A carboline derivative as a novel mammalian DNA topoisomerase II targeting agent.

The DNA intercalating, ellipticine analog drug, 5,11-dimethyl-5H-indol[2,3-b]quinoline, is able to stabilize in vitro the topoisomerase II-DNA cleavable complex and to induce DNA breaks in BPV I episome in rat fibroblasts. Cytotoxicity studies with DC3F cells resistant to ellipticine strongly suggest that topoisomerase II is a cellular target involved in the mechanism of cytotoxic action of this carboline derivative.

Synthesis and pharmacological properties of some dipyrido[1,3]diazepinones.

The synthesis of two isomeric dipyrido[1,3]diazepinones (3a,4) and N-monosubstituted derivatives of 3a by cyclocondensation of corresponding bipyridinediamines (1, 2) with urea was described. The alkylation of 3a and 4 with alkyl halides 6 in K2CO3/DMF/TBAB system gave N,N'-disubstituted compounds 7 and 8. Dipyrido[1,3]diazepinones 8a and 3b-d showed a weak general depressive action on the central nervous system and they were also devoid of antidepressant, anxiolytic, anticonvulsant and serotoninolytic or serotoninomimetic properties.

Synthesis and pharmacological properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines.

The synthesis and properties of 13H-naphtho[1',2':7,6] [1,4] diazepino[2,3-b] pyridines (7a--g) were described. New compounds were studied in rats and in mice in the tests used for preclinical assessment of antidepressant or anxiolytic activity. Compound 7c showed weak antagonism towards the reserpine-induced hypothermia and shortened immobility time in the despair test. None of the tested compounds had an anxiety-relieving action.

Synthesis and pharmacological properties of some derivatives of 3-phenylimidazo[4,5-b]pyridine.

The one-pot synthesis and properties of some derivatives of 3-phenylimidazo [4,5-b]pyridine (4a-g) were described. The central action of compounds 4a, 4f and 4g has been investigated using behavioral tests in mice and rats. The tested compounds showed a potent sedative effect. Compound 4f has central serotoninolytic properties in the m-CPP induced hyperthermia in rats.

Microbial transformation of azacarbazoles. IV. Conversion of chloro-substituted alpha-carbolines by Kitasatosporia setae strain.

Biotransformation of alpha-carboline derivatives substituted at positions C-5, C-6, C-7 and C-8 with chlorine, carried out with Kitasatosporia setae strain yielded corresponding 1-methyl-alpha-iso-carbolines. The formation of products is dependent on the position of chlorine in substrate molecule. When chlorine is introduced at C-6, the yield of N-1 methylation is low, about 5%. Derivatives of alpha-carboline substituted with chlorine at C-7 and C-8 form corresponding alpha-iso-carbolines with yield up to 20% and 30%, respectively, whereas 5-chloro-alpha-carboline is converted into 5-chloro-1-methyl-alpha-iso-carboline with 60% yield. Apparently, additional pathway of microbial transformation of 2-chloro-alpha-carboline has been found. Primarily formed 2-chloro-1-methyl-alpha-iso-carboline subjected to complex enzymic conversion yields quantitatively 2-methoxy-1-methyl-alpha-iso-carboline-9-N-oxide. It has been found that 2-chloro-1-methyl-alpha-iso-carboline exhibit strong cytotoxic activity, against KB cells tissue culture, ID50 = 0.01 microM/ml and inhibits growth of Kitasatosporia setae strain, MIC = 0.5 microM/ml. Toxicity of formed 2-methoxy-1-methyl-alpha-iso-carboline-N-9-oxide is markedly lower, ID50 = 0.3 microM/ml and MIC = 3.5 microM/ml. The remaining C-5, C-6, C-7 and C-8 chloroderivatives of alpha-iso-carboline occur to be less active than 2-chloro-1-methyl-alpha-iso-carboline.

Microbial transformation of azacarbazoles. IX. Preliminary studies on hydroxylation of 2,3-benzo-1,4-dimethyl-alpha-iso-carboline by Paecilomyces flavinosus.

Microbial transformation of 2,3-benzo-1,4-dimethyl-alpha-iso-carboline performed with several strains of fungi Beauveria bassiana, Verticillum lecani and Paecilomyces flavinosus yielded common products which were expected to be hydroxylated derivatives of starting compound. Among the microorganisms tested, strain Paecilomyces flavinosus P-5 was selected to perform quantitative bioconversion of 2,3-benzo-1,4-dimethyl-alpha-iso-carboline for preparative scale.

Antineoplastic activity of new linear hydrazine derivatives.

A series of hydrazine derivatives was tested for antineoplastic activity. Cyanoacetic acid hydrazide (I), cyanoacetic acid methylhydrazide (II) and N-thioamido-N'-cyano-acethylhydrazine (VI) appeared to be the most active agents against sarcoma 180, Ehrlich carcinoma and Nemeth Kellner lymphoma. The maximum tumor weight inhibition ranged from 70 to 90%. N, N'-bis-cyano-acethylhydrazine (IV) and N-isonicotinoyl-hydrazine (VIII) showed significant antitumor activity in Ehrlich carcinoma and Nemeth Kellner lymphoma systems. None of hydrazine derivatives were active against L1210 leukemia. The most active agents, I, II and VI were further evaluated in leukemia P388, melanoma B16, Lewis lung carcinoma and mammary carcinoma 16/C, and the agent VI was additionally tested in plasmacytoma MP26, colon carcinoma 26 abd Walker carcinosarcoma 256 systems. However, there was no effect with any agent or dose tested against any neoplasm.

Microbial transformation of azacarbazoles. I. N-methylation of alpha-, beta-, and gamma-carbolines by Kitasatosporia setae strain.

Microbial transformation of selected azacarbazoles, compounds noted for their activity as antitumor agents, conducted with Kitasatosporia setae strain resulted in N-methylation of pyridine nucleus of alpha-, beta- and gamma-carboline molecule. Formed quaternized intermediates were converted in alkaline conditions into corresponding iso-carbolines. The structure of the final products, alpha-, beta- and gamma-iso-carbolines have been established on the basis of spectral data and confirmed by chemical synthesis.

Antineoplastic activity of azacarbazoles. III. Synthesis and antitumor evaluation of selected 2-, 3- aza- and diazaanalogues of carbazole.

Preliminary screening of the antitumor properties of selected azacarbazoles revealed that of all the compounds tested only 2,7-diazacarbazole (compound IX) and 3,6-diazacarbazole (compound XI) caused the inhibition of Sarcoma 180 growth up to 70%. beta- and gamma-Carbolines and their derivatives in presented testing system were inactive. None of the tested compounds displayed marked activity against murine leukemias and was active in the cytotoxicity test of KB cells.

Antineoplastic activity of azacarbazoles. I. Synthesis and antitumor properties of alpha-carboline and its selected derivatives.

alpha-Carboline and its several derivatives have been synthesized and evaluated for their antitumor activity against L1210 lymphoid leukemia, P388 lymphocytic leukemia and Sarcoma 180. It was found that of these compounds only alpha-carboline and its derivatives substituted in C-4 position with a methyl group or in 6-C position with a methyl group and fluorine or chlorine atoms caused moderate inhibition of the tumor growth of Sarcoma 180. The introduction of bromide, iodide atoms, hydroxy-, amino-groups or some other substituents in C-6 position of alpha-carboline molecule reduced significantly the biological activity of the tested compounds against Sarcoma 180. Additionally, the introduction of an ethyl or ethoxycarbonyl group to the pyrrole ring at N-9 also obliterated antitumor properties of these analogues. None of the tested compounds displayed a significant activity against murine leukemias. In the cytotoxicity test of KB cells all the compounds were inactive.

Structure-activity relationship studies on selected iso-alpha-carbolines. I.

In the course of microbial transformation of the antitumor compounds, it has been found that iso-alpha-carbolines and their certain derivatives undergo N-1 methylation by Kitasatosporia setae. The resulting products, iso-alpha-carbolines exhibit antibacterial and antifungal properties in the concentration range of 0.2-2.5 mumol/ml. In the cytotoxicity test only derivatives substituted at C-2 and C-4 display moderate activity against KB cells. None of the compounds tested show a significant inhibitory effect against P388 lymphocytic leukemia.

Antifungal properties of 1,2-dihydro-3-methylpyrido-(3,2-e)-as-triazine dihydrochloride (I-476).

Antifungal activity of compound I-476 (1,2-dihydro-3-methylpyrido[3,2-e]as-triazine dihydrochloride) was evaluated in vitro and in vivo. Minimal concentration inhibiting the growth of pathogenetic and saprophytic fungi in vitro ranged from 3.1 to 25 micrograms/ml. The in vivo experiments were performed in a model of experimental candidiasis in Balb/c mice. Antifungal activity of I-476 was measured by the survival time of the animals and the number of living Candida albicans cells in the kidney and spleen of the animals infected and then treated with the compound in question. A single intraperitoneal dose of I-476 markedly prolonged the survival time of mice with experimental candidiasis. The compound administered for 5 subsequent days, diminished the number of Candida albicans cells in the kidney and spleen or caused their complete elimination from these organs.

Biological activity of 1,4-dihydropyridine derivatives.

Six new 1,4-dihydropyridine derivatives were evaluated in vitro for antimicrobial and cytotoxic effects and in vivo for antineoplastic activity. These compounds inhibited the growth of most of Gram-positive and Gram-negative bacteria at concentrations of 50 and 100 micrograms/ml. Concentrations effective against fungi were somewhat lower (25-50 micrograms/ml). The growth of mycobacteria was inhibited at concentrations of 3.1-25 micrograms/ml. Compound IV inhibited the growth of pathogenic mycobacteria including M. tuberculosis resistant to SM and INH at 3.1 or 6.2 micrograms/ml. In cytotoxicity assays, compound II, IV and V appeared the most active. However, none of the 1,4-dihydropyridine derivatives affected the survival time of mice with P388 and L1210 leukemias or melanoma B16. The growth of subcutaneous tumors of sarcoma 180 was inhibited by compounds I, III, IV and V. The effect was dose related.

Cancerostatics. IV. On the synthesis of some noval 1-Azacarbazole derivatives as antineoplastic agents.

By condensation of 2-chloro-3-nitropyridine with some anilines the corresponding 2-anilino-3-nitropyridines 1a--11 were obtained. Hydrogenation of these compounds and subsequent diazotization of the 2-anilino-3-aminopyridine derivatives 2a--2l gave triazoles 3a--3l which thermally decomposed in PPA or in liquid paraffine afforded the required 6- and 8-substituted 1-azacarbazole derivatives 4a--3, i--l. Some of these compounds showed significant activity against transplanted mouse sarcoma 180. None of them were active against L 1210 and P 388 leukemias.

Antitumor properties of selected 1,2,4-triazine derivatives.

Several new 3-thio-1,2,4-triazine derivatives were synthesized and investigated for antimicrobial and antitumor activity in in vitro and in vivo systems. Some of the investigated compounds inhibited growth of gram-positive bacteria and fungi at the concentration of 5-20 microgram/ml. Two methyl-nitro-imidazole-triazine derivatives (XI and XIII) inhibited the development of chicken fibroblast at 0.1 microgram/ml. Three out of fourteen compounds tested (V, XII and XIII) inhibited by 75% growth of sarcoma 180 when injected s.c. for 14 consecutive days in the doses of 50 and 100 mg/kg. At the same doses no effect was noted on leukemia L 1210 and P 388. Correlation between chemical structure, cytotoxic activity, antitumor effect and antimicrobial activity is discussed.

Antifungal properties of a novel 1,2,4-triazine derivative I 319.

The antifungal activity of the sodium salts, of 3-thiolo-5-phenyl-1,2,4-triazine (I 319) was determined in vitro and in vivo. The minimal inhibitory concentration (MIC) of I 319 for 33 pathogenic and saprophytic fungal strains ranged from 3.1 to 25 microgram/ml. In vivo, experiments were performed on a model of subacute candidiasis in Balb/c mice infected intraperitoneally with Candida albicans. The antifungal activity was estimated on the basis of the extension of the mice life span and on the number of living yeast cells present in the kidneys, liver and spleen of treated and control mice. A single i.p. dose of I 319 (25 mg/kg) prolonged the survival time of treated animals up to 200%. Five subsequent doses of the compound diminished the number of C. albicans cells in the tissues of these mice. The DL50 of I 319 for mice (i.p.) was about 250 mg/kg.

Cancerostatics. III. Synthesis and some chemical transformations of 3-cyano-5(pyridyl-4.)pyrid-2-one.

In reaction of 3-dimethylamino-2-(pyridyl-4')acrolein with cyanoacetic acid and malononitrile new derivatives of 3,4'-dipyridyl were obtained. The synthesis of pyridyl-4-cyanoacetaldehyde 2 is also described. One of these compounds (8) showed significant cytostatic activity against transplanted Ehrlich ascites carcinoma and Nemeth-Kellner lymphoma.

Cancerostatica. I. synthesis of some pyrazolo[1,5-a]pyrimidine and pyrazolo [3,4-b] pyridine derivatives.

In basic medium 2-phenyl-and 2-(pyridyl-4')-derivatives of 3-dimethylaminoacrlein yields with 5-aminopyrazol-3-one the corresponding pyrazolo [1,5-a] pyrimidines. However, in acid medium, 2-phenyl-3-dimethylaminoacrolein cyclised to derivatives of pyrazolo[3,4-b] pyridine. A reaction mechanism is proposed. Some of these compounds showed significant cytostatic activity against transplanted Ehrlich asc. carcinoma and Nemeth-Kellner lymphoma.