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Biomedical subjects

K C Agrawal

Publications and source records attributed to K C Agrawal.

At least 55 records · Page 3Linked to original sources
PubMed1981

Potential radiosensitizing agents. 2. Synthesis and biological activity of derivatives of dinitroimidazole with oxiranes.

A series of 1-substituted 2,4-dinitroimidazole analogues have been synthesized and tested for their radiosensitizing ability for selectively sensitizing hypoxic mammalian cells to the lethal effect of radiation. The reaction of 2,4-(5)-dinitroimidazole (1) with a variety of oxiranes upon heating in absolute ethanol yielded the expected 1-substituted 2,4-dinitroimidazoles (2) and also resulted in the formation of a novel class of isomeric nitroimidazo[2,1-b]oxazoles 3 and 4) by intramolecular cyclization. The results of radiosensitizing activity of these agents against hypoxic Chinese hamster cells (V-79) indicated that 2,4-dinitroimidazoles were better sensitizers than the nitroimidazo[2,1-b]oxazoles, suggesting the necessity of the 2-nitro function in the molecule. The 1-(2-hydroxy-3-methoxypropyl)-2,4-dinitroimidazole (2d) was found to be the most effective radiosensitizer of this series.

Animals↗
PubMed1979

Potential radiosensitizing agents. Dinitroimidazoles.

New compounds of the nitroimidazole series have been synthesized as radiosensitizers which selectively sensitize hypoxic cells to the lethal effect of radiation. The reaction of 2,4(5)-dinitroimidazole (2) with chloroethanol or hydrochloric acid yielded 4(5)-nitro-5(4)-chloroimidazole (3), which upon reaction with ethylene oxide yielded the 4-nitro-5-chloroimidazole-1-ethanol (6). Reaction of 2 with ethylene oxide resulted in a mixture of two compounds, the 2,4-dinitroimidazole-1-ethanol (4) and 2,3-dihydro-5-nitroimidazo[2,1-b]oxazole (5). The structure of the new heterocyclic compound 5 was confirmed by 1H NMR, mass spectrum, and X-ray crystallography. These agents were tested for their ability to sensitize hypoxic Escherichia coli cells to killing by ionizing radiation. Compound 4 was found to be the most active agent of this series of compounds.

Chemical Phenomena↗
PubMed1978

Relationship between structure and antineoplastic activity of arylsulfonylhydrazones of 2-formylprydine N-oxide.

The effects of various structural modifications on the antineoplastic activity of the benzenesulfonylhydrazone of 2-formylpyridine N-oxide have been ascertained in mice bearing either Sarcoma 180 or leukemia L1210. To accomplish this a variety of derivatives substituted at the aldehyde proton, the aryl ring, and the 4 position of the pyridine nucleus were synthesized. Antineoplastic activity was retained when nitro, amino, chloro, bromo, fluoro, and methoxy groups were introduced into either the meta or para positions of the phenyl ring of the parent compound. In addition, substitution of the terminal phenyl group by a pyridine ring or by a bulky aromatic ring such as alpha-naphthyl, beta-naphthyl, or fluorenyl did not abolish the marked antitumor activity expressed by this class of agents. Insertion of a nitro function or a morpholino group in the 4 position of the pyridine nucleus of the benzenesulfonylhydrazone of 2-formylpyridine N-oxide resulted in two potent anticancer agents, while the introduction of a chloro function in the 4 position led to a pronounced decrease in biological activity. Furthermore, the essentiality of the aldehydic proton for tumor-inhibitor activity was demonstrated by the inactivity of two derivatives in which the aldehydic proton was replaced by a methyl group or by an oxygen atom.

Animals↗
PubMed1978

The Woodlawn mental health studies: tracking children and families for long-term follow-up.

Elementary school children in a large public urban school system (Chicago) can be tracked into adolescence, together with their families, by using student numbers established by the Chicago Public Schools. This paper reports on the linkage between a psychiatric follow-up study and the data bank of the Chicago Public Schools. The authors were able to find information about the location and grade placement of 87% of an urban ghetto neighborhood's first grade children after a seven to ten-year lapse in contact. The children about whom information was found did not differ from those missing in the early measures of their school achievement and psychological wellbeing. However, first grade measures of school success of failure did relate to grade placement of children ten years later, as did first grade ratings of bizarreness.

Chicago↗
PubMed1978

Hypoxic radiosensitizers: prospects for effective compounds with fewer toxic side-effects.

Several radiosensitizing chemicals, including a family of simple nitroimidazoles, were examined in E. coli and compared with misonidazole for toxic side-effects on endpoints such as mutagenesis, cell killing and inhibition of the synthesis of the inducible enzyme beta-galactosidase. While all the compounds were similar to misonidazole or better in radiosensitization, marked differences in the various side effects were found. There results show that for E. coli it is possible to find compounds that sensitize as well as misonidazole but which have decreased mutagenicity and fewer other side-effects. Of the compounds examined, KA121 (2,5-dinitroimidazole) is the most promising for future study because it combines good radiosensitization with low mutagenicity and toxicity.

Escherichia coli↗
PubMed1977

Tetramisole analogues as inhibitors of alkaline phosphatase, an enzyme involved in the resistance of neoplastic cells to 6-thiopurines.

A series of tetramisole derivatives was synthesized and tested for inhibitory activity against alkaline phosphatase which was partially purified from a murine ascitic neoplasm resistant to 6-thiopurines (Sarcoma 180/TG). These agents included derivatives substituted with halogens, CH3, or NO2 groups at either the meta or para position of the phenyl ring of tetramisole and 2,3-dehydrotetramisole. The phenyl ring of tetramisole and 2,3-dehydrotetramisole was also replaced by a naphthyl ring, and the phenyl ring of 2,3-dehydrotetramisole was substituted by a thienyl ring system. The presence of both the thiazolidine and dihydroimidazole rings of tetramisole was found to be essential for enzyme inhibitory activity. Substitution of a naphthyl for the phenyl group and dehydrogenation at the 2,3 position of the thiazolidine ring were found to significantly enhance inhibitory activity for alkaline phosphatase. Tests employing (S)-(-)-6-(4-bromophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole oxalate in combination with 6-thioguanine demonstrated that the inhibitor of alkaline phosphatase was capable of increasing the toxicity of 6-thioguanine to Sarcoma 180/TG cells in tissue culture.

Alkaline Phosphatase↗
PubMed1977

4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, a second-generation antineoplastic agent of the alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone series.

4-Methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ-1) was studied to determine its potential for clinical trail as a second-generation antineoplastic agent of the alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone class. MAIQ-1 was shown to be among the most potent known inhibitors of the major target for the expression of antineoplastic activity by this class of agents, the enzyme ribonucleoside diphosphate reductase, requiring only 0.06 micronM for 50% inhibition. This potency at the enzymatic level was consistent with its antineoplastic activity against the murine neoplasms Sarcoma 180, Leukemia L1210, Leukemia P388, and the B16 melanoma. The acetylation of the 5-amino group of the model substrate 5-amino-1,4-dimethylisoquinoline was lower than that of 5-amino-1-methylisoquinoline when incubated with acetyl-coenzyme A and rat liver homogenate. This finding suggests that the presence of the 4-methyl function offers steric hinderance to enzymatic substitution of the adjacent 5-amino group. In vivo metabolism of MAIQ-1 in mice, studied with [3'-14C]MAIQ-1 showed that relatively slow excretion of this agent occurred, since the cumulative urinary excretion of radioactivity was only 35% in 48 HR. About 51% of excreted urinary radioactivity was present in chromatograms in an area corresponding to the iron chelate of MAIQ-1, and only a minor quantity of material migrating like acetylated MAIQ-1 was present in urine, a finding consistent with enzymatic data with liver homogenates. The results indicate that MAIQ-1 has the antineoplastic activity, enzyme inhibitory potency, and relative resistance to metabolic inactivation required of an agent of this class for clinical trials.

Animals↗
PubMed1976

Synthesis of site-directed chelating agents II: 2-formyl-3-hydroxy-4,5-bis (hydroxymethyl)pyridine thiosemicarbazone.

2-Formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone was synthesized in an attempt to direct the chelating potential of this agent to the active site of the zinc-requiring enzyme pyridoxal phosphokinase. Evaluation of the antineoplastic activity of this agent in the sarcoma 180 and L-1210 leukemia systems in mice showed potent activity. The presence or absence of pyridoxine hydrochloride in the diet did not influence the degree of inhibition of the growth of sarcoma 180 ascites cells. In addition, 2-formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone was inactive against a subline of sarcoma 180 resistant to 1-formylisoquinoline thiosemicarbazone, suggesting that the former agent may have a biochemical mechanism of action similar to that of the latter. In keeping with this expectation, 2-formyl-3-hydroxy-4,5-bis(hydroxymethyl)pyridine thiosemicarbazone inhibited the synthesis of DNA but not of RNA or protein in sarcoma 180 ascites cells in vitro.

Animals↗
PubMed1976

Antineoplastic and biochemical properties of arylsulfonylhydrazones of 2-formylpyridine N-oxide.

The structural parameters necessary for the antineoplastic potency of a new class of anticancer agents, arylsulfonylhydrazones of 2-formylpyridine N-oxide, were examined in mice bearing Sarcoma 180 ascites cells. The findings indicated that (a) replacement of the pyridine ring with benzene, quinoline, or isoquinoline resulted in loss of activity (b) movement of the formylhydrazone side chain from the 2 to the 3 or 4 positions of the pyridine N-oxide produced inactive agents (c) the pyridine N-oxide function was essential for anticancer activity, except for 4-substituted derivatives which were active without the N-oxide group, (d) replacement of the SO2 group by CO resulted in complete loss of activity, and (e) a carbon atom could be inserted between the SO2 and aryl ring with retention of anticancer potency. One of the most active members of this series, 1-oxidopyridine-2-carboxaldehyde p-toluenesulfonylhdrazone, exhibited antineoplastic activity against a broad spectrum of transplanted tumors including Sarcoma 180, Hepatoma 129, Ehrlich carcinoma, leukemia L1210, and a subline of Sarcoma 180 resistant to alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones. This agent caused inhibition of thymidine-3H and uridine-3H incorporation into DNA and RNA, respectively, of Sarcoma 180 ascites cells; protein biosynthesis was relatively insensitive to the action of this compound.

Animals↗
PubMed1976

Potential antitumor agents. 14. 4-Substituted 2-formylpyridine thiosemicarbazones.

A series of 4-substituted 2-formylpyridine thiosemicarbazones has been synthesized which contain a tertiary N at the 4 position. These materials were obtained by reacting 4-nitro-2-picoline N-oxide, either directly or after conversion to the corresponding 4-chloro derivative, with a variety of secondary amines. Rearrangement of the 4-substituted 2-picoline N-oxides with Ac2O yielded respective methyl acetates, which upon acid hydrolysis, MnO2 oxidation, and reaction with thiosemicarbazide resulted in the desired compounds. An alternate procedure which consisted of reacting 4-chloro-2-formylpyridine ethylene acetal with various amines, followed by hydrolysis and reaction with thiosemicarbazide, was also employed. Introduction of an alkyl group at the 3 position of the pyridine ring of 4-morpholino-2-formylpyridine thiosemicarbazone was achieved by utilizing 2,3-dimethyl-4-nitropyridine N-oxide; this material was converted to the corresponding 4-chloro derivative which was then subjected to nucleophilic substitution. 4-Morpholino-2-formylpyridine thiosemicarbazone was the most active antineoplastic agent of this series in mice bearing Sarcoma 180 ascites cells and was significantly superior to 5-hydroxy-2-formylpyridine thiosemicarbazone in this test system.

Animals↗
PubMed1975

Potential antitumor agents. 12. 2-Formyl-4-aminophenylpyridine thiosemicarbazones.

The antitumor agent 2-formyl-4-(m-amino)phenylpyridine thiosemicarbazone (4-APPT) has been synthesized by a new route to give significantly better overall yields than previously reported. 4-Phenyl-2-picoline was formed by methylation o4-phenylpyridine with CH3Li which upon nitration produced a mixture of o-, m-, and p-nitro-substituted derivatives. These isomers were separated by the solubility differences of their hydrochloride or nitrate salts in 10, 27, and 40% yields, respectively. Identification and confirmation of the structure of these isomers were carried out by mmr. Each isomer was individually subjected to a series of reactions to oxidize the 2-CH3 group to the corresponding carboxaldehyde and to reduce the NO2 function to an amino group. These agents were tested for antineoplastic activity in mice bearing Sarcoma 180 ascites cells; while the o- and p-amino-substituted derivatives were inactive, the m-amino-substituted agent (4-APPT) approved to be an extremely potent antineoplastic agent.

Aniline Compounds↗