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A series of ω-(4-aminophenylsulfonamido)alkyl disulfides and ω-(4-aminophenylsulfonamido)alkanethiosulfates was synthesized from the reaction of p-acetamidobenzenesulfanilyl chloride and either the aminoalkyl disulfide dihydrobromide or the aminoalkyl bromide hydrobromide followed by sodium thiosulfate. Several of the compounds showed inhibitory activity against dihydropteroate synthetase isolated from a sulfanilamide-resistant strain of Neisseria gonorrhoeaeof the same order of activity as that of sulfanilamide. An increase in the hydrophobic nature of the sulfanilamide structure did not increase inhibitory activity against this enzyme.

Aseries of N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-5-aralkylidenerhodanines was synthesized, and the acetyl groups were removed to give N-β-D-glucopyranosyl-5-aralkylidenerhodanines without cleavage of the rhodanine ring by means of acid hydrolysis. Alkaline hydrolysis with ammonia in methanol resulted in cleavage to N-glucosylthiourea, providing evidence for N-glycoside formation. A number of the rhodanine derivatives, especially those with nitro or chloro groups in the aromatic ring, showed antibacterial activity. N-β-D-Glucopyranosyl-5-(4-nitrobenzylidene)rhodanine showed antiviral activity by inhibition of viral RNA synthesis. Some effect on hlood sugar levels also was observed with several rhodanines.

N-Methylthiourea, methanesulfonamide, and trifluoro- methanesulfonamide derivatives of amphetamine, 4-nitroamphetamine, and 4-aminoamphetamine were synthesized. The N-methylthiourea derivative of amphetamine, as well as the triethylammonium salt of the dithiocarbamate, produced significant depressor effects in normo- tensive dogs. N,N′-Bis(methanesulfonyl)-l-methyl-2-(4:amino- phenyl)ethylamine and N-trifluoromethanesulfonyl-l-methyl-2-phe- nylethylamine, but not N-methanesulfonyl-l-methyl-2-phonylethylamme and N-trifluoroacetyl-1-methyl-2-(4-trifluoromethanesulfonamidophenyl)ethylamine, showed significant antiobesity effects in rats.

A series of heterocyclic analogs of amphetamine was synthesized. The heterocycles employed included the 2-furyl, 2-thienyl, 3-methyl-2-thienyl, 3-pyridyl, and 6-methyl-2-pyridyl rings. The aliphatic amine group was converted to the N-methylthiourea, dithiocarbamate, methanesulfonyl, trifluoromethanesulfonyl, and trifluoroacetyl functions since similar conversions of the β-phenethylamine structure had shown blood pressure-lowering effects and some loss of behavioral effects. p-Chlorophenyl and 1-naphthyl analogs were also converted to these derivatives. Behavioral and other biological effects, including antiarthritic, passive cutaneous anaphylactic, and antimicrobial, were observed. The 3-methyl-2-thienyl analog of amphetamine significantly increased papillary muscle contractile force without producing arrhythmias.

A method of measuring the inhibition of sulfation of mucopolysaccharides employed the coupled-enzyme system of Wortman. The procedure utilized the phenol and mucopolysaccharide sulfotransferases of rabbit liver extract. Compounds tested as inhibitors included substituted salicyclic acids and related compounds, some hydroxamic acids, other agents capable of metal-ion complexation, and miscellaneous compounds, mostly containing sulfur. The most effective inhibitors were vanillin oxime, salicylhydroxamic acid, and other substituted salicylic acid derivatives of weaker acid strength than salicylic acid.

Metal-binding stability constants for several heterocyclic aminoalkyl disulfides and thiosulfates with Ni(II) and Al(III) were determined. The data obtained indicated that both classes of compounds were acting as bidentate chelating agents and that the heterocyclic rings apparently prevented tridentate behavior of the disulfides because of steric hindrance. The magnitude of the constants indicated that metal complexes of these compounds could exist in a cellular environment, but no correlation with radiation-protective activity was apparent.

Binding parameters for a series of N-heterocyclic aminoethyl disulfides and thiosulfates to DNA were determined at different ionic strengths and pH values. None of the thiosulfates showed any binding ability, but the disulfides revealed DNA binding abilities that were suppressed both by increased ionic strength and hydrogen-ion concentration. No correlation between DNA binding ability and radiation protective activity in mice was evident.

A series of coordination compounds of platinum(II) and palladium(II) with several amino‐ and heterocyclic aminoalkyl mercaptans was synthesized, and their structures were determined by IR absorption and elemental analyses. Because of the tendency of the mercapto group to undergo oxidation on reaction with metals, as observed with copper(II), the complexes were obtained by use of the aminoalkyl‐thiosulfates, which decomposed to the thiol in either acid or alkaline solution. Furthermore, palladium‐sulfide complex formation by reaction with an aminoalkyltrithiocarbonate made it possible to distinguish between metal‐sulfur and metal‐nitrogen bonds in the 650‐400‐cm−1region. Anticancer screening against L‐1210 lymphoid leukemia in mice did not reveal positive activity among the compounds tested.

Condensations of carbon disulfide were carried out with amino, chloro, and diamino heterocycles to give condensed ring thiazoline-2-thiones and imidazoline-2-thiones, with cyanomethyl heterocycles to give dithio acid derivatives, and with heterocyclic sulfonamides to give sulfonyldithiocarbamates. Of several examples tested, pyrido[3,2-d]thiazoline-2-thione, disodium 2-(5-chloro-2-thienyl)-3,3-dimercaptoacrylonitrile, triethylammonium 4-sulfamoylphenyldithiocarbamate, ammonium β-phenethyldithiocarbamate, and methyl N-(thiophene-2-sulfonyl)dithiocarbamate, only the last-named compound showed any radiation protection for mice. Several compounds gave negative tests for antimalarial activity.

Reaction of 1-methylquinolinium-2-dithioacetic acid zwitterions with excess methyl iodide in dimethylformamide gave the corresponding bis(2-methylthio)vinyl derivatives. These compounds were more soluble in both aqueous and organic media than the dithioacetic acid zwitterions but showed comparable antileukemic activity in mice. Reaction with morpholine converted a bis(2-methylthio)vinyl derivative almost quantitatively to the 2-mono(methylthio)-2-morpholino derivative. Leukemia cell culture studies of the 6-methyl derivative showed no effect on cell cycle processes.

A series of thiosemicarbazones and thioureas having an open-chain analogue of the ribosyl group, the 2-acetoxyethoxymethyl moiety, has been synthesized. Significant growth inhibitory activity versus gram-positive and gram-negative organisms, a yeast, and a mold has been found with the 2-acetoxyethoxymethyl derivatives of N-alkyl-aryl-, and heteroaryl-thiosemicarbazones and thioureas. The molecules may function as inhibitors of ribonucleotide reductase or in utilization of the carbamyl group in pyrimidine biosynthesis.

The title compounds were prepared in the attempt to provide methylthio and bis(methylthio) analogues of the radioprotective pyridinium- and quinolinium-2-dithioacetic acid derivatives in which the methylthio function is attached to an amino group through an aliphatic chain. The methyl 3-amino-2-phenyldithiopropenoates were obtained by the reaction of amines with 4-phenyl-3-methylthio-1,2-dithiolium iodide, and the 1,1-bis(methylthio)-3-amino-2-phenyl-1-propenes were obtained by methylation and reduction of the dithiopropenoates. The methyl dithiopropenoates with aliphatic substituents on the nitrogen gave only fair or poor radiation protection in mice, and one example of the reduced bis(methylthio) derivatives tested was inactive. The precursor 1,2-dithiole-3-thione and its methiodide, predicted to be radiation protective, were found inactive in this test.

With the assumption that the radiation-protective ability (whole body protection of mice) of the bis(methylthio) and methylthio amino derivatives of the 1-methylquinolinium-2-dithioacetic acids may be due to complexation of copper or zinc ions in vivo, the ability of these compounds to form stable metal complexes has been observed. Metal ion stability constants have been determined for three of the compounds with Al(lll), Cu(ll), Fe(lll), and Zn(ll) ions, and stabilities somewhat larger than those for simple peptides were found. Structures of the Cu(ll) and Fe(lll) complexes are proposed, based on elemental analyses and infrared absorption. The Cu(ll) complexes are 1:1 ligand:metal structures that precipitated as double salts with CuCl2, and the Fe(lll) complexes are 2:1 structures in which the ligands incorporated an additional sulfur atom.

Cyclic voltammetry data were obtained for 12 salts of quinolines, one pyridine, and one open-chain imine which possess varying degrees of anticancer activity. The structural features include sidechain bis(2-methylthio)vinyl, 2-methylthio-2-aminovinyl, dithioacetic acid, 2-quinolylvinyl, 2-styrylvinyl, and guanidine sulfide functionalities. Reduction potentials ranged from −0.43 to −1.08V. The electrochemical results are correlated with structure. A possible mechanism of anticancer action is addressed.

A series of tetracaine analogs based on the lidocaine structure, having a 2'-methyl-(or 2',6'-dimethyl)-4'-butylaminoanilide moiety with α substitution on the dialkylaminoacyl function, has been synthesized. Local anesthetic activity was found with the N-butyl derivatives in both the 2'-methyl and 2',6'-dimethyl series using both the method of rabbit cornea loss of reflex and spinal anesthesia in sheep. Duration of activity of the compounds was greater than that of lidocaine, but less than that of tetracaine, with comparable dosage levels.

A series of N‐heterocyclic and N‐heterocyclic alkyl derivatives of bis(2‐aminoethyl) disulfide and aminoethanethiosulfuric acid was synthesized as potential antiradiation and anticancer agents. The compounds were prepared by the reactions of the heterocyclic halides with bis(2‐aminoethyl) disulfide and aminoeth‐anethiosulfuric acid. A dithio acid derivative, 3,3‐dimercapto‐2‐cyanoacryloylpyrrolidide, was also prepared. Several compounds, including the dithio acid derivative, provided good radiation protection to mice. None of the compounds screened showed appreciable anticancer activities in two leukemia systems.

Based on the antimalarial activity in mice of bis(4‐p‐acetamidobenzenesulfonamidophenyl) disulfide, a series of N‐heterocyclic alkyl disulfides and thiosulfates was synthesized and screened for antimalarial activity. Several related dithio acid dianions and S‐blocked derivatives were also screened to provide an indication of the possible role that thiol anions might play in malaria chemotherapy. Activity was limited by toxicity with these compounds, and none of those tested, with the exception of bis(4‐p‐acetamidobenzenesulfonamidophenyl) disulfide, showed curative activity in either a mouse or chick test.

A method for obtaining N-β-D-glucopyranosylthioureas was found in the aminolysis of N-(2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyl)-5-aralkylidenerhodanines. Aminolysis of the triacetylated or tribenzoylated ribosylrhodanines generally did not give ribosylthioureas but resulted in glycosidic cleavage, although N-(2, 3, 5-tri-O-benzoyl-β-D-ribofuranosyl)thioureas were obtained using morpholine and hydroxylamine. Ring closure of N-β-D-glucopyranosylthiourea with ethyl bromopyruvate gave ethyl 2-(N-β-D-glucopyranosyl)aminothiazole-4-carboxylate, and ammonolysis led to the corresponding 4-carboxamide. Antimicrobial screening against five microorganisms showed that N-(2, 3, 5-tri-O-acetyl-β-D-ribofuranosyl)rhodanine and the glucosylaminothiazole-4-carboxylate had the broadest spectrum of inhibitory activity, although the thioureas usually showed inhibition of some organisms.

The determination of DNA-binding specificities for a series of bis(methylthio)vinylquinolinium iodides and two bis(aminoalkyl)-anthraquinones was accomplished by spectral analysis, equilibrium dialysis, elevation of melting temperature, and inhibition of DNA function as a template for Escherichia coliRNA-polymerase transcription activity in vitro. Studies of complex formation were carried out by comparison of difference spectra of the compounds in the presence of native double-stranded DNA and separated-strand DNA. Base specificity of the interaction between DNA and the compounds was demonstrated for both series, particularly for the anthraquinones, for the guanine-cytosine base pair. Comparison of the difference spectra of the compounds in the presence of DNA with varied base-pair ratios showed a strong preference of the anthraquinones for the guanine-cytosine base pair, but the quinolinium compounds showed no preference. The linear-binding isotherm for the quinolinium compounds indicated one type of binding site, while two types of binding sites were apparent for the anthraquinones. Since only one anthraquinone was active in leukemia tests, factors other than DNA binding must account for the activity of the antileukemic derivative.

The radiation-protective bis(methylthio) and methylthio amino derivatives of 1-methylpyridinium- and 1-methylquinolinium-2-dithioacetic acids, a series of non-thiol sulfur-containing compounds, have been examined for their ability to complex Cu(II) ion and remain stable in the presence of α-amino acids, peptides, and a protein. Copper-binding stability constants were found that were considered sufficiently large to be capable of existence under cellular conditions, with log Ksvalues in the range of 13–15. Copper-binding constants for α-amino acids are comparable to those for the radioprotective ligands, but overall binding constants for simple peptides are usually 104–106lower in magnitude. Essentially no change was found in the UV spectra of the Cu(II) complexes in the presence of α-amino acids and simple peptides, and the binding capacity to bovine serum albumin was quite low for two Cu(II) complexes of the best protective ligands, with values of 10−6–10−7M. The possibility that these radioprotectors may act in vivo as copper complexes, possibly as superoxide dismutase mimics, is thus feasible. The magnitude of the copper-binding stability constants, the lack of copper exchange between the radioprotective ligands and amino acids or peptides, and the very low tendency of the copper complexes of the radioprotective ligands to bind to a protein indicate the potential of the complexes to contribute to the radioprotective ability of the ligands.

Stability constants are reported for the complexation of a series of 3, 6-dialkylsalicylic acids and pyridine analogs of salicylic acid with Cu (II), Fe (III), and Al (III) ions. These compounds were selected in an attempt to increase the affinity of salicylates for ferric ion. The 3, 6-dialkyl substituents lowered metal complex stabilities, but the presence of a ring-nitrogen adjacent to the phenolic group increased complex stabilities considerably. The 3, 6-dialkylsalicylic acids revealed somewhat greater analgesic effects than salicylic acid, but less anti-inflammatory action.

Dithiocarbamates of exceptionally strong bases in the pyridine and pyrimidine series, e.g., the 1-alkyl-2- and 4-imino derivatives, have been obtained. Significant protection in mice against ionizing radiation was provided by a dithiocarbamate of one of the strong bases, whereas the dithiocarbamates of weaker bases have generally shown a lower level of protection.

A series of S-acyl derivatives of β-mercaptoethylamine (MEA) has been prepared in an attempt to provide compounds having protective effects in animal cells against ionizing radiation and which are less toxic than MEA itself. In general, toxicity to animals was reduced and good protective ability against X-radiation was retained in some of the esters. The dithiocarbamic acid of MEA was also prepared, but attempts to acylate this compound, which showed good antiradiation effects in close to toxic dose levels in mice, gave a variety of decomposition products.

Mono-N-alkyl and N,N'-dialkyl derivatives of 2-mercaptoethylguanidine (MEG) have been synthesized as potential radioprotective agents with the assumption that increase in liposolubility of MEG will improve its radioprotective ability. The compounds were obtained by reaction of bromoethylamine with the appropriate alkylated thiourea to give the corresponding aminoethylisothiouronium bromide hydrobromide, which was rearranged to the desired MEG derivative in alkaline solution. The alkyl MEG hydrobromides, unlike MEGBr itself, could be isolated from aqueous solution. Conversion to the trithiocarbonates generally gave products of better crystalline properties. The structure of the trithiocarbonate of MEG was supported by NMR analysis.

Spectrophotometric measurements have been made of systems of catalase and of lactic dehydrogenase containing either salicylic acid, 2-mercaptoethylamine, 2-mercaptoethylguanidine, or sodium diethyldithiocarbamate. Absorption differences indicated complex formation between the dithiocarbamate and lactic dehydrogenase and at least salt formation with catalase. No definite indication of complex formation between these enzymes and either salicylic acid or the basic mercaptans was given by the method employed, although salt or weak field complex formation is a possibility with the latter.

To provide stable derivatives of 2-mercaptoethylamine (MEA) and 2-mercaptoethylguanidine (MEG) and to test one of the current hypotheses of the mechanism of radiation protection in animals (that metal binding is an important reaction in impeding cellular oxidations), metal complexes of MEA and MEG have been prepared. Reaction of the trithiocarbonate zwitterions of MEA and MEG with metal salts provided straight chain (2: 1) metal complexes, and direct reaction of MEA and MEG with metal salts in acid solution provided cyclic (1: 1) chelates. Structures of these compounds have been elaborated. One of the compounds, the Zn (II) complex of MEG has shown appreciable radiation protection in mice.

Several commercial hematinic preparations have been tested for their ability to liberate ionic iron at different conditions of pH and in the presence of simulated gastric and intestinal fluids. A chromatographic method was employed in which both Fe(II) and Fe(III) ions were measured by means of absorbance determinations. It was concluded that chelated, or complexed, iron is carried through the gastrointestinal tract with less loss and lower toxicity than is ionic iron.

Metal-binding stability constants for a series of imidazole, pyrimidine, and related heterocyclic thiones, and a few nonsulfur-containing heterocycles, with Cu (II), Al (III), and Fe (III) ions were determined. Relatively high avidities for the metal ions were found. The magnitudes of the constants, in comparison with those of both cyclic and open-chain compounds of known chelating ability, indicated that four-membered chelate rings involving nitrogen and sulfur atoms were formed. Compounds having the higher metal-binding strengths showed some antimicrobial activity.

Dithiocarbamates of strong heterocyclic bases (pKa 8–12) in the acridine and quin-aldine series have been obtained, with further examples of the formation of imino-N-carbodithioates. Significant radiation protection of mice was found for the di-thiocarbamate ester of 9-aminoacridine, whereas dithiocarbamates of both stronger and weaker bases were nonprotective.

A series of 8-alkoxyquinolinium hydrobromides and 8-alkoxy-N-alkylquinolinium quaternary iodides has been synthesized. Quaternization of the 8-alkoxy ethers was difficult or impossible with alkyl groups larger than ethyl. The quaternary salts showed characteristic antibacterial activities lower than that from 8-hydroxy-quinoline itself. The lower ethers had antibacterial activities which showed more variation with liposolubility and may be attributed to metal ion complexation.

“That metal complexes can be chemically more vigorous than the metal cations on their own is evident from consideration of the metal-containing enzymes” (3) .

β-Phenethylbiguanide (DBI) was found capable of forming chelates with copper and nickel ions, but no cobalt, ferric, ferrous, zinc, or calcium chelates could be isolated. A 1:1 copper-DBI chelate was formed in acid media, and a 1:2 chelate was formed in neutral or basic solution. At pH 4 where both copper complexes existed in equilibrium, DBI was found to have an affinity for copper ion of the same order as glycine. DBI is also capable of chelating with the 1:1 copper-glycine complex. Among a series of alkyl-substituted biguanides, some correlation between ability to chelate copper ion and hypoglycemic activity was observed.

Stability constants are reported for the chelation of ferric and aluminum ions by a series of salicylic acid derivatives having amino, alkyl, chloro, and nitro groups in the ring. The sequence of complex stabilities found is in agreement with current organic theory and shows a parallelism with the ionization constants. Three of the biological effects known for salicylates, antibacterial, analgesic-antipyretic, and fungicidal, can be related to the magnitude of complex stability or ionization constant.