-exposed rats than in controls. Morphological changes of rat livers and spleens were assessed by histological evaluation (H&E staining), which found that these tissues were abnormal in appearance. Also, cytological examination of the blood showed immature white blood cells in a smear using Liu’s and Papanicolaou stains, indicating that gross abnormalities and histopathological changes were pathologically observed. NMU leukemia incidence was 97.1%. In this study, immunohistochemical (IHC) analysis was valuable in classifying the leukemia of poorly differentiated blasts induced by NMU. Paraffin blocks were stained for MPO, CD3, CD15, CD20, and CD34 markers. The NMU-induced group was positive for MPO, but negative for CD3, CD15, CD20, and CD34. These CD markers suggest that they are useful in helping diagnose APL (M3) leukemia. The model of NMU-induced leukemogenesis in an S-D rat suggests a more definite way to classify APL. This APL will provide an important tool for chemical carcinogenesis and leukemia studies.     

Two new α-pyrones and other components from the cladodes of<Emphasis Type="Italic">Opuntia dillenii</Emphasis>

The aqueous ethanolic extract from the fresh cladodes of Opuntia dillenii HAW. was found to show anti-inflammatory activity. Two new alpha-pyrones, named opuntioside II (1) and opuntioside III (2), were isolated from the extract together with six known compounds. The structures of the new compounds were determined on the basis of chemical and physicochemical evidence.     

Two new <Emphasis Type="Italic">β</Emphasis>-carboline alkaloids from the stems of <Emphasis Type="Italic">Picrasma quassioides</Emphasis>

Two new β-carboline alkaloids, 1-acetyl-4-methoxy-8-hydroxy-β-carboline (1) and 1-acetyl-4,8-dimethoxy-β-carboline (2), together with 10 known compounds; seven β-carboline alkaloids (3–9), two canthin-6-one alkaloids (10 and 11), and one quassinoid (12) were isolated from the stems of Picrasma quassioides. The structure of the new compounds 1 and 2 were determined by spectroscopic analyses including 1D- and 2D-NMR and HRMS interpretation. All the isolates (1–12) were evaluated for their cytotoxicity against human ovarian carcinoma A2780 and SKOV3 cell lines using MTT assays. Of the isolates, compounds 5–7 exhibited the most potent cytotoxicity on both A2780 and SKOV3 cell lines in vitro.     

Comparison of the developmental effects of 5-methoxy-<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>-diisopropyltryptamine (Foxy) to (±)-3,4-methylenedioxymethamphetamine (ecstasy) in rats

Rationale  We have previously shown that (±)-3,4-methylenedioxymethamphetamine (MDMA) treatment from postnatal days (P)11 to P20 leads to learning and memory deficits when the animals are tested as adults. Recently, the club drug 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) has gained popularity. Objective  Due to the similarities between MDMA and 5-MeO-DIPT and the substitution of 5-MeO-DIPT for MDMA, the purpose of this study was to compare the developmental effects of these drugs. Methods  Within a litter, animals were treated from P11 to P20 with either MDMA, 5-MeO-DIPT, or saline. Results  MDMA-treated animals showed increased anxiety in a measure of defensive marble burying, as well as deficits in spatial and path integration learning. 5-MeO-DIPT-treated animals showed spatial learning deficits; however, there were no deficits observed in spatial memory or path integration learning. 5-MeO-DIPT-treated animals also showed hyperactivity in response to a challenge dose of methamphetamine. Conclusions  The results show that treatment with either 5-MeO-DIPT or MDMA during development results in cognitive deficits and other behavioral changes but the pattern of effects is distinct for each drug. Supported by NIH grants DA021394 (CV) and training grant T32 ES07051 (MRS, TLS).