Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Boron analogues of piperidine, piperazine, morpholine, and imidazole proved to be cytotoxic against the growth of murine and human tissue culture cells. Significant activity was demonstrated for single-cell suspensions of L1210 lymphoid leukemia, Tmolt3 lymphoblastic leukemia, and HeLa-S3 cervical carcinoma. Trimethylamine-imidazole carbonyldihydroborane 17 demonstrated activity against solid tumor growth of human colorectal adenocarcinoma, KB nasopharynx, and osteosarcoma. In addition, 4-methylpiperidine-carbomethoxyborane 12, 2-methylimidazole-3-cyanoborane 16, and 1-methylimidazole-3-(N-ethylcarbamoyl)borane 19 were active against the KB nasopharynx growth. Piperidine-cyanoborane 2, piperidine-carboxyborane 4, and 1-methylimidazole-3-(N-ethylcarbamoyl)borane 19 were effective in reducing the growth of osteosarcoma cells. The imidazole derivatives 13-19, as well as 4-methylpiperidine-carboxyborane 11 and carbomethoxyborane 12, demonstrated good activity against lung bronchogenic and glioma growth. In the in vivo studies, N-methylmorpholine-carboxyborane 7,4-phenylpiperidine-carboxyborane 9, 4-phenylpiperidine-carbomethoxyborane 10, 4-methylpiperidine-carboxyborane 11, imidazole cyanoborane 14, and 1-methylimidazole-3-carbomethoxyborane 18 demonstrated the best activity against Lewis Lung growth and P388 lymphocytic leukemia growth in mice. Mode of action studies in L1210 leukemia cells demonstrated that piperidine-carboxyborane 4 and N-methylmorpholine-carboxyborane 7 inhibited DNA synthesis, purine synthesis at PRPP amido transferase and IMP dehydrogenase sites, and thymidine kinase and thymidine diphosphate kinase activities, while lowering d(NTP) pool levels. Also, DNA strand scission was evident after incubation with these drugs.
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PMID:Synthesis and antineoplastic activity of some cyano-, carboxy-, carbomethoxy-, and carbamoylborane adducts of heterocyclic amines. 181 71

4-isothiocyanate-2,2,6,6-tetramethyl-piperidine-1-oxyl has the strongest effects on the DNA synthesis and viability of isolated leukemia 7712 cells. This compound is a very potent inhibitor of DNA synthesis with 50% inhibition of cell DNA synthesis occurring at 2.2 micrograms/ml, while the LD50 for white mice is 277 mg/kg. During the concentration of 50 micrograms/ml, the inhibition of DNA synthesis is 99.7%, which is unable to damage the DNA replicate template. The inhibition of this compound, a combination of nitroxide and isothiocyanate, appears to be stronger than that of the sum of the two separate actions. Much more moderate effects are seen for all the other nitroxide radicals. After reducing nitroxide to hydroxylamine, there is no inhibition for DNA synthesis. The free radical mechanism of carcinogenesis and antitumor action has been discussed.
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PMID:DNA synthesis inhibition of nitroxide radicals on leukemia cells. 182 Nov 28

A new antibacterial antibiotic tetrazomine was found from the fermentation broth of an actinomycete strain which was isolated from beach sand collected at Chichijima, Ogasawara Islands, Tokyo, Japan. The strain Y-09194L, was identified as Saccharothrix mutabilis subsp. chichijimaensis subsp. nov. The antibiotic exhibited broad antimicrobial activity against Gram-positive and Gram-negative bacteria in vitro. It also exhibited strong cytotoxic activity against P388 leukemia cells and showed antitumor activity against P388 leukemia. The apparent molecular formula of tetrazomine was determined as C24H34N4O5. It has a rare structure which consists of six rings including piperidine, piperadine, oxazole, and pyrrolidine.
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PMID:Tetrazomine, a new antibiotic produced by an actinomycete strain. Taxonomy, fermentation, isolation and characterization. 206 Nov 91

A series of 32 cationic platinum(II) complexes of the form cis-[PtA2(Am)Cl]+, where A is a monodentate (NH3 or i-PrNH2) or A2 is a bidentate (ethylenediamine or 1,2-diaminocyclohexane) amine and Am is either a heterocyclic amine based on a pyridine, pyrimidine, purine, piperidine, or a saturated amine (RNH2) ligand, was prepared and screened against in vivo murine tumor models. Each compound was tested against Sarcoma 180 ascites (S180a) in mice, with 20 members of the series showing activity (ILS greater than 50%). Antitumor activity also was demonstrated in 4 of 16 compounds tested in the L1210 murine leukemia model (ILS greater than 25%) and in 3 of 3 tested in the P388 murine leukemia model (ILS greater than 30%). The most active and potent analogues of the series were obtained when A was NH3 and Am was N1-pyridine, N1-4-methylpyridine, N1-4-bromopyridine, N1-4-chloropyridine, N3-cytosine, or N7-2'-deoxyguanosine. Complexes containing chelating and saturated amine ligands (A), as well as two trans isomers of active cis analogues (trans-[Pt(NH3)2(Am)Cl]+, where Am = N1-pyridine or N1-4-methylpyridine), were inactive in the S180a screen. All complexes were characterized by means of elemental analysis, HPLC, and 195Pt NMR spectroscopy, and the structure of one analogue, cis-[Pt(NH3)2(N3-cytosine)Cl](NO3), was determined by using single-crystal X-ray diffraction methods. While members of this series of compounds demonstrate antitumor activity in vivo, these new agents are not classical analogues of cisplatin (i.e. cis-[PtA2X2] complexes), as they contain three nitrogen donors and only one leaving group. The results of these studies suggest that further work should be conducted to better define the limits of the structure-activity relationships among platinum(II) complexes.
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PMID:Chemical and biological properties of a new series of cis-diammineplatinum(II) antitumor agents containing three nitrogen donors: cis-[Pt(NH3)2(N-donor)Cl]+. 290 24

Dipyridamole restores sensitivity to Adriamycin (ADR) in drug-resistant cells. In an effort to elucidate the relationship between activity and chemical structure of dipyridamole, the ability to enhance the growth inhibitory effect of ADR, in multidrug-resistant (MDR) P388 murine leukemia cells, was determined for 43 derivatives and related compounds. Since both substituted pyrimidopyrimidines and pteridines enhanced the growth-inhibitory effect of ADR in drug resistant cells, the core skeleton may not be directly involved and rather serve as a carrier for the substituents connected with this activity. The exact positions of the active substituents on the core skeleton did not seem to be critical for exertion of the activity. Activity was dependent on the presence of 3 tertiary amine groups. However, not all tertiary amines showed the same potency which might be related to the degree of basicity and/or the spatial structure of these groups. The most active derivatives carried piperidine and pyrrolidine groups while derivatives with thiomorpholine, 3-hydroxypiperidine or dimethylamine groups had low activity. Activity was also dependent on the presence of a substituent with partial electronegative charges as found in a diethanolamine group. However, this function could be carried out, with even higher efficiency, by a substituent containing 6 pi electrons.
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PMID:Circumvention of adriamycin resistance by dipyridamole analogues: a structure-activity relationship study. 292 78

Nitrosourea derivatives 18-22 which utilize either a piperidine or pyridine ring as a carrier group were synthesized and evaluated for anticancer activity. N'-(1-Benzyl-4-piperidinyl)-N-(2-chloroethyl)-N-nitosourea hydrogen maleate (19) exhibited good activity against intracranial L1210 leukemia as well as the mouse ependymoblastoma brain tumor system. Compound 19 exhibited comparable activity in the Lewis lung carcinoma system to N,N'-bis(2-chloroethyl)-N-nitrosourea. Replacement of the N-benzyl group in both the 3-piperidinyl- and 4-piperidinylnitrosoureas resulted in less active compounds in all tumor systems tested. The 3-pyridylnitrosourea 22 was inactive in the L-1210 leukemia system.
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PMID:Synthesis of nitrosourea derivatives of pyridine and piperidine as potential anticancer agents. 740 Nov 13

A series of alkylating phosphoramidate analogs of 5-fluoro-2'-deoxyuridine has been prepared and their growth inhibitory activity evaluated against murine L1210 leukemia and B16 melanoma cells in vitro. These compounds were designed to undergo intracellular release of the phosphoramidate anions, which it was hoped would function as irreversible inhibitors of thymidylate synthase. The expectation was that binding of the nucleoside moiety would be followed by alkylation of the enzyme via the phosphoramidate. The chloride, bromide, iodide, and tosylate analogs were highly potent inhibitors of L1210 cell proliferation, with increased inhibition observed at both higher drug concentrations and longer exposure times. Addition of thymidine completely reversed the inhibition for all compounds, suggesting that these compounds are acting via inhibition of thymidylate synthase. Although the nonalkylating morpholine analog 1f was ca. 50-fold less potent than the methyl(chloroethyl)amino compound, the piperidine analog 1g was only 2-fold less potent, confirming that nitrogen basicity may be as important as the presence of an alkylating group. Addition of thymidine reversed the growth inhibition of the morpholine and piperidine analogs, suggesting that these compounds may also undergo intracellular conversion to 5-fluoro-2'-deoxyuridine 5'monophosphate. The thymidine and deoxyuridine derivatives 2 and 3 showed minimal growth inhibition in the L1210 assay. The alkylating analogs showed modest cytotoxicity against B16 melanoma cells, and the potency of the analogs was more dependent upon the alkylating moiety than on the 5-substituent.
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PMID:Synthesis and biological evaluation of 5-fluoro-2'-deoxyuridine phosphoramidate analogs. 762 6

Although N-acetylcysteine is an antioxidant which has been expected to be a cancer chemopreventive agent, its safety and risk assessment have not been evaluated. N-acetylcysteine increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, whereas the amount of 8-oxodG in HP100, which is a hydrogen peroxide (H(2)O(2))-resistant cell line derived from HL-60, was not increased. To clarify the mechanism of cellular DNA damage, we investigated DNA damage and its site specificity induced by N-acetylcysteine, using (32)P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. N-acetylcysteine induced extensive DNA damage in the presence of Cu(II). The DNA cleavage was enhanced by piperidine treatment, suggesting that N-acetylcysteine plus Cu(II) caused not only deoxyribose phosphate backbone breakage but also base modification. N-acetylcysteine plus Cu(II) frequently modified thymine and guanine residues. Bathocuproine, a specific Cu(I) chelator, and catalase inhibited the DNA damage, indicating the participation of Cu(I) and H(2)O(2) in the DNA damage. Typical hydroxyl radical scavengers did not inhibit N-acetylcysteine plus Cu(II)-induced DNA damage, whereas methional completely inhibited it. These results suggest that reactive species derived from the reaction of H(2)O(2) with Cu(I) participates in N-acetylcysteine plus Cu(II)-induced DNA damage. The content of 8-oxodG in calf thymus DNA was increased by N-acetylcysteine in the presence of Cu(II). The present study has demonstrated that N-acetylcysteine could induce metal-dependent H(2)O(2) generation and, subsequently, damage to cellular and isolated DNA. Therefore, it is reasonable to consider that N-acetylcysteine may have the dual function of carcinogenic and anti-carcinogenic potentials. This work requires further studies on safety and risk assessment of N-acetylcysteine.
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PMID:N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA. 1042 96

Catechol, a naturally occurring and an important industrial chemical, has been shown to have strong promotion activity and induce glandular stomach tumors in rodents. In addition, catechol is a major metabolite of carcinogenic benzene. To clarify the carcinogenic mechanism of catechol, we investigated DNA damage using human cultured cell lines and 32P-labeled DNA fragments obtained from the human p53 and p16 tumor suppressor genes and the c-Ha-ras-1 proto-oncogene. Catechol increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which is known to be correlated with the incidence of cancer, in a human leukemia cell line HL-60, whereas the amount of 8-oxodG in its hydrogen peroxide (H2O2)-resistant clone HP100 was not increased. The formation of 8-oxodG in calf thymus DNA was increased by catechol in the presence of Cu(2+). Catechol caused damage to 32P-labeled DNA fragments in the presence of Cu(2+). When NADH was added, DNA damage was markedly enhanced and clearly observed at relatively low concentrations of catechol (<1 microM). DNA cleavage was enhanced by piperidine treatment, suggesting that catechol plus NADH caused not only deoxyribose phosphate backbone breakage but also base modification. Catechol plus NADH frequently modified thymine residues. Bathocuproine, a specific Cu(+) chelator and catalase inhibited the DNA damage, indicating the participation of Cu(+) and H2O2 in DNA damage. Typical hydroxyl radical scavengers did not inhibit catechol plus Cu(2+)-induced DNA damage, whereas methional completely inhibited it. These results suggest that reactive species derived from the reaction of H2O2 with Cu(+) participates in catechol-induced DNA damage. Therefore, we conclude that oxidative DNA damage by catechol through the generation of H2O2 plays an important role in the carcinogenic process of catechol and benzene.
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PMID:Site specificity and mechanism of oxidative DNA damage induced by carcinogenic catechol. 1147 Jul 55

The syntheses of 5a'-homo-vinblastine (3a) and its C-20' methyl congener 62a were achieved. In contrast to vinblastine, these compounds did not allow isolation of atropisomers because of their lower conformational inversion barrier. However, annelation of a six-membered ring to the conformationally mobile D'-piperidine ring provided an isolated atropisomer 81a, which could be converted to its lower energy conformation 65a on heating. The 5a'-homo-vinblastine congeners 3a, 62a, and 65a showed vinblastine-like inhibition of tubulin polymerization and cytotoxicity to L1210 leukemia cells, albeit at lower potency for the latter activity, than that found with the corresponding compounds in the vinblastine series.
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PMID:Syntheses of 5a'-homo-vinblastine and congeners designed to establish structural determinants for isolation of atropisomers. 1148 49


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