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)

Five heretofore undescribed analogues of methotrexate (MTX) and aminopterin (AMT) were synthesized and tested as dihydrofolate reductase (DHFR) inhibitors and tumor cell growth inhibitors. The meta isomer of AMT was obtained from 2,4-diamino-6-(bromomethyl)pteridine and m-(aminobenzoyl)-L-glutamic acid, while the ortho isomer was obtained via the same route by using alpha-methyl gamma-tert-butyl o-(aminobenzoyl)-L-glutamate instead of the free acid. Analogues of MTX and AMT containing a double bond in the side chain were prepared from dimethyl D,L-2-amino-4-hexenedioate and 4-amino-4-deoxy-N10-methylpteroic acid and 4-amino-4-deoxy-N10-formylpteroic acid, respectively. Finally, a positional isomer of MTX with the CH2CH2COOH moiety moved from the alpha-carbon to the adjacent carboxamide nitrogen was synthesized from 3-[N-(carboxymethyl)amino]propanoic acid diethyl ester and 4-amino-4-deoxy-N10-methylpteroic acid. The positional isomers of AMT were weak DHFR inhibitors and showed very little growth-inhibitory activity against L1210 murine leukemia cells or the MTX-resistant L1210/R81 mutant line in culture. The MTX and AMT analogues with the CH2CH2COOH moiety replaced by a CH2CH = CHCOOH side chain showed anti-DHFR activity similar to that of the previously described saturated compound N-(4-amino-4-deoxy-N10-methylpteroyl)-L-2-aminoadipic acid, but were less potent than the parent drugs. The MTX analogue with the CH2CH2COOH side chain displaced from C to N was weakly bound to DHFR, confirming the importance of an intact CONH moiety, and showed greatly diminished cell growth inhibitory potency relative to MTX. None of the compounds was a substrate for folylpolyglutamate synthetase (FPGS) from mouse liver. Furthermore, inhibition of folic acid polyglutamylation in vitro at equimolar 500 microM concentrations of drug and substrate was negligible. The structural changes embodied in these five novel compounds are therefore too great for binding to the FPGS active site.
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PMID:Methotrexate analogues. 31. Meta and ortho isomers of aminopterin, compounds with a double bond in the side chain, and a novel analogue modified at the alpha-carbon: chemical and in vitro biological studies. 335 53

2,3-Benzo-alpha-carboline, 7,8-benzo-alpha-carboline and their 4-methyl derivatives were subjected to microbial conversion yielding corresponding benzo-alpha-iso-carbolines. All obtained products showed significant antimicrobial and cytotoxic properties. ID50 values were found to be at range 0.01-0.001 microM/ml, regarding in vitro KB tumor cells system data. It has been found that introduction of methyl group at para-position to the nitrogen of pyridine nucleus strongly increases cytotoxic and microbial activity of benzo-alpha-iso-carbolines. Apparently it has been indicated that antitumor activity of benzo-alpha-iso-carbolines is strongly dependent on shape and size of the molecule. Of all the compounds tested only 2,3-benzo-1,4-dimethyl-alpha-iso-carboline increases life span of leukemia P388 bearing mice up to 160%.
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PMID:Microbial transformation of azacarbazoles. VII. Antitumor properties of benzo-alpha-iso-carbolines formed by Kitasatosporia setae strain from corresponding benzo-alpha-carbolines. 344 29

(R,S)alpha-[N,N-[bis (2-chloroethyl)]-amino]-N-(o-methoxyphenyl)-pyrrolidin-2,5-dione hydrochloride (I), a new nitrogen mustard incorporated into a 2,5-pyrrolidinedione ring system, was found to be active against P388 lymphocytic leukaemia when administered by i.p., s.c. and p.o. routes. The anti-tumour activity, exhibited by compound (I), against intracerebrally grafted P388 tumour is of interest. However, (R,S)alpha-[N,N-[bis (2-chloroethyl)]-amino]-N-(p-n-butoxyphenyl)-pyrrolidin-2,5-dione dihydrate (II), was found to be active against the P388 tumour following i.p. administration only.
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PMID:Anti-tumour effect of alpha-amino N-substituted-pyrrolidin-2,5-dione-N-mustards on the growth of P388 lymphocytic leukaemia. 345 98

Spirohydantoin mustard (SHM), a central nervous system directed nitrogen mustard with anticancer activity, was metabolized in the presence of mouse liver postmitochondrial supernatant (9000g fraction) to a nonpolar alkylating metabolite. The metabolite was isolated by thin-layer chromatography of chloroform or ethyl acetate extracts of incubation mixtures, and its structure was established by mass spectral analysis, synthesis, and cochromatography. The metabolite, spirohydantoin aziridine, was mutagenic for Salmonella typhimurium TA1535 in the Ames assay but inactive as an antitumor agent against P388 leukemia in vivo.
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PMID:Isolation, synthesis, and antitumor evaluation of spirohydantoin aziridine, a mutagenic metabolite of spirohydantoin mustard. 354 61

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.
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PMID:Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl. 367 74

The antitumor activity of imidazolium-bisimidazole-tetrachlororuthenate (III) against the P388 leukemia and against the B16 melanoma was investigated. The test compound showed high activity against these tumor models. The tumor inhibiting effect was in the range or better than the effects of the compounds cyclophosphamide, cisplatin, or 5-fluorouracil, which were tested as positive controls. The effective substance is a new, water soluble, anionic, nitrogen-heterocyclic coordinated, ruthenium species, exhibiting antitumor activity.
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PMID:Antitumor activity of imidazolium-bisimidazole-tetrachlororuthenate (III). A representative of a new class of inorganic antitumor agents. 370 Apr 62

Spiromustine is a hydantoin-containing nitrogen mustard currently in Phase I clinical trial. Since the in vitro plasma half-life of this compound (6.4 min, 37 degrees C, pH 7.4) appeared to be influenced by the hydantoin ring, analogues containing 2-5 methylene spacer groups between this ring and the nitrogen mustard moiety were prepared and evaluated for hydrolytic stability and antitumor activity. Stability correlated with structure and pKa values. The proximity of the hydantoin ring to the mustard function was a stabilizing factor. Activity against murine P-388 leukemia was demonstrated and a gradual decrease in this activity was observed as the hydrolytic instability increased. A relationship between analogue structure and a mass spectral rearrangement ion was identified.
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PMID:Spiromustine analogues. Relationships between structure, plasma stability, and antitumor activity. 370 19

Fifteen sulfur-containing compounds were examined for their ability to both protect normal hematopoietic stem cells (NCFU) from the cytotoxic effect of nitrogen mustard (HN2), and potentiate the cytotoxicity of HN2 to AKR leukemia cells (LCFU). All except four agents demonstrated some protection of NCFU with WR-2721 being most active. Five of the agents were also protective for LCFU with cysteine and glutathione being most active. However, a number of agents potentiated the cytotoxicity of HN2 to LCFU, the most active being disulfiram and AET followed by cysteamine, DMSO, WR-638, and WR-3689. The dose-response relationship for the potentiation was defined for DMSO. A second leukemia model, L1210, was also studied for potentiation of HN2 cytotoxicity by four of the most active agents--WR-2721, AET, DMSO, and disulfiram. The first two agents showed no effect (either protection or potentiation) when given either 15 min or 6 hr before HN2 administration. The last two agents, however, potentiated the cytotoxicity to a level similar to that found with the AKR leukemia.
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PMID:Potentiation of nitrogen mustard cytotoxicity to leukemia cells by sulfur-containing compounds administered in vivo. 374 35

7-Methoxy-1,2-aziridinomitosenes were prepared from mitomycin A and its N-methyl homologue by catalytic reduction followed by air oxidation. Treatment of these products with amines, including ammonia, ethylenimine, 2-methylethylenimine, propargylamine, and furfurylamine gave the corresponding 7-(substituted amino) derivatives. Screening of these compounds against P-388 leukemia in mice revealed some good activities. The more easily reduced compounds gave prolongation of life span comparable to that of mitomycin C, but their optimal doses were higher. Among these compounds, a methyl group on the aziridine nitrogen increased potency. The 7-amino derivatives, which were difficult to reduce to hydroquinones, were essentially inactive. The aziridinomitosenes were subjected to a Hansch-type analysis, but no statistically significant correlation was found.
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PMID:Preparation and antitumor activity of 7-substituted 1,2-aziridinomitosenes. 376 7

A series of water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results obtained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cis-dichloro-diammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice inoculated with L1210 leukemia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were administered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against L1210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1, 5, and 9 following i.p. inoculation of B16 melanoma to B6D2F1 mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). N-Benzyl-iminodiacetato(1,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containing material. The exact chemical identity of the active component of this mixture is currently under investigation. The results obtained to date, however, suggest that the N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.
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PMID:Water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes as potential antitumor agents. 377 45


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