Synthesis and spectral studies of platinum complexes with amide-group containing ligands

Summary Complexes of platinum(II) with 2-(acetylamino)benzoic acid, 2-(benzoylamino)benzoic acid, maleanilic acid, malea-1-naphthanilic acid, 2-(phenylamino)benzoic acid, 2-[(2-aminophenylamino)carbonyl]benzoic acid, 2-(aminobenzoyl)benzoic acid, 2-[1-naphthalenylamino)-carbonyl]benzoic acid, 2-(2-aminobenzoylamino)-benzoic acid have been prepared and characterized by elemental analysis, molar conductivity measurements, thermal data and i.r., electronic and n.m.r. spectra.     

Zur Synthese sulfonierter Derivate von 2,3-Dimethylanilin und 3,4-Dimethylanilin

On the Synthesis of Sulfonated Derivatives of 2,3-Dimethylaniline and 3,4-Dimethylaniline Baking the hydrogensulfate salt of 2,3-dimethylaniline ( 1 ) or of 3,4-dimethylaniline ( 2 ) led to 4-amino-2,3-dimethylbenzenesulfonic acid ( 4 ) and 2-amino-4,5-dimethylbenzenesulfonic acid ( 5 ), respectively (Scheme 1). The sulfonic acid 5 was also obtained by treatment of 2 with sulfuric acid or by reaction of 2 with amidosulfuric acid. 3-Amino-4,5-dimethylbenzenesulfonic acid ( 3 ) and 5-Amino-2,3-dimethylbenzenesulfonic acid ( 6 ) were prepared by sulfonation of 1,2-dimethyl-3-nitrobenzene ( 9 ) to 3,4-dimethyl-5-nitrobenzenesulfonic acid ( 11 ) and of 1,2-dimethyl-4-nitrobenzene ( 10 ) to 2,3-dimethyl-5-nitrobenzenesulfonic acid ( 12 ), respectively, with subsequent Béchamp reduction (Scheme 1). Preparations of 2-amino-3,4-dimethylbenzenesulfonic acid ( 7 ) and of 6-amino-2,3-dimethylbenzenesulfonic acid ( 8 ) were achieved by the sulfur dioxide treatment of the diazonium chlorides derived from 3,4-dimethyl-2-nitroaniline ( 24 ) and from 2,3-dimethyl-6-nitroaniline ( 31 ) to 3,4-dimethyl-2-nitrobenzenesulfonyl chloride ( 29 ) and 2,3-dimethyl-6-nitrobenzenesulfonyl chloride ( 32 ), respectively, followed by hydrolysis to 3,4-dimethyl-2-nitrobenzenesulfonic acid ( 30 ) and 2,3-dimethyl-6-nitrobenzenesulfonic acid ( 33 ), and final reduction (Scheme 3). Compound 7 was also synthesized by reaction of 4-chloro-2,3-dimethylaniline ( 23 ) with amidosulfuric acid to 2-amino-5-chloro-3,4-dimethylbenzenesulfonic acid ( 20 ) and subsequent hydrogenolysis (Scheme 2). 4′-Bromo-2′, 3′-dimethyl-acetanilide ( 13 ) and 4′-chloro-2′, 3′-dimethyl-acetanilide ( 14 ) on treatment with oleum yielded 5-acetylamino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 17 ) and 5-acetylamino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 18 ), respectively. Their structures were proven by hydrolysis to 5-amino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 21 ) and 5-amino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 22 ), followed by reductive dehalogenation to 3 .     

Solid-phase extraction of acidic herbicides

A discussion of solid-phase extraction method development for acidic herbicides is presented that reviews sample matrix modification, extraction sorbent selection, derivatization procedures for gas chromatographic analysis, and clean-up procedures for high-performance liquid chromatographic analysis. Acidic herbicides are families of compounds that include derivatives of phenol (dinoseb, dinoterb and pentachlorophenol), benzoic acid (acifluorfen, chloramben, dicamba, 3,5-dichlorobenzoic acid and dacthal--a dibenzoic acid derivative), acetic acid [2,4-dichlorophenoxyacetic acid (2,4-D), 4-chloro-2-methylphenoxyacetic acid (MCPA) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)], propanoic acid [dichlorprop, fluazifop, haloxyfop, 2-(4-chloro-2-methylphenoxy)propanoic acid (MCPP) and silvex], butanoic acid [4-(2,4-dichlorophenoxy)butanoic acid (2,4-DB) and 4-(4-chloro-2-methylphenoxy)butanoic acid (MCPB)], and other miscellaneous acids such as pyridinecarboxylic acid (picloram) and thiadiazine dioxide (bentazon).     

Synthesis and spectral studies of copper(II) complexes with amide group ligands

Complexes of copper(II) with 2-(acetylamino)benzoic acid, 2-(benzoylamino) benzoic acid, 2-(aminocarbonyl)benzoic acid, 2-[(phenylamino)carbonyl]benzoic acid, 2-[(1-naphthalenylamino)carbonyl]benzoic acid, 2-[(2-aminophenylamino)carbonyl]benzoic acid, 2-aminobenzanilide, 2(aminobenzoyl)benzoic acid, maleanilic acid and malea-1-naphthalanilic acid have been prepared and characterized by chemical analyses, molar conductivity, magnetic susceptibility measurements, thermal data, IR, electronic and ESR spectra. The visible and ESR spectral studies of these complexes (except those of maleanilic acid and malea-1-naphthalanilic acid) indicate that they are monomeric having either square planar or distorted octahedral geometry around Cu(II). The Cu(II) complexes of maleanilic acid and malea-1-naphthalanilic acid have been tentatively assigned dimeric structures. From the ESR spectra of Cu(II) complexes various parameters have been calculated.     

Zur Synthese sulfonierter Derivate von 2-Fluoranilin

Syntheses of Sulfonated Derivatives of 2-Fluoroaniline Synthesis of 4-amino-3-fluorobenzenesulfonic acid ( 3 ) was achieved in two ways: reaction of 2-fluoroaniline ( 1 ) with amidosulfonic acid and by first conventionally converting 4-nitro-3-fluoroaniline ( 8 ) to 4-nitro-3-fluorobenzenesulfonyl chloride ( 9 ) followed subsequently by hydrolysis to 3-fluoro-4-nitrobenzenesulfonic acid ( 10 ) and reduction. Hydrogenolysis of 3 gave sulfanilic acid ( 7 ). Both, sulfonation of fluorobenzene ( 6 ) to 4-fluorobenzenesulfonic acid ( 11 ) followed by nitration and sulfonation of 1-fluoro-2-nitrobenzene ( 12 ) led to 4-fluoro-3-nitrobenzenesulfonic acid ( 13 ). Reduction of 13 gave the isomeric 3-amino-4-fluorobenzenesulfonic acid ( 4 ), which was also obtained both by sulfonation of 1 and by sulfonation of o-fluoroacetanilide ( 14 ) followed by hydrolysis. Selective hydrogenolyses of 2-amino-5-bromo-3-fluorobenzenesulfonic acid ( 15 ), prepared by reaction of 4-bromo-2-fluoroaniline ( 16 ) with amidosulfonic acid, and of 4-amino-2-bromo-5-fluorobenzenesulfonic acid ( 20 ), obtained by sulfonation of 5-bromo-2-fluoroaniline ( 19 ) yielded the isomers 2-amino-3-fluorobenzenesulfonic acid ( 5 ) and 3 , respectively. The fourth isomer, 3-amino-2-fluorobenzenesulfonic acid ( 2 ), was synthesized by sulfur dioxide treatment of the diazonium chloride derived from 2-fluoro-3-nitroaniline ( 21 ) to 2-fluoro-3-nitrobenzenesulfonyl chloride ( 22 ), followed by hydrolysis to 2-fluoro-3-nitrobenzenesulfonic acid ( 23 ) and final Béchamp-reduction.     

Pentacyclic triterpenoids from the aerial parts of Lantana camara

Three new pentacyclic triterpenoids, camaryolic acid (1), methylcamaralate (2) and camangeloyl acid (3) and six known compounds beta-sitosterol 3-O-beta-D-glucopyranoside (4), octadecanoic acid (5), docosanoic acid (6), palmitic acid (7), camaric acid (8) and lantanolic acid (9) were isolated from the aerial parts of Lantana camara. Structures of the new compounds were elucidated by spectroscopic and chemical methods.     

Energetics and structural properties, in the gas phase, of trans-hydroxycinnamic acids

We have studied the energetics and structural properties of trans-cinnamic acid (CA), o-, m-, and p-coumaric acids (2-, 3-, and 4-hydroxycinnamic acids), caffeic acid (3,4-dihydroxycinnamic acid), ferulic acid (4-hydroxy-3-methoxycinnamic acid), iso-ferulic acid (3-hydroxy-4-methoxycinnamic acid), and sinapic acid (3,5-dimethoxy-4-hydroxycinnamic acid). The experimental values of Δ(f)H(m)°(g), determined (in kJ·mol(-1)) for CA (-229.8 ± 1.9), p-coumaric acid (-408.0 ± 4.4), caffeic acid (-580.0 ± 5.9), and ferulic acid (-566.4 ± 5.7), allowed us to derive Δ(f)H(m)°(g) of o-coumaric acid (-405.6 ± 4.4), m-coumaric acid (-406.4 ± 4.4), iso-ferulic acid (-565.2 ± 5.7), and sinapic acid (-698.8 ± 4.1). From these values and by use of isodesmic/homodesmotic reactions, we studied the energetic effects of π-donor substituents (-OH and -OCH(3)) in cinnamic acid derivatives and in the respective benzene analogues. Our results indicate that the interaction between -OCH(3) and/or -OH groups in hydroxycinnamic acids takes place without significant influence of the propenoic fragment.     

金属指示剂-紫外分光法研究Ti(Ⅳ)-羧酸、羟基羧酸的配位作用

本文以铬变酸为Ti(Ⅳ)的金属指示剂,研究了pH1.50时10种羧酸对Ti(Ⅳ)的相对配位能力,用推导出的公式处理光吸收的测量值并定量地求出其相对配位能力,还研究了Ti(Ⅳ)和羧酸、羟基羧酸的紫外光谱,探讨了成键方式。     

Metabolism of terniary compounds. V. Decomposition of diincarbonic acids and hydrocarbons in vivo

10,12-Heneicosadiynoic acid (I), 5,7-hexadecadiynoic acid (IV), and 10,12-docosadiynedioic acid (VI) were fed to rats. As metabolites 4,6-undecadiynedioic acid (II), 5,7-dodecadiynedioic acid (V), and 4,6-decadiynedioic acid (VII) respectively were isolated from the urine. 10,12-Heptadecadiynoic acid (III) also yielded metabolite II. Furthermore 9,11-eicosadiyne (X) and for comparison purposes eicosane (XI), hexadecanedioic acid (VIII), and docosanedioic acid (IX) were fed. X and XI were incorporated into depot fat and liver lipids to a cetain degree. The diynes I, II, IV, and X are new compounds.     

Synthesis of mixed acid anhydrides from methane and carbon dioxide in acid solvents

[reaction: see text] The reaction of CH(4) with CO(2) has been performed in anhydrous acids using VO(acac)(2) and K(2)S(2)O(8) as promoters. NMR analysis establishes that the primary product is a mixed anhydride of acetic acid and the acid solvent. In sulfuric acid, the overall reaction is CH(4) + CO(2) + SO(3) --> CH(3)C(O)-O-SO(3)H. Hydrolysis of the mixed anhydride produces acetic acid and the solvent acid. When trifluoroacetic acid is the solvent, acetic acid is primarily formed via the reaction CH(4) + CF(3)COOH --> CH(3)COOH + CHF(3).     

Gold- and gold-palladium/poly(1-vinylpyrrolidin-2-one) nanoclusters as quasi-homogeneous catalyst for aerobic oxidation of glycerol

Glycerol was oxidized catalytically under aerobic conditions in the presence of monometallic nanoclusters of gold on poly(1-vinylpyrrolidin-2-one) (PVP) to give hydroxymalonic acid (tartronic acid) as the major product, together with 2,3-dihydroxypropanoic acid (glyceric acid) and hydroxyacetic acid (glycolic acid) as minor products. In contrast, oxalic acid was selectively obtained when bimetallic Au-Pd:PVP nanoclusters were used as the catalyst.     

Zur Synthese sulfonierter Derivate von 4- und 5-Aminoindan

On the Synthesis of Sulfonated Derivatives of 4- and 5-Aminoindan Baking the hydrogensulfate salt of 4-aminoindan (1) and 5-aminoindan (2) led, respectively, to 4-aminoindan-7-sulfonic acid (3) and 5-aminoindan-6-sulfonic acid (4). Acid 4 was also obtained by direct sulfonation of 2. 4-Aminoindan-6-sulfonic acid (5) and 6-aminoindan-4-sulfonic acid (6) were prepared by sulfonation of 4-nitroindan (7) and 5-nitroindan (9) , respectively, to 4-nitroindan-6-sulfonic acid (8) and 6-nitroindan-4-sulfonic acid (10) , followed by a Béchamp-reduction. Treatment of 1 with amidosulfuric acid gave 3 , whereas the same reaction with 2 led to a mixture of 4 and 5-aminoindan-4-sulfonic acid (11). Independent synthesis of 11 was achieved by the following sequence of reactions: sulfur dioxide treatment of the diazonium chloride derived from 4-amino-5-nitrodan (13) gave 5-nitroindan-4-sulfonyl chloride (14) ; hydrolysis to 5-nitroindan-4-sulfonic acid (15) , and final reduction. The 4-aminoindan-5-sulfonic acid (16) was synthesized by treatment of 4-amino-7-bromoindan (18) with amidosulfuric acid to give 4-amino-7-bromoindan-5-sulfonic acid (19) followed by hydrogenolysis. Sulfonation of 4-acetyl-amino-7-bromoindan (17) with oleum followed by hydrolysis led to 7-amino-4-bromoindan-5-sulfonic acid (20) , the structure of which was confirmed by reductive dehalogenation to 5 .     

Triterpenes from the spores of Ganoderma lucidum and their cytotoxicity against meth-A and LLC tumor cells

Six new highly oxygenated lanostane-type triterpenes, called ganoderic acid gamma (1), ganoderic acid delta (2), ganoderic acid epsilon (3), ganoderic acid zeta (4), ganoderic acid eta (5) and ganoderic acid theta (6), were isolated from the spores of Ganoderma lucidum, together with known ganolucidic acid D (7) and ganoderic acid C2 (8). Their structures of the new triterpenes were determined as (23S)-7beta,15alpha,23-trihydroxy-3,11-dioxolanosta-8, 24(E)-diene-26-oic acid (1), (23S)-7alpha,15alpha23-trihydroxy-3,11-dioxolanosta-8, 24(E)-diene-26-oic acid (2), (23S)-3beta3,7beta, 23-trihydroxy-11,15-dioxolanosta-8,24(E)-diene-26-oic acid (3), (23S)-3beta,23-dihydroxy-7,11,15-trioxolanosta-8, 24(E)-diene-26-oic acid (4), (23S)-3beta,7beta,12beta,23-tetrahydroxy-11,15-dioxolanos ta-8,24(E)-diene-26-oic acid (5) and (23S)-3beta,12beta23-trihydroxy-7,11,15-trioxolanosta-8,24(E )-diene-26-oic acid (6), respectively, by chemical and spectroscopic means, which included the determination of a chiral center in the side chain by a modification of Mosher's method. The cytotoxicity of the compounds isolated from the Ganoderma spores was carried out in vitro against Meth-A and LLC tumor cell lines.     

SYNTHESIS AND CHARACTERIZATION OF POLY(ASPARTIC ACID) AND ITS DERIVATIVES AS BIODEGRADABLE MATERIALS

ABSTRACT

Three types of modified poly(aspartic acid)s, such as poly(aspartic acid-co-aminocarboxylic acid) (4), alkylamine modified poly(aspartic acid) (5) and crosslinked poly(aspartic acid) (6), were synthesized and calcium-ion chelating ability, hygroscopicity and water absorption were evaluated. The calcium-ion chelating ability of 4 depended on the kind of aminocarboxylic acids and the content of aminocarboxylic acid in the copolymer. The highest value was 3 times higher than that of poly(acrylic acid) with a M_w of 14000. The highly modified PASP, e.g., 50 mol% lauryl amine modified poly(aspartic acid), showed the highest by grogroscopicity among homopoly(aspartic acid)s and modified poly(aspartic acid)s. The maximum swelling of poly(aspartic acid) hydrogel prepared by the γ-irradiation of homopoly(as-partic acid) was 3400 g-deionized water/g-dry hydrogel.     

Copper(II)-mediated resolution of alpha-halo carboxylic acids with chiral O,O'-dibenzoyltartaric acid: spontaneous racemization and crystallization-induced dynamic resolution

Herein we present a new example of coordination-mediated resolution of racemic acids by a chiral acid. The reaction of copper(II) acetate monohydrate, optically pure O,O'-dibenzoyltartaric acid (DBTA) and racemic alpha-bromo-2-chlorophenylacetic acid (HL1) in acetonitrile solution afforded a binuclear copper(II) complex with D-DBTA dianion, alpha-bromo-2-chlorophenylacetate and acetate as ligands. After decomposition of the complex with acid, the optically active acid ((R)-HL1) was obtained. Similarly, alpha-bromo-2-fluorophenylacetic acid (HL2), alpha-bromo-2-bromophenylacetic acid (HL3), alpha-chloro-2-chlorophenylacetic acid (HL4), alpha-chloro-2-fluorophenylacetic acid (HL5), alpha-bromophenylacetic acid (HL6), alpha-bromo-4-chlorophenylacetic acid (HL7), 2-bromopropionic acid (HL8) and 2-chloropropionic acid (HL9) were resolved by the same method. Satisfactory results were obtained for HL2 to HL5. For HL6 and HL7, only racemic acids were obtained. For the two alpha-halo aliphatic acids (HL8 and HL9), poor enantioselectivity was obtained. It is more interesting that three acids (HL1, HL2 and HL3) could spontaneously racemize in acetonitrile solution, which resulted in crystallization-induced dynamic resolution (CIDR) with greater than 50% yield.     

A new caffeoyl quinic acid from aster scaber and its inhibitory activity against human immunodeficiency virus-1 (HIV-1) integrase

The phytochemical study of the aerial parts of Aster scaber Thunb. (Asteraceae) yielded a new caffeoyl quinic acid, (-) 3,5-dicaffeoyl-muco-quinic acid (2) and three known compounds, (-) 3,5-dicaffeoyl quinic acid (1), (-) 4,5-dicaffeoyl quinic acid (3), (-) 5-caffeoyl quinic acid (4). The structures were established by high resolution spectroscopic methods. The antiviral effects against HIV-1 integrase of the compounds was evaluated. (-) 3,5-Dicaffeoyl-muco-quinic acid (2) exhibited potent antiviral activity with an IC50 value of 7.0 +/- 1.3 microg/ml.     

Umsetzungen von säurechloriden mit trimethylsilyldiphenylphosphin : II. Darstellung und eigenschaften aromatischer Säurephosphide

Aromatic acid chlorides react with trimethylsilyldiphenylphosphine (I) to give the acid phosphides (IIa-i) and (V), and the acid chloride phosphide (IV). With excess of (I), (IIc), and (IIi) yield the α-diphenylphosphinylbenzyl esters of the corresponding diphenylphosphinic acids (IIIc) and (IIIi). (IIIi) is also formed by oxidation of (IIi) with oxygen. The COP bond of the acid phosphides is easily solvolysed. In terephthalic acid chloride diphenylphosphide (IV) the acid chloride group can react selectively. Thus p-anisidine gives the anisididediphenylphosphide (VI) and methanol the diphenylphosphide methyl ester (VII). Benzene sulfonylchloride reacts with (I) to give the phenylthiol ester of the diphenylphosphinic acid (VIII).     

Stereoblock poly(lactic acid): synthesis via solid-state polycondensation of a stereocomplexed mixture of poly(L-lactic acid) and poly(D-lactic acid)

Stereoblock poly(lactic acid) consisting of D- and L-lactate stereosequences can be successfully synthesized by solid-state polycondensation of a 1:1 mixture of poly(L-lactic acid) and poly(D-lactic acid). In the first step, melt-polycondensation of L- and D-lactic acids is conducted to synthesize poly(L-lactic acid) and poly(D-lactic acid) with a medium-molecular-weight, respectively. In the next step, these poly(L-lactic acid) and poly(D-lactic acid) are melt-blended in 1:1 ratio to allow formation of their stereocomplex. In the last step, this melt-blend is subjected to solid-state polycondensation at temperature where the dehydrative condensation is allowed to promote chain extension in the amorphous phase with the stereocomplex crystals preserved. Finally, stereoblock poly(lactic acid) having high-molecular-weight is obtained. The stereoblock poly(lactic acid) synthesized by this way shows a higher melting temperature in consequence of the controlled block lengths and the resulting higher-molecular-weight. The product characterization as well as the optimization of the polymerization conditions is described. Changes in M(w) of stereoblock poly(lactic acid) (sb-PLA) as a function of the reaction time.     

Zur Synthese sulfonierter Derivate von 4-Amino-1,3-dimethylbenzol und 2-Amino-1,3-dimethylbenzol

Syntheses of Sulfonated Derivatives of 4-Amino-1, 3-dimethylbenzene and 2-Amino-1, 3-dimethylbenzene Direct sulfonation of 4-amino-1, 3-dimethylbenzene (1) and sulfonation of 4-nitro-1,3-dimethylbenzene ( 4 ) to 4-nitro-1,3-dimethylbenzene-6-sulfonic acid ( 3 ) followed by reduction yield 4-amino-1,3-dimethylbenzene-6-sulfonic acid ( 2 ). The isomeric 5-sulfonic acid ( 5 ) however is prepared solely by baking the acid sulfate salt of 1 . Reaction of sulfur dioxide with the diazonium chloride derived from 2-amino-4-nitro-1,3-dimethylbenzene ( 7 ) leads to 4-nitro-1,3-dimethylbenzene-2-sulfonyl chloride ( 8 ), which is successively hydrolyzed to 4-nitro-1,3-dimethylbenzene-2-sulfonic acid ( 9 ) and reduced to 4-amino-1, 3-dimethylbenzene-2-sulfonic acid ( 6 ). Treatment of 4-amino-6-bromo-1,3-dimethylbenzene ( 12 ) and 4-amino-6-chloro-1, 3-dimethylbenzene ( 13 ), the former obtained by reduction of 4-chloro-6-nitro-1,3-dimethyl-benzene ( 10 ) and the latter from 4-chloro-6-nitro-1, 3-dimethylbenzene ( 11 ), with oleum yield 4-amino-6-bromo-1,3-dimethylbenzene-2-sulfonic acid ( 14 ) and 4-amino-6-chloro-1,3-dimethylbenzene-2-sulfonic acid ( 15 ) respectively; subsequent carbon-halogen hydrogenolyses of 14 and 15 lead also to 6 (Scheme 1). Baking the acid sulfate salt of 2-amino-1, 3-dimethylbenzene ( 17 ) gives 2-amino-1, 3-dimethylbenzene-5-sulfonic acid ( 16 ), whereas the isomeric 4-sulfonic acid ( 18 ) can be prepared by either of the following three possible pathways: Sulfonation of 2-nitro-1,3-dimethylbenzene ( 20 ) to 2-nitro-1,3-dimethylbenzene-4-sulfonic acid ( 21 ) followed by reduction or sulfonation of 2-acetylamino-1,3-dimethylbenzene ( 19 ) to 2-acetylamino-1,3-dimethylbenzene-4-sulfonic acid ( 22 ) with subsequent hydrolysis or direct sulfonation of 17 . Further sulfonation of 18 yields 2-amino 1,3-dimethylbenzene-4,6-disulfonic acid ( 23 ), the structure of which is independently confirmed by reduction of unequivocally prepared 2-nitro- 1,:3-dimethylbenzene-4,6-disulfonic acid ( 24 )(Scheme 2).     

Alpha-glucosidase inhibitors ellagic acid derivatives with immunoinhibitory properties from Terminalia superba

Fractionation of stem barks of Terminalia superba yielded two new ellagic acid derivatives, 3,4'-di-O-methylellagic acid 3'-O-beta-D-xylopyranoside (1) and 4'-O-galloy-3,3'-di-O-methylellagic acid 4-O-beta-D-xylopyranoside (2) together with known 3,3'-di-O-methylellagic acid, ellagic acid and 3,3'-di-O-methylellagic acid 4'-O-beta-D-xylopyranoside. Compounds (1) and (2) showed significant alpha-glucosidase inhibition activity and possessed significant immunoinhibitory activities with no cytotoxic effects.