Evaluation of some Mannich bases of 1-aryl-1-ethanones and related ketones for anticonvulsant activities.
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Animals↗
Biomedical subjects
K Shyam
Publications and source records attributed to K Shyam.
Methylating agents as trypanocides.
Methylating agents, such as streptozotocin, procarbazine, N-methyl-N-nitrosourea, dimethyl sulfate, 1,2-dimethylhydrazine, and a series of 1,2-bis(sulfonyl)-1-methylhydrazines synthesized in this laboratory, were evaluated and shown to be therapeutically active against murine models of African trypanosomiasis. At high dose levels, methylating agents halted trypanosome proliferation and transformed cells into bizarre forms containing multiple nuclei and kinetoplasts. These cells disappeared from the bloodstream of mice bearing these organisms in 48-72 h. When administered at repetitive low doses, methylating agents induced the entire population of trypanosomes to differentiate into biochemically distinct short-stumpy forms in a synchronous manner. These results suggest that methylating agents may be used as biochemical tools in the study of trypanosome differentiation.
Alkylating Agents↗
Synthesis and evaluation of 1,2,2-tris(sulfonyl)hydrazines as antineoplastic and trypanocidal agents.
Several 1,2,2-tris(sulfonyl)hydrazines, conceived as prodrugs of 1,2-bis(sulfonyl)hydrazines, were synthesized and evaluated for antineoplastic and trypanocidal activities in mice. 1-Methyl-1,2,2-tris(methylsulfonyl)hydrazine emerged as an extremely efficacious antitrypanosomal agent, whereas 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine was inactive. In contrast, 1-(2-chloroethyl)-1,2,2-tris(methylsulfonyl)hydrazine displayed potent antineoplastic activity, producing several 60-day "cures" of mice bearing leukemia L1210, leukemia P388, or Sarcoma 180. Furthermore, the fact that the tris(sulfonyl) derivatives will not generate isocyanates, which contribute to the host toxicity of nitrosoureas like 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), makes them agents of significant promise in trypanosomal and cancer chemotherapy.
Animals↗
Cytotoxic and DNA-damaging effects of 1,2-bis(sulfonyl)hydrazines on human cells of the Mer+ and Mer- phenotype.
A series of 1,2-bis(sulfonyl)hydrazines with the capacity to function as alkylating agents have been evaluated for their toxicity towards Mer- HT29 and Mer- BE cells, and for their ability to produce DNA damage expressed as single-strand breaks and DNA interstrand cross-links. Compounds of this class with methylating potential showed a marked difference in their capacity to inhibit the growth of Mer- and Mer+ cells, being considerably more toxic to BE Mer- cells. Dose-dependent DNA single-strand breaks were induced by these agents, with the quantity of breaks produced in Mer- and Mer+ cells being essentially the same. Maintenance of these lesions did not appear to explain the differential in toxicity to BE and HT29 cells. A chloroethylating compound of this class was also more toxic to Mer- BE cells than to Mer+ HT29 cells, but the differential toxicity was considerably less than that of the methylating agents of the series. The chloroethylating agent did not produce measurable single-strand breaks of the DNA of treated cells, but caused more DNA interstrand cross-links in Mer- cells than in Mer+ cells. Thus, DNA interstrand cross-links may be at least in part responsible for the cell kill produced by this agent. The findings suggest that methylating and chloroethylating derivatives of the 1,2-bis(sulfonyl)hydrazine family have different biochemical determinants of their cytodestructive actions.
Alkylating Agents↗
Novel 1-haloalkyl-2-nitroimidazole bioreductive alkylating agents.
Solid tumors contain hypoxic cells which are relatively resistant to radiation treatment and to most forms of chemotherapy. These cells can be preferentially targeted using chemotherapeutic agents that are specifically activated by cellular reductase enzymes in the absence of oxygen. A new class of bioreductive alkylating agents based on the 2-nitroimidazole nucleus has been developed which contains a haloalkyl substituent on the N-1 position of the imidazole ring. Compounds of this series were readily reduced by mammalian NADPH-cytochrome c reductase, and reduction led to the production of an electrophilic center. This reactive component was hypothesized to be responsible for the preferential cytotoxicity of the agents of this class to hypoxic tumor cells through alkylation of cellular components.
Alkylating Agents↗
1,2-Bis(sulfonyl)hydrazines. 3. Effects of structural modification on antineoplastic activity.
A series of 1,2-bis(sulfonyl)hydrazines was synthesized and evaluated for antineoplastic activity against the L1210 leukemia and the B16 melanoma. The most active agent to emerge from this study, 1,2-bis(methylsulfonyl)-1-methylhydrazine, produced a maximum % T/C for mice bearing the L1210 leukemia or the B16 melanoma of 340% and 278%, respectively. Two N-chloroethyl analogues, conceived as bifunctional alkylating agents, were also synthesized and evaluated for antineoplastic activity against the L1210 leukemia and the B16 melanoma. Although such a modification resulted in retention of antineoplastic activity against both tumor cell lines, it did not result in enhanced antineoplastic activity.
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Synthesis and evaluation of 2-substituted 1-methyl-1-(4-tolylsulfonyl)hydrazines as antineoplastic agents.
Several N-2 substituted 1-methyl-1-(4-tolylsulfonyl)hydrazines were synthesized and evaluated for antineoplastic activity against the L1210 leukemia and the B16 melanoma. The most active compound to emerge from this study, 2-(methylsulfonyl)-1-methyl-1-(4-tolylsulfonyl)hydrazine, produced maximum percent T/C values with L1210 leukemia and B16 melanoma tumor bearing mice of 207 and 209, respectively. While the attachment of an aryl-, aralkyl-, or alkylsulfonyl moiety to N-2 resulted in retention of activity against both tumor systems, the corresponding benzoyl, 4-nitrobenzoyl, and (2-nitrophenyl)sulfenyl analogues only displayed activity against the L1210 leukemia.
Animals↗
1,2-bis(arylsulfonyl)hydrazines. 2. The influence of arylsulfonyl and aralkylsulfonyl substituents on antitumor and alkylating activity.
Several 1,2-bis(arylsulfonyl)-1-methylhydrazines were synthesized and evaluated for antineoplastic activity against the L1210 leukemia. The most active compound to emerge from this study, 2-[(4-chlorophenyl)sulfonyl]-1-methyl-1-(4-tolylsulfonyl)hydrazine , increased the survival time of tumor-bearing mice by 88%. The alkylating activity of the synthesized analogues and several compounds reported earlier was determined by measuring the absorbance at 540 nm of the alkylated product of 4-(4-nitrobenzyl)pyridine. The results obtained support the concept that the ability to alkylate is a necessary but not a sufficient condition for the expression of antitumor activity by agents of this class.
Alkylating Agents↗
Synthesis and evaluation of 1-(arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines++ + as antineoplastic agents.
1-(Arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines, with the potential to function as biological methylating agents, were synthesized and evaluated as antineoplastic agents against the L1210 leukemia and the B16 melanoma in mice. All of the compounds of this class had significant activity against the B16 melanoma, with the most active compound, 2-[(methoxycarbonyl)sulfenyl]-1-methyl-1-[(4- methylphenyl)sulfonyl]hydrazine, producing percent T/C values for B16 melanoma tumor bearing mice of between 182 and 232 at dosage levels of from 12.5 to 50 mg/kg daily for 6 consecutive days. In contrast to the related class of agents, the N,N'-bis(sulfonyl)hydrazines reported earlier by this laboratory,1 the 1-(arylsulfonyl)-2-[(methoxycarbonyl)sulfenyl]-1-methylhydrazines were found to be inactive against the L1210 leukemia in vivo.
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Relationship between structure and antineoplastic activity of (arylsulfonyl)hydrazones of 4-pyridinecarboxaldehyde.
The effects of various structural modifications on the antineoplastic activity of (arylsulfonyl)hydrazones of 4-pyridinecarboxaldehyde were examined in mice bearing either Sarcoma 180 or P388 leukemia. The introduction of different functional groups into the phenyl ring of the benzenesulfonyl moiety did not alter tumor inhibitory activity appreciably, and the pyridine ring could be replaced by 4-nitrobenzene without loss of antineoplastic activity. However, the aldehyde proton and the hydrazone proton alpha to the sulfonyl group were essential, and their substitution resulted in inactive anticancer agents.
Animals↗
Synthesis and evaluation of N,N'-bis(arylsulfonyl)hydrazines as antineoplastic agents.
Several N,N'-bis(arylsulfonyl)hydrazines, with the potential to function as biological methylating agents, were synthesized and evaluated for antineoplastic activity against the L1210 leukemia and other transplanted rodent tumors. In general, the N-methyl-N,N'-bis(arylsulfonyl)hydrazines that possess the capacity to generate an alkylating species under physiological conditions showed significant antineoplastic activity, while N,N'-bis(phenylsulfonyl)-hydrazine and N-methyl-N,N'-dibenzoylhydrazine were inactive.
Animals↗
bis-Mannich bases of styryl ketones as antileukemic agents.
A novel series of bis-Mannich bases have been synthesized and evaluated against P388 lymphocytic leukemia in mice. Two compounds showed a perceptible beneficial response in this screen and all the compounds displayed marked murine toxicity. A representative compound inhibited respiration in mitochondria isolated from rat and mouse liver cells by 90% approximately at a dose of 2.5 mumol and it caused a small elevation in mouse liver glutathione equivalent concentrations at 5 mg/kg.
Animals↗
Syntheses and evaluation of some mannich bases derived from acetophenones against P388 lymphocytic leukemia and toxicological assessment of 3-dimethyl-amino-2-dimethylaminomethyl-1-(4-methoxyphenyl)-1-propanone dihydrochloride in rats.
A number of analogues of 3-dimethylamino-2-dimethylaminomethyl-1-(4-methoxyphenyl)-1-propanone dihydrochloride (IIa) and related compounds which showed activity against P388 lymphocytic leukemia were prepared, and of the 16 analogues, three met the criterion for activity in this screen. The toxicity of IIa was examined in rats and either a single dose of 25 mg/kg or nine daily doses of 12.5 mg/kg administered by the intraperitoneal route produced marked irritation and damage to the tissue with which it came into contact. Compound IIa did not show significant activity against eight other tumor systems.
Acetophenones↗
Decomposition of 1-aryl-3-dimethylamino-1-propanone methobromides under weakly acidic conditions.
Under basic conditions, some 1-aryl-3-dimethylamino-1-propanone methodbromides (2) were shown to decompose too readily to measure by the electronic absorption spectroscopy technique available. However, at pH = 5.9 and 20 degrees centigrade, the rate of deamination to the corresponding 1-aryl-2-propen-1-ones was able to be followed using Guggenheim's method and a Hammett plot showed that the rate of deamination correlated with the arly substituent constants (o). The rho value for this process was +1.00. In contrast the corresponding 1-arly-3-dimethylamino-1-propanone hybrobromides (1) did not decompose under simulated physiological conditions (pH = 7.4, 37 degrees centigrade). Neither 1 or 2 were active against P388 lymphocytic leukemia in mice but the methobromides displayed greater murine toxicity.
Animals↗
Evaluation of some Mannich bases derived from substituted acetophenones against P-388 lymphocytic leukemia and on respiration in isolated rat liver mitochondria.
Series of 3-dimethylamino-1-aryl-1-propanone hydrobromides (IV) and 3-dimethylamino-2-dimethylaminomethyl-1-aryl-1-propanone dihydrobromides (V) were synthesized. Evaluation of these derivatives against P-388 lymphocytic leukemia growth revealed that two compounds show promise as antineoplastic agents. Compounds of the V series were unstable in phosphate buffer (in contrast to series IV), and when the same nuclear substituent was present in both series of compounds, V was approximately 100 times more active than IV in both the stimulation and inhibition of respiration of mitochondria isolated from rat liver cells. Representatives from both series showed that respiration in mitochondria was affected by changing the pH of the aqueous buffer from 7.4 to 6.9 or 6.4 and by reducing the temperature from 37 degrees to 20 degrees. The compounds showed reactivity toward a biomimetic thiol.
Acetophenones↗
The effects of the methylating agent 1,2-bis(methylsulfonyl)-1-methylhydrazine on morphology, DNA content and mitochondrial function of Trypanosoma brucei subspecies.
Repeated exposure of trypanosomes in vitro or in vivo to low concentrations of the methylating agent 1,2-bis(methylsulfonyl)-1-methylhydrazine induces a series of moderately synchronous morphological and biochemical changes. Cell division halts and the long-slender bloodstream forms transform to short-stumpy forms via larger intermediate-stage cells which contain approximately double the normal G2 content of DNA. In common with naturally occurring short-stumpy trypanosomes, drug-induced short-stumpy forms do not infect rodents and when transferred to Cunningham's medium, transform to and replicate as procyclics. Furthermore, these short-stumpy forms exhibit alpha-ketoglutarate supported motility and oxygen consumption, acquire the ability to reduce nitroblue tetrazolium (NADH diaphorase positivity) and appear to be in the G1 or G0 stage of the cell cycle based upon DNA content.
Animals↗