Cadmium Mobilization in Vivo by Intraperitoneal or Oral Administration of Monoalkyl Esters of meso–2, 3–Dmercaptosuccinic Acid in the Mouse

Abstract: The relative activities of a series of nine monoalkyl esters of meso-2, 3–dimercaptosuccinic acid have been examined as agents for the mobilization of cadmium from mice one week after intraperitoneal administration of cadmium chloride. Eight of these are newly synthetized; all are of the type ROOCCH(SH)CH(SH)COOH, were R=Me, MMDMS; R = C₂H₅, MEDMS; R = (CH₂)₂CH₃, Mn-PDMS; R = CHMe₂) Mi-PDMS; R = (CH₂)₃CH₃, Mn-BDMS; R = CH₂CHMe₂, Mi-BDMS; R = (CH₂)₄CH₃, Mn-ADMS; R=(CH₂)₂CHMe₂, Mi-ADMS; and R = (CH₂)₅CH₃, Mn-HDMS. All are soluble in dilute sodium bicarbonate solutions and can be administered as aqueous solutions. Cadmium mobilization data were collected on each compound using mice previously loaded with cadmium; the monoesters were administered at a level of 0.40 mmol/kg intraperitoneally daily for five days. Data on whole body cadmium mobilization indicated that the monoester with the isoamyl group was the most effective under the conditions used. The relative whole body cadmium mobilization increased with the number of carbon atoms in the alkyl group of the monoester up to C₅ and then decreased for the C₆ compound. Cadmium removal from the kidneys and liver was also measured. It was found that the monoisoamyl ester was the most effective in removing cadmium from both the liver and the kidneys. The monoisoamyl ester also proved to be very effective in mobilizing cadmium from both the liver and the kidneys when given orally. This is the first compound which is reported capable of mobilizing cadmium in vivo from aged deposits after oral administration.     

Protection of Guinea Pigs against Soman Poisoning by Pretreatment withp-Nitrophenyl Phosphoramidates

Severalp-nitrophenyl phosphoramidates with the general formula RO(NH₂)P(O)OC₆H₄-p-NO₂, in which R = CH₂CH₃,CH₂CH₂F, CH₂CHF₂, CH₂CF₃, CH₂CH₂CH₂CH₃, and CH₂CH₂Cl, as well as (NH₂)₂P(O)OC₆H₄-p-NO₂were administered intravenously to guinea pigs as pretreatment compounds for protection against the lethal effects of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) poisoning. Administration of phosphoramidates at a dose that produces 30% acetylcholinesterase (AChE) inhibition in the blood of atropinized guinea pigs at the moment of soman poisoning increases the subcutaneous LD50 of soman up to almost fivefold depending on which compound was used. A synergistic effect with atropine was observed. Three of these compounds offered a higher degree of protection against soman poisoning than pyridostigmine. Furthermore, the surviving animals pretreated with the two phosphoramidates that provided the highest protective ratio were in a better condition at 24 hr after soman intoxication than those pretreated with pyridostigmine. Due to the limited number of compounds and their different characteristics, it appeared difficult to demonstrate a relationship between the rate of spontaneous reactivation of AChE inhibited by the pretreatment compound and the protection against soman. Nevertheless, the results indicate that a several-fold decrease in the rate of spontaneous reactivation relative to that of pyridostigmine may increase the protective ratio against soman.     

Medicinal Chemistry: Enantioselectivity of Some 1-(Benzofuran-2-yl)-1-(1-H-imidazol-1-yl) Alkanes as Inhibitors of P450Arom

The low stereospecificity of the enantiomers of 1-[(benzofuran-2-yl)-4-chlorophenyl-methyl]imidazole ( 6 , R = H, R' = 4′-Cl) and the corresponding 4-fluoro compound as inhibitors of aromatase (P450_Arom) has been explored using 1-(5,7-dichlorobenzofuran-2-yl)-1-(1H-imidaz-1-yl)ethane ( 7 , R₁=R₂ = Cl, R = CH₃), -propane ( 7 , R₁=R₂ = Cl, R = C₂H₅), and the corresponding 5,7-dibromo compounds resolved as their dibenzoyl-D (or -L) tartrates. Low enantioselectivity ratios of 4.8 (5,7-diCl) and 12.6 (5,7-diBr) were shown for the ethanes. The values for the corresponding propanes were 8.3 and 5.2, respectively, and for these compounds the stereoselectivity was reversed.     

Anticancer activities of some arylcarbamoylalkyltriphenylphosphonium chlorides

A series of novel arylcarbamoylalkyltriphenylphosphonium chlorides were synthesized. The newly synthesized compounds, [R-(p-C₆H₄)-NH-CO-R₁P^⊕(C₆H₄)₃]Cl^θ, R = H (2), CH₃ (4), NO₂ (6), R₁ = –CH₂− (b), CH₃CH< (a), –CH₂CH₂− (c), –CH₂CH₂CH₂ (d), the analogs of an anticancer drug, were characterized by infrared (IR), ¹H nuclear magnetic resonance (NMR), ¹³C-NMR, ³¹P-NMR, mass spectrometry (MS), thermogravimetry (TG), and conductivity measurements. The anticancer activities of the obtained compounds were measured by MTT. The preliminary results indicated that some compounds showed potent anticancer activities against HCT-8, Bel-7402, A549, and S180.     

Different Modes of Blockade by p-Phenylene-polymethylene Bis-ammonium Compounds of the Nicotinic Acetylcholine Receptor Channel in Skeletal Muscle Cells of Mice

Abstract— The structure-activity relationships of five newly synthesized p-phenylene-polymethylene bis-ammonium (PMBA: C₆H₄[(CH₂)_nN⁺R₃]₂) compounds were investigated on the blockade of the nicotinic acetylcholine receptor (nAChR) channel. The cell-attached patch clamp configuration was used to measure single-channel currents in the endplate region of single flexor digitorum brevis muscle cells of adult mice. The bis-trimethylammonium compounds PMBA-1 (n = 4, R = CH₃) and PMBA-23 (n = 6, R = CH₃) produced channel opening above 0·3 μm and open channel blockade above 10 and 3 μm , respectively. The bis-triethylammonium compounds PMBA-43 (n = 1, R = CH₂CH₃) and PMBA-24 (n = 6, R = CH₂CH₃) showed no channel opening action, but PMBA-21 (n = 4, R = CH₂CH₃) opened channels weakly at 3 and 10 μm . These bis-triethylammonium compounds exerted different blocking actions on acetylcholine-activated channel currents. Above 10 μm PMBA-43, like tetraefhylammonium, blocked open channels by decreasing the mean open time by rapid partial closing of the channel during the open-phase. At 10 μm , PMBA-21 blocked open and closed channels by decreasing the opening frequency by means of an irregular sequence of short pulses. At 0·3 μm , PMBA-24 blocked closed or nonconducting channels by decreasing the opening frequency without producing changes in mean open time. These results indicate that by lengthening the distance between two nitrogen atoms in the bis-triethylammonium group of PMBA, open channel blockade changes to closed channel blockade. PMBA compounds were classified into three types of nAChR channel blockers: PMBA-43 as an open, PMBA-21 as an open and closed, and PMBA-24 as a closed or nonconducting channel blocker.     

α,ω-双-[对-氨基苯氧基]-戊烷及-庚烷-N,N′-双取代衍生物的合成

α,ω-双-[对-氨基苯氧基]-烷类化合物对感染日本血吸虫病的实驗动物具有显著的疗效,惟毒性較高,我們合成了α,ω-双-[对-氨基苯氧基]-戊烷及-庚烷的N,N′-双取代衍生物10种,希望疗效增加而毒性减低。n=5或7; R=H,R′=CH₂SO₃Na R=H,R′=CH₂CN R=H,R′=COOC₂H₅ R,R′=-(CH₂)₅- R,R′=-(CH₂)₂O(CH₂)₂- 由相应的α,ω-双-[对-氨基苯氧基]-烷类和羟甲磺酸鈉作用生成α,ω-双-[对-氨基苯氧基]-戊烷(及-庚烷)-N,N′-双甲磺酸鈉。它和氰化鉀反应,即得相应的N,N′-双乙臍衍生物。α,ω-双-[对-氨基苯氧基]-戊烷(及-庚烷)-N,N′-双甲酸乙酯則由相应的α,ω-双-[对-氨基苯氧基]-烷类和氯代甲酸乙酯作用而得。α,ω-双-[对-六氫呲啶基苯氧基]-戊烷(及-庚烷)和α,ω-双-[对-N-氧氮六圜基苯氧基]-戊烷(及-庚烷)則分别由相当的α,ω-双-[对-氨基苯氧基]-烷类和二溴戊烷或β,β′-二溴乙醚作用生成。其中α,ω-双-[对-N-六氫吡啶基苯氧基]-戊烷井另由N-对羟苯基六氫吡啶和二溴戊烷縮合生成。     

The mobilization of intracellular cadmium by alkoxyethyl esters of meso-2,3-dimercaptosuccinic acid

The cadmium mobilizing properties of two newly synthesized esters of meso-2,3-dimercaptosuccinic acid in mice have been examined. They are: di(2'-methoxyethyl) meso-2,3-dimercaptosuccinate ([-CH(SH)COOCH2CH2OR]2, R = CH3; MEDMS), and di(2'-ethoxyethyl) meso-2,3-dimercaptosuccinate ([-CH(SH)COOCH2CH2OR]2, R = CH2CH3; EEDMS), conveniently prepared from dimercaptosuccinate acid with 2-methoxyethanol and 2-ethoxyethanol, respectively. Mobilization studies in mice of aged in vivo cadmium deposits using five ip injections of 0.40 mmol/kg of each chelator in peanut oil clearly indicate that both compounds, MEDMS and EEDMS, are significantly superior to 2,3-dimercaptopropan-1-ol (BAL) in depleting the whole body burden of cadmium. The reductions caused by MEDMS and EEDMS were approximately 20 and 26%, respectively, whereas under similar dosage regimens BAL effected about only a 12% reduction. The esters were neither equal nor superior to BAL for the reduction of renal cadmium levels, MEDMS being the least effective. For the mobilization of hepatic cadmium deposits, both were quite promising (MEDMS, 20%; EEDMS, 34% reduction) compared to BAL (only 2% reduction). There was no accumulation of cadmium with either MEDMS or EEDMS in any of the other organs examined--spleen, testes, pancreas, and particularly the brain. These compounds enhance the fecal excretion of cadmium by a factor of 25- to 40-fold but have very little effect on the urinary excretion of this element. The present study reveals that the order of overall efficacy is EEDMS greater than MEDMS greater than BAL, considering the liver and whole body burdens of cadmium, but BAL greater than EEDMS greater than MEDMS in terms of the efficacy in reducing cadmium levels in the kidneys.     

The preparation of three new partially deuterated hexadecanethiols for applications in surface chemistry

The synthesis of three partially deuterated hexadecanethiols has been achieved. Thiols CH₃(CH₂)₇(CD₂)₈SH, CD₃(CD₂)₇(CH₂)₈SH and CD₃(CH₂)₁₅SH were targeted, as these compounds, after formation of self‐assembled monolayers on Au(1 1 1) or Au nanoparticles, can provide mechanistic information pertaining to reactive atom migrations within the assembly. The syntheses of each of these compounds called upon Grignard coupling chemistry, which was activated by Li₂CuCl₄. Applicable deuterium containing fragments were either commercially obtained or constructed from by way of an inexpensive and efficient ring opening, protection and dimerization of THF‐d₈. Sulfur incorporation was by thiolacetate substitution or addition reactions. The protocols presented possess general applicability in a number of syntheses requiring block‐deuterated fattyalkyl sections. Copyright © 2008 John Wiley & Sons, Ltd.     

The mobilization of intracellular cadmium by butyl and amyl esters of meso-2,3-dimercaptosuccinic acid

The esters of the general structure, [CH(SH)COOR]2, i.e., Di-BDMS, R = CH2CH(CH3)2; Ds-BDMS, R = CH(CH3)CH2CH3; Di-ADMS, R = CH2CH2CH(CH3)2; and D3-ADMS, R = CH(CH2CH3)2 from the reaction of meso-2,3-dimercaptosuccinic acid with isobutyl, sec-butyl, isoamyl, and 3-amyl alcohols, respectively, have been prepared, characterized, and examined as chelating agents for the removal of cadmium from its aged intracellular deposits. All of these compounds depleted cadmium from such deposits and significantly reduced the whole body levels of cadmium. In the case of three (Ds-BDMS, Di-BDMS, and Di-ADMS) of these compounds, the reductions achieved are equal to or greater than that produced by 2,3-dimercapto-1-propanol (BAL) under similar circumstances. None of these compounds caused any redistribution of cadmium to the brain, and two of them (Di-BDMS and Di-ADMS) caused a very much larger reduction in the liver levels of cadmium than BAL. None was as effective as BAL in reducing kidney levels of cadmium. These compounds are not soluble in water and are administered as solutions in peanut oil. A comparison of the behavior of these compounds with others which have been reported to be effective in reducing body burdens of cadmium in chronic cadmium intoxication reveals that they are among the most effective. An analysis of the manner in which mobilizing efficacy changes with structure indicates that higher, purely alkyl analogs are not expected to be superior to these compounds, though other structural variations may be.     

Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2, and H3 receptors

Histamine is a transmitter that activates the four receptors H₁R to H₄R. The H₃R is found in the nervous system as an autoreceptor and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1‐(2,3‐dihydro‐1‐benzofuran‐2‐yl)methylpiperazines (LINS01 compounds) have the selectivity for the H₃R over the H₄R. Here, we describe their pharmacological properties at the human H₁R and H₂R in parallel with the H₃R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H₃R‐induced histamine responses, but no inhibition of H₂R‐induced responses was seen. Three compounds were weakly able to inhibit H₁R‐induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N‐methyl group improves H₃R affinity while the N‐phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity.     

Reduction of the Estrogenic Side Effects of the Mammary Tumor-Inhibiting Drug [1,2-Bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II) by Variation of Ring Substituents

[1,2-Bis(4-methoxy/4-hydroxyphenyl)ethylenediamine]dichloroplatinum-(II) complexes with Cl-, CH₃-, or OCH₃-substituents in the ortho-positions of the aromatic rings (meso- 1 -PtCl₂, D,L - 1 -PtCl₂, meso- 2 -PtCl₂, D,L - 2 -PtCl₂, meso- 3 -PtCl₂, meso- 4 -PtCl₂, meso- 5 -PtCl₂) were tested on the MDA-MB 231 breast cancer cell line, the lymphocytic leukemia P388, and the estrogen receptor-positive and -negative MXT mammary carcinoma of the mouse (MXT,ER(+)-MC, MXT,ER(?)-MC). The comparison of the effects of methoxy-substituted complexes (meso- 1 -PtCl₂, D,L - 1 -PtCl₂, meso- 3 -PtCl₂) with those of the respective hydroxy-substituted ones (meso- 2 -PtCl₂, D,L - 2 -PtCl₂, meso- 4 -PtCl₂) shows that a reduction of estrogenic effects as well as a total loss of the mammary tumor-inhibiting activity takes place on methylation of the 4-OH group. The exchange of the 2,6-standing chlorine atoms by methyl groups in meso- 2 -PtCl₂ led to the non-estrogenic, but on the MXT,ER(+)-MC highly effective derivative meso- 4 -PtCl₂ which proved to be also cytotoxic on ER(?)-tumors such as MXT,ER(?)-MC, and the P 388 leukemia.     

Spontaneous and oxime-induced reactivation of acetylcholinesterase inhibited by phosphoramidates

Methamidophos (CH₃O(NH₂)P(O)SCH₃) and phosphoramidates, with the general structure RO(NH₂)P(O)OC₆H₄-p-NO₂, in which R = C₂H₅, ClCH₂CH₂, FCH₂CH₂ and F₃CCH₂, as well as (NH₂)₂P(O)OC₂H₄-p-NO₂ were synthesized to investigate the relationship between the rates of inhibition and of spontaneous reactivation of AChE inhibited by these organophosphates and their potential as prophylactics against nerve agent poisoning. The phosphoramidates inhibit electric eel acetylcholinesterase (EEAChE), the bimolecular inhibition rate constants ranging from 5×l0⁴ to 3×l0⁶ M^–1·min^–1 at pH 7.5, 25° C. The inhibited enzymes reactivate spontaneously, with half-lives ranging from 1.3 to 15 h at pH 7.5, 25° C. These half-lives increase 2–4 fold when the temperature is raised to 37° C. Reactivation is accelerated by micromolar concentrations of oximes such as obidoxime and HI-6. Aging of the inhibited enzymes was not observed. Nevertheless, reactivation appears to be incomplete for some of the inhibited enzymes. The title compounds seem promising as prophylactic agents against nerve agent intoxication.     

Lactams IX. A new approach to the synthesis of 5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidines

A new method for the synthesis of derivatives of pyrrolo[2,3-d]pyrimidine has been developed, including the ethylation of 3-carboethoxy-2-pyrrolidone with triethyloxonium fluoborate and the condensation of 2-ethoxy-3-carboethoxy-1,2-dihydropyrrolidine with compounds of the general formula R-C(=NH)NH₂, where R is NH₂, SH, OH, SCH₃, or CH₃.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 5, pp. 16–20, May, 1967.     

1‐[(2,3‐Dihydro‐1‐benzofuran‐2‐yl) methyl]piperazines as novel anti‐inflammatory compounds: Synthesis and evaluation on H3R/H4R

The histamine receptors (HRs) are members of G‐protein‐coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H₃R and H₄R have been explored as targets for drug discovery, including in the search for dual‐acting H₃R/H₄R ligands. The H₄R, the most recent histamine receptor, is a promising target for novel anti‐inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1‐[(2,3‐dihydro‐1‐benzofuran‐2‐yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H₃R/H₄R ligands herein. The results showed the compounds presented affinity (K_i) for H₃R/H₄R in micromolar range, and they are more selective to H₃R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl‐substituted compound LINS01005 has shown the higher affinity of the set for H₄R, but no considerable selectivity toward this receptor over H₃R. LINS01005 showed interesting anti‐inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX‐2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti‐inflammatory agents.     

Pharmacokinetics and tissue distribution of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; a novel ALK5 inhibitor and a potential anti-fibrosis drug

The authors investigated the pharmacokinetics and metabolism of 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide (IN-1130), a novel ALK5 inhibitor, which suppresses renal and hepatic fibrosis, and also exerts anti-metastatic effects on breast cancer-bearing MMTV-cNeu mice model. Plasma half-lives of orally administered IN-1130 were 62.6 min in mice, 76.6?±?10.6 min in dogs, 156.1?±?19.3 min in rats, and 159.9?±?59.9 min in monkeys. IN-1130 showed a high apparent permeability coefficient (P_app) of (45.0?±?2.3)?×?10^?6 cm s^?1 in in vitro permeability tests in a Caco-2 cell monolayer model. The bioavailability of orally administered IN-1130 was 84.9% in dogs and 34.4% in monkeys (oral dose, 5.5 mg kg^?1), 11.4% in rats and 8.95% in mice (oral dose, 50.3 mg kg^?1), respectively. Orally given IN-1130 was readily distributed into liver, kidneys and lungs. The major metabolite of IN-1130 (M1) was detected in the systemic circulation of rat and mouse and was purified and tentatively identified as 3-((4-(3-hydroxyquinoxaline-6-yl)-5-(6-methylpyridine-2-yl)-1H-imidazol-2-yl)methyl)benzamide or 3-((4-(2-hydroxyquinoxalin-6-yl)-5-(6-methylpyridine-2-yl)-1H-imidazol-2-yl)methyl)benzamide. The highest levels of M1 were found in liver. The results of this study suggest that IN-1130 has the potential to serve as an effective oral anti-fibrotic drug.     

Mobilisation of Cadmium by meso‐ and racemic‐2,3‐Dimercaptosuccinic Acid (DMSA) in Rats

A higher efficiency of cadmium binding with racemic than with meso‐2,3‐dimercaptosuccinic acid (rac‐DMSA; meso‐DMSA) was found in an in vitro speciation model by Fang et al. (1996). This finding has not yet been tested in vivo. This paper presents results on mobilisation of cadmium by meso‐ and rac‐DMSA in rats. Cadmium chloride was administered as the radioactive isotope ¹⁰⁹Cd intraperitoneally to all animals. One group was an untreated control and two groups were treated with meso‐ and rac‐DMSA, respectively. Treatment with chelators was applied twice, immediately after ¹⁰⁹Cd and 24 hr afterwards intraperitoneally at the dose of 1 mmol/kg, each. Six days later radioactivity was measured in the liver and kidneys. Whole‐body counting was carried out on days 1, 2, 3 and 6 of the experiment. At the end of the experiment, both treatments caused a decrease in ¹⁰⁹Cd whole‐body retention with rac‐DMSA being more efficient (decrease from 83% in control to 74% and 64% in groups treated with meso‐ and rac‐DMSA, respectively). The same reduction of ¹⁰⁹Cd was obtained by both chelators in the liver (from 57% to about 47%). In the kidney only rac‐DMSA produced significant reduction of ¹⁰⁹Cd (from 5.3% to 3.5%). In conclusion, these results show modest reduction of cadmium in the body by two isoforms of DMSA with rac‐DMSA being slightly more efficient than meso‐DMSA.     

Aromatic compounds from the halotolerant fungal strain of <Emphasis Type="Italic">Wallemia sebi</Emphasis> PXP-89 in a hypersaline medium

A new cyclopentanopyridine alkaloid, 3-hydroxy-5-methyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (1), together with 11 known aromatic compounds were isolated from the secondary metabolites of the halotolerant fungal strain Wallemia sebi PXP-89 in 10% NaCl. Their structures including the absolute configurations of (2S,3S)-1-(4-hydroxyphenyl)butane-2,3-diol (2), (2R,3S)-1-(4-hydroxyphenyl)butane-2,3-diol (3), and (S)-3-hydroxy-4-(4-hydroxyphenyl)-2-one (4) were elucidated by spectroscopic analysis and a modified Mosher’s method. Compound 1 exhibited antimicrobial activity against Enterobacter aerogenes with a MIC of 76.7 μM. The absolute configurations of compounds 2–4 were determined for the first time.     

Antitumor activities of some new 1,3,2-oxaza- and 1,3,2-diazaphosphorinanes against K562, MDA-MB-231, and HepG2 cells

New X-substituted 1,3,2-oxazaphosphorinanes, where X?=?NHC₆H₅ (1), NHC₆H₄S(O)₂NH₂-4 (2), NHC₆H₄OCH₃-4 (3), NHC₆H₄NO₂-4 (4), OC₆H₄CH₃-4 (5), NHC(O)C₆H₄NO₂-4 (6), plus one X-substituted 1,3,2-diazaphosphorinane, where X?=?NHC₆H₄S(O)₂NH₂-4 (7), were synthesized and characterized by NMR, IR spectroscopy, and elemental analysis. The antitumor activities of these compounds, cyclophosphamide (CP), sulfanilamide (SA), and two X-substituted 5,5-dimethyl-1,3,2-diazaphosphorinanes, where X?=?NHC₆H₅ (8) OC₆H₄CH₃-4 (9), were evaluated by cell culture on K562, MDA-MB-231, and HepG2 cell lines using MTT cell proliferation assay. The IC₅₀ values for CP and compounds 1–9 were in the range of 0.06?μM (for inhibition of HepG2 cells by compound 3) to 3.17?μM (for inhibition of HepG2 cells by compound 8). It was found that compounds 2 and 7 containing sulfonamide substituent and also SA itself are the best candidates for antitumor activity very close to CP.     

Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals

Pentavalent and trivalent organoarsenic compounds belong to the major metabolites of inorganic arsenicals detected in humans. Recently, the question was raised whether the organic arsenicals represent metabolites of a detoxification process or methylated species with deleterious biological effects. In this study, the effects of trivalent arsenite (AsO₃ ³⁻; iA^III), the pentavalent organoarsenic compounds monomethylarsonic acid (CH₃AsO(OH)₂; MMA^V) and dimethylarsinic acid ((CH₃)₂AsO(OH); DMA^V) and the trivalent compounds monomethylarsonous acid (CH₃As(OH)₂, MMA^III) and dimethylarsinous acid ((CH₃)₂As(OH); DMA^III) were tested on glutamate receptors and on voltage-operated potassium and sodium channels heterologously expressed in Xenopus oocytes. Membrane currents of ion channels were measured by conventional two-electrode voltage-clamp techniques. The effects of arsenite were tested in concentrations of 1–1,000 μmol/l and the organic arsenical compounds were tested in concentrations of 0.1–100 μmol/l. We found no significant effects on voltage-operated ion channels; however, the arsenicals exert different effects on glutamate receptors. While MMA^V and MMA^III significantly enhanced ion currents through N-methyl-d-aspartate (NMDA) receptor ion channels with threshold concentrations <10 μmol/l, DMA^V and DMA^III significantly reduced NMDA-receptor mediated responses with threshold concentrations <0.1 μmol/l; iA^III had no effects on glutamate receptors of the NMDA type. MMA^III and DMA^V significantly reduced ion currents through α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor ion channels with threshold concentrations <10 μmol/l (MMA^III) and <1 μmol/l (DMA^V). MMA^V and iA^III had no significant effects on glutamate receptors of the AMPA type. The effects of MMA^V, MMA^III, DMA^V and DMA^III on glutamate receptors point to a neurotoxic potential of these substances.Katharina Krüger and Janina Gruner contributed equally to this work.     

A fragmentation study on four C19-diterpenoid alkaloids by electrospray ionization ion-trap time-of-flight tandem mass spectrometry

High-resolution electrospray ionization ion-trap time-of-flight tandem mass spectrometry (HR-ESI-IT-TOF-MSⁿ) in positive-ion mode was used to determine the accurate masses and fragmentation pathways of four C₁₉-diterpenoid alkaloids, aconitine (1), yunnaconitine (2), crassicauline A (3), and benzoylmesaconine (4). The [M+H]⁺ ions of compounds 1–4 were readily observed in conventional single-stage mass spectrometry. Based on the MS^1–6 analyses, detailed fragmentation rules of the four compounds were proposed. The neutral losses of AcOH, MeOH, H₂O, CO, C₂H₄, PhCOOH and p-OMePhCOOH segments were the characteristic eliminations from the precursor ions due to the presence of acetyl, methoxyl, hydroxyl, N-ethyl, benzoyl and p-methoxyl-benzoyl units in the structures. Benefited from the high resolution of the mass analyzer, the loss of 28 Da corresponding to CO or CH₄ segment in product ions was unambiguously distinguished. The losing sequence of the main substituent groups was summarized as: C(8)-acetyl>C(16)-methotyl>C(15)-hydroxyl>C(6)-methoxyl>C(1)-methoxyl/C(3)-hydroxyl>C(18)-methoxyl>>C(13)-hydroxyl. The sequential loss of (16)-methoxyl moiety and CO (generating from enol–ketone tautomerism) groups could be recognized as the characteristic eliminations for the compounds with C(16)-methoxyl and C(15)-hydroxyl groups simultaneously. The application of HR-ESI-IT-TOF-MSⁿ technique to investigate the fragmentation of C₁₉-diterpenoid alkaloids provided useful information to understand their fragmentation behaviors.