ABSTRACT
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 alpha-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 K beta values in the range of 13-15. Copper-binding constants for alpha-amino acids are comparable to those for the radioprotective ligands, but overall binding constants for simple peptides are usually 10(4)-10(6) lower in magnitude. Essentially no change was found in the UV spectra of the Cu(II) complexes in the presence of alpha-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(-7) M. 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.
Subject(s)
Copper/chemistry , Pyridinium Compounds/chemistry , Quinolinium Compounds/chemistry , Radiation-Protective Agents/chemistry , Amino Acids/chemistry , Drug Stability , Peptides/chemistry , Protein Binding , Serum Albumin, Bovine/chemistry , Spectrophotometry, UltravioletABSTRACT
A variety of N-(alkyl/alkenyl/aryl-N-heterocyclic ureas and thioureas were synthesized as potential antihypertensives. The selected heterocyclic nuclei were the 6-substituted quinoline and the pyridine. Eleven synthesized compounds and seven related compounds in the series were evaluated orally at a dose of 100 mg/kg in conscious deoxycorticosterone acetate/saline-treated hypertensive rats by the tail-cuff method. Seventeen out of the eighteen tested compounds possessed significant antihypertensive activity (p < 0.05). 1-n-Propyl-3-[2'-(6-methoxy)quinolyl]urea (9), showing 29.1% reduction in systolic blood pressure, was the most active compound in the series. Two other compounds producing a fall in systolic blood pressure of the same magnitude were 1-allyl-3-[2'-(6-methyl)quinolyl]thiourea (4) and 1-n-propyl-3-[(2'-pyridyl)methyl]urea (17). Compound 17 with rapid onset caused significant relaxation (p < 0.01) of isolated rabbit femoral artery and guinea pig atrium but had no effect on heart rate. However, none of these exhibited higher potency than prazosin (5 mg/kg). The potency, onset, and duration of action improved when the heterocyclic nucleus was pyridine.
Subject(s)
Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Thiourea/chemistry , Thiourea/pharmacology , Urea/chemistry , Urea/pharmacology , Animals , Dose-Response Relationship, Drug , Male , Rabbits , Rats , Rats, Wistar , Time FactorsABSTRACT
OBJECTIVE: Sulfur-containing compounds have been used in the search for whole-body radiation-protective compounds, in the design of amphetamine derivatives that retain appetite-suppressive effects but lack most behavioral effects characteristic of amphetamines, and in the search for the cause of kidney stone formation in recurrently stoneforming patients. METHODS: Organic synthetic procedures were used to prepare radiation-protective compounds having a variety of sulfur-containing functional groups, and to prepare amphetamine derivatives having electron-attracting sulfur functions. In the case of the kidney stone causation research, isolation of urinary mucopolysaccharides (MPS) from recurrently stoneforming patients was carried out and the extent of sulfation of the MPS was determined by electrophoresis. RESULTS: Whole-body radiation-protective agents with a high degree of protection against lethal doses of gamma-radiation in mice were found in a series of quinolinium and pyridinium bis(methylthio) and methylthio amino derivatives. Mechanism studies showed that the copper complexes of these agents mimicked the beneficial action of superoxide dismutase. Electron-attracting sulfur-containing functions on amphetamine nitrogen, as well as 4'-amino nitrogen provided amphetamine derivatives with good appetite-suppressant effects and few or no adverse behavioral effects. Higher than normal levels of sulfation of the urinary MPS of stone formers suggested a cause for recurrent kidney stone formation. A sulfation inhibitor was found to prevent recurrence of stone formation and inhibit growth of existing stones. CONCLUSIONS: The inclusion of various sulfur-containing functions in organic molecules yielded compounds having whole-body radiation protection from lethal doses of gamma-radiation in animals. The presence of electron-attracting sulfur functions in amphetamine gave derivatives that retained appetite-suppressant effects and eliminated most adverse behavioral effects. A therapy for recurrent urolithiasis resulted from inhibition of MPS sulfation, after the finding that stoneforming patients had abnormally high levels of MPS sulfation.
Subject(s)
Amphetamines/chemistry , Radiation-Protective Agents , Sulfur , Appetite Depressants/chemistry , Boston , Chemistry, Pharmaceutical , Cysteamine/chemistry , Drug Design , Glycosaminoglycans/chemistry , Glycosaminoglycans/urine , Humans , Kidney Calculi/etiology , Kidney Calculi/prevention & control , Radiation-Protective Agents/chemistry , Radiation-Protective Agents/therapeutic use , Recurrence , Sulfur/therapeutic use , Whole-Body IrradiationABSTRACT
High doses of 60Co radiation (4.0-8.0 Gy) in mice, rats and rabbits caused increases in rate of platelet aggregation during the first 5 days after irradiation. The inhibitory effects of the extracts of five Chinese drug plants and acetylsalicylic acid on rate of platelet aggregation were observed in both in vitro and in vivo tests, averaging 23-53% in vitro and 46-69% in vivo. Antiradiation tests on mice vs. 7.5-8.0 Gy of gamma-radiation, using the plant extracts and acetylsalicylic acid as protective agents, increased survival rates by 8-50% for the plant extracts and 35% for acetylsalicylic acid.
Subject(s)
Aspirin/pharmacology , Drugs, Chinese Herbal/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/radiation effects , Radiation-Protective Agents/pharmacology , Animals , Aspirin/therapeutic use , Gamma Rays , Male , Mice , Platelet Aggregation/drug effects , Rabbits , Radiation Injuries, Experimental/prevention & control , RatsABSTRACT
A series of guanylhydrazones derived from 2- and 4-pyridine and 4-quinoline carboxyaldehydes was synthesized from S-methylisothio-semicarbazide hydroiodide using known procedures. The compounds are analogous to anticancer and antiviral thiosemicarbazones, but several of the guanylhydrazones derived from 4-quinoline carboxaldehyde showed no activity against P388 lymphocytic leukemia in mice. Guanylhydrazones derived from all three heterocyclic aldehydes revealed significant blood pressure lowering effects in the rat, however.
Subject(s)
Aldehydes/chemical synthesis , Antineoplastic Agents/chemical synthesis , Guanidines/chemical synthesis , Hydrazones/chemical synthesis , Pyridines/chemical synthesis , Quinolines/chemical synthesis , Aldehydes/pharmacology , Animals , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Chemistry, Physical , Guanidines/pharmacology , Hemodynamics/drug effects , Hydrazones/pharmacology , Leukemia P388/drug therapy , Male , Mice , Mice, Inbred Strains , Pyridines/pharmacology , Quinolines/pharmacology , Rats , Rats, Inbred StrainsABSTRACT
Series of N-substituted diethyl aspartates and N-substituted-3-oxo-1,4-piperazine-2-acetic acid esters were synthesized as potential inhibitors of aspartate transcarbamoylase. The aspartates were obtained by addition of substituted alkyl amines to diethyl maleate, or conversion of the hydroxy ethyl amino adduct to other functions. The 3-oxo-1,4-piperazine-2-acetic acid esters were prepared by addition of ethylene diamine to diethyl maleate, followed by cyclization. Addition of 1,2-diamino-2-methylpropane gave the corresponding 5,5-dimethyl-3-oxo-1,4-piperazine-2-acetic acid ester. N-Acyl derivatives in each series were obtained using the bromoacyl chlorides. A majority of the compounds in each series showed antimicrobial activity against five representative microorganisms, as well as significant activity against aspartate transcarbamoylase. Four of the compounds were found to have significant specificity against several tumor cell lines. A distance of two carbons between N and a reactive function was found to give the best activity for either antimicrobial, antienzyme, or tumor cell specificity activities, in either the open chain aspartates or cyclic piperazines. Little difference in anti-enzyme activity was found between the aspartates and piperazines, but introduction of the planar phenyl substituents lowered inhibitory activity.
Subject(s)
Aspartate Carbamoyltransferase/antagonists & inhibitors , Aspartic Acid/analogs & derivatives , Phosphonoacetic Acid/analogs & derivatives , Aspartic Acid/pharmacology , Chemical Phenomena , Chemistry, Physical , Drug Screening Assays, Antitumor , Microbial Sensitivity Tests , Phosphonoacetic Acid/pharmacologyABSTRACT
N4-(2-Acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC) belongs to a series of molecules known to have broad antimicrobial inhibitory activity. These molecules contain the 2-acetoxyethoxy moiety which could conceivably take up a conformation analogous to that of the ribosyl group. Moreover, the thiosemicarbazone moiety, when in the presence of a suitable enzymatic site, could mimic the triazine group, which is found in a number of antifolate drugs. AATSC, which has both bacterial inhibitory activity and water solubility, was accordingly evaluated for its antifolate activity against the bovine liver dihydrofolate reductase. AATSC is shown to be a fully uncompetitive inhibitor of that enzyme. Furthermore, AATSC enhances the activity of methotrexate. Such a potentiation could be useful for therapeutic purposes.
Subject(s)
Anti-Infective Agents/pharmacology , Folic Acid Antagonists , Methotrexate/pharmacology , Pyridines/pharmacology , Thiosemicarbazones/pharmacology , Animals , Cattle , Drug Synergism , Kinetics , Magnetic Resonance Spectroscopy , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Alkenes/chemical synthesis , Disulfides/chemical synthesis , Radiation-Protective Agents/chemical synthesis , Alkenes/pharmacology , Alkenes/toxicity , Animals , Chemical Phenomena , Chemistry , Chemistry, Physical , Disulfides/pharmacology , Disulfides/toxicity , Female , Lethal Dose 50 , Mice , Mice, Inbred C57BL , Radiation-Protective Agents/toxicityABSTRACT
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(III), Cu(II), Fe(III), and Zn(II) ions, and stabilities somewhat larger than those for simple peptides were found. Structures of the Cu(II) and Fe(III) complexes are proposed, based on elemental analyses and infrared absorption. The Cu(II) complexes are 1:1 ligand:metal structures that precipitated as double salts with CuCl2, and the Fe(III) complexes are 2:1 structures in which the ligands incorporated an additional sulfur atom.
Subject(s)
Metals/metabolism , Quinolines/chemistry , Radiation-Protective Agents/chemistry , Aluminum/metabolism , Copper/metabolism , Drug Stability , Iron/metabolism , Zinc/metabolismABSTRACT
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 -1.08 V. The electrochemical results are correlated with structure. A possible mechanism of anticancer action is addressed.
Subject(s)
Antineoplastic Agents/pharmacology , Quinolines/pharmacology , Oxidation-Reduction , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
A new class of radiation-protective compounds has been found in the bis(methylthio) and methylthio amino derivatives of 1-methylquinolinium- and 1-methylpyridinium-2-dithioacetic acids. The compounds gave good protection to mice vs. 1000-rad gamma-radiation in ip doses of 10 mg/kg or less, much lower than those required for the aminoalkyl thiols (approximately 150-600 mg/kg). The dithioacetic acid zwitterions were prepared from the base-catalyzed reaction of carbon disulfide with quinaldine and picoline methiodides, and the bis(methylthio) derivatives resulted from reaction with methyl iodide at room temperature. Replacement of one methylthio moiety took place readily on reaction of the bis(methylthio) derivatives with 1 molar equiv of an amine. The best protective activity was found with the methylthio piperidino derivative in both the quinolinium and pyridinium series.
Subject(s)
Pyridinium Compounds/chemical synthesis , Quinolines/chemical synthesis , Radiation-Protective Agents/chemical synthesis , Animals , Dose-Response Relationship, Drug , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mice , Pyridinium Compounds/pharmacology , Quinolines/pharmacology , Spectrophotometry, Infrared , Structure-Activity Relationship , Whole-Body IrradiationABSTRACT
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.
Subject(s)
Anti-Infective Agents , Thiosemicarbazones/chemical synthesis , Thiourea/analogs & derivatives , Anti-Bacterial Agents , Anti-Infective Agents/chemical synthesis , Aspergillus niger/drug effects , Candida albicans/drug effects , Chemical Phenomena , Chemistry , Escherichia coli/drug effects , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Thiosemicarbazones/pharmacology , Thiourea/chemical synthesis , Thiourea/pharmacologyABSTRACT
DNA-binding strengths of three anthracene-9,10-dicarboxaldehyde hydrazones were examined by spectral shifts of the drug-DNA combinations, spectral titration by Scatchard plots, elevation of DNA melting temperature during complexation and comparison of spectral shifts in the presence of DNA's having variable base contents. Dissociation of the DNA-complexes was also observed. The results showed a strong degree of binding by the three compounds. They did not exhibit noticeable base-pair specificity, but both associated with and dissociated rapidly from DNA. Scatchard plots for DNA association indicated two types of binding; the stronger was most likely due to intercalation of the planar anthracene ring into the DNA double helix. No direct correlation can be drawn between the observed anti-cancer activities and DNA binding affinities of these compounds in vitro.
Subject(s)
Anthracenes/metabolism , Antineoplastic Agents/metabolism , DNA/metabolism , Intercalating Agents/metabolism , Mitoguazone/analogs & derivatives , DNA Damage , Dactinomycin/metabolism , Mitoguazone/metabolismABSTRACT
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 salicylic 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.
Subject(s)
Glycosaminoglycans/metabolism , Liver/enzymology , Sulfurtransferases/antagonists & inhibitors , Ammonium Sulfate , Animals , Chemical Phenomena , Chemistry , Depression, Chemical , Drug Stability , Ferric Compounds/metabolism , In Vitro Techniques , Male , Rabbits , Salicylates/metabolismABSTRACT
Metal-binding stability constants for a series of N- and N,N'-substituted thioureas with Cu(II), Ni(II), Al(III), and Fe(III) ions were determined by potentiometric titration. The sequence of constants for thiourea, N-methylthiourea, and N,N'-dimethylthiourea indicated steric effects of the methyl groups and that both nitrogen and sulfur were involved in the complexation. The magnitude of the constants was somewhat lower than those of the simple peptides. The mechanism of protection against ionizing radiation by thioureas is probably due to hydrogen-atom transfer rather than binding of metal ions that catalyze cellular oxidations.
Subject(s)
Metals , Radiation-Protective Agents , Thiourea , Aluminum , Chemical Phenomena , Chemistry , Copper , Drug Stability , Iron , NickelABSTRACT
A simple method for obtaining the title compounds was found in the alkaline rearrangement of S-2-aminoethylisothiouronium salts, which were obtained from the condensation of thiourea or substituted thioureas with 2-bromoethylamine hydrobromide. No activity was found for the substituted guanidines against P388 lymphocytic leukemia in mice, or as H2-receptor antagonists.
Subject(s)
Antineoplastic Agents/chemical synthesis , Guanidines/chemical synthesis , Quinolines/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Guanidines/pharmacology , Guinea Pigs , In Vitro Techniques , Leukemia P388/drug therapy , Magnetic Resonance Spectroscopy , Mice , Myocardial Contraction/drug effects , Quinolines/pharmacology , Receptors, Histamine H2/drug effectsABSTRACT
Esters of several glutathione analogues have been synthesized in which the glycine moiety was replaced by straight-chain fatty acids and the mercapto group was benzylated . Two of the derivatives (sufficiently water-soluble for the assay) were found to inhibit glyoxalase I to a greater extent than did S-methylglutathione. The two glyoxalase I inhibitors did not inhibit P388 lymphocytic leukemia in mice, however.
Subject(s)
Antineoplastic Agents/chemical synthesis , Glutathione/chemical synthesis , Lactoylglutathione Lyase/antagonists & inhibitors , Lyases/antagonists & inhibitors , Animals , Chemical Phenomena , Chemistry , Chemistry, Physical , Glutathione/analogs & derivatives , Leukemia P388/drug therapy , MiceABSTRACT
Dihydrofolate synthetase (EC 6.3.2.12) from N. gonorrhoeae was isolated and enzyme characteristics were determined. The purified enzyme was found quite stable when stored at -60 degrees C. About 50% of the enzyme activity was destroyed within 6 weeks when kept at 4 degrees C. Maximum velocity was observed at pH 9.3. The enzyme required a monovalent cation, K+ or NH4+, and divalent cation, Mg2+ or Mn2+, for its function. ATP at 5 mM concentration gave maximum activity. Km values for dihydropteroate and L-glutamate at pH 9.3 were 3.5 X 10(-5) M and 6.5 X 10(-4) M, respectively. Patterns of product inhibition by dihydrofolate were found to be non-competitive with respect to dihydropteroate, having a Ki value of 5.1 +/- 0.8 X 10(-4) M, and competitive with respect to L-glutamate, having a Ki value of 6.2 X 10(-4) M.
Subject(s)
Neisseria gonorrhoeae/enzymology , Peptide Synthases/analysis , Adenine Nucleotides/pharmacology , Cations, Divalent/pharmacology , Cations, Monovalent/pharmacology , Kinetics , Neisseria gonorrhoeae/drug effects , Peptide Synthases/antagonists & inhibitors , Peptide Synthases/isolation & purificationABSTRACT
Reaction of 2-bis(2-methylthio)vinyl-1-methylquinolinium iodide with several heterocyclic aliphatic amines at 30-70 degrees resulted in replacement of one methylthio group to give the title compounds. Reaction with pyrrolidine gave an unidentified product lacking sulfur. Antileukemic screening against P-388 lymphocytic leukemia showed positive activity only with the 6-methyl-morpholino derivative, whereas the 6-unsubstituted morpholino derivative was inactive. This result is in contrast to previous testing results with the 2-bis(2-methylthio)vinyl compounds where both 6-substituted and 6-unsubstituted derivatives showed activity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Quinolinium Compounds/chemical synthesis , Animals , Leukemia P388/drug therapy , Mice , Quinolinium Compounds/pharmacologyABSTRACT
A series of omega-(4-aminophenylsulfonamido)alkyl disulfides and omega-(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 gonorrhoeae of 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.