Immunotropic activity of vratizolin (ITCL, Denotivir).

The aim of this study was to evaluate immunotropic properties of vratizolin, a known antiviral drug, in several in vitro and in vivo assays in mouse and human models. We demonstrated that vratizolin exerted strong immunosuppressive actions both in the humoral and cellular immune response to SRBC in mice. The compound affected not only the inductive phase of delayed type hypersensitivity (DTH) but also the effector phase of that response. Vratizolin was effective when given intraperitoneally and orally. The inhibitory action of vratizolin was comparable to that of cyclosporin A (CsA), the reference drug. Vratizolin exhibited also suppressory properties with regard to PHA-induced proliferation of human peripheral blood lymphocytes and that effect exceeded the inhibitory action of CsA. We also showed that vratizolin inhibited to some degree LPS-induced cytokine production in human peripheral blood cultures. The activities of TNF-alpha, IL-1 and IL-6 were inhibited on average by 37, 26 and 35%, respectively. This was in contrast to the effects of CsA which strongly inhibited only IL-1 production. Lastly, we demonstrated that vratizolin markedly inhibited growth of several tumor cell lines. In particular, the compound significantly inhibited growth of mouse leukemia L-1210 and human acute lymphoblastoid leukemia CCRF-CEM cell lines. The presented data suggest that the immunosuppressory action of vratizolin, although similar to that of CsA, is mediated by a different mechanism. The properties of vratizolin, described in this report, indicate that the drug should be further investigated for possible immunosuppressory and antitumor application.

Synthesis and immunological activity of new 5-amino-3-methyl 4-amido and 4-ureilene isoxazole derivatives.

5-Amino-3-methylisoxazole-4-carboxylic acid amides and ureilenes have been synthesized from 5-amino-3-methylisoxazole-4-carbonyl azide. The compounds were investigated for potential immunotropic activity in several immunological tests. The most interesting suppressory activities in the humoral and cellular immune response were compared to activities of analogous compounds previously described as immunostimulatory.

Synthesis and structure elucidation of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides and their immunological activity.

A series of 5-aminomethinimino-3-methyl-4-isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5-amino-3-methyl-4-isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5-alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4. The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response (4d), humoral immune response (4a), or cellular immune response (4c). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.

Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part III.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-13 were synthesized and evaluated for their pharmacological activity. Compounds 5, 7, 9, 10 and 12 showed antiaggressive effect, compounds 6 and 10 showed synergism with hexobarbital while compound 6 exerted analgesic activity.

Antitumor and immunosuppressive activity of Merbarone's analogues and arylidenehydrazinopyrimidines.

The synthesis of Merbarone's analogues, the 4-thio- or 4-oxo derivatives of 5-carbamoyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine is described, starting from 5-carboxy-6-methyl-2-oxo-4-thioxo-1,2,3,4-tetrahydropyrimidine+ ++. That was also used as staring material for synthesis of NCS624947 analogues, the 4-arylidenehydrazino-5-carbamoylpyrimidines. The reduction of arylidenehydrazinopyrimidines with hydrogen on Pd/C was also performed. The obtained compounds were successfully tested for anticancer and immunomodulating activity.

Synthesis and cytotoxic activity of new isothiazolo[5,4-d]pyrimidine derivatives.

The synthesis of new 5-amino-3-methylisothiazolo[5,4-d]pyrimidines series is reported. The cytotoxic activity of these compounds has been determined on the two tumor cell lines (P-388 and KB). Two representative compounds 7 and 8 displayed a significant cytotoxic action. The results point a possible involvement of structural features in the inhibition effect against tumors.

Synthesis and biological properties of 5-hydroxy-methylpyrimidines.

Reduction of 4-arylamine-6-methyl-2-phenyl-5-pyrimidine carboxylic acid and its ethyl esters as well as 5,7-dihydrofuro (3,4-d)-pyrimidines resulted in obtaining some 4-arylamine-6-methyl-2-phenyl-5-hydroxymethylpyrimidines exhibiting strong immunomodulatory and cytostatic properties.

Synthesis of isothiazole derivatives with potential biological activity.

The synthesis of acyl and ureido derivatives of substituted amides of 3-methyl-5-aminoisothiazole-4-carboxylic acid is presented. The structures of the compounds obtained were established on the basis of IR, 1H NMR and elemental analysis. The influence on the circulatory system of the derivatives was investigated. All structures of the compounds obtained were fully confirmed by IR and 1H NMR as well as by elemental analysis (Table).

Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part II.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-20 were synthesized and evaluated for their pharmacological activity. Compounds 11-14, 17-19 showed antiaggressive effect, compounds 5, 8, 9, 11, 12 and 19 displayed antiserotonin activity while compound 14 exerted antireserpine action.

Pyrimidobenzodiazepines. Synthesis of pirenzepine analog.

The synthesis of Pyrimido[4,5-b][1,5]benzodiazepine derivatives from 4-(o-aminophenylene)amino-5-ethoxy-carbonyl-1,2-dihydro-6-methyl-2 - oxopyrimidine has been described. Pyrimidobenzodiazepine 5 alkylated with N-methyl-N'-chloroacetyl-piperazine gives a product related to pirenzepine. Compound 5 shows weak antianxiety and antidepressive action.

[Imidazopyrimidodiazepines--new heterocyclic system; synthesis and properties]. / Imidazopirymidodiazepiny--nowy uklad heterocykliczny. Synteza i wlasciwosci.

The synthesis of the new tricyclic system ring 6-methyl-2,3,10,11-tetrahydroimidazo (1',2',3'-CD) pyrimido (5,4-b) (1,4) diazepinediones-5,8 is described. The 4-aryl- and 5-amino-imidazopyrimidodiazepines have also been obtained. The synthesis started from derivatives of 2-hydroxy-6-methyl-5-pyrimidine carboxylic acids. Some of the chemical and biological properties of new compounds are described.

Synthesis and properties of 7-methyl-5-oxo-1,5-dihydro-8-[1,2,4]-triazolo [4,3-c]pyrimidinecarboxylic acid derivatives.

The synthesis of the new triazolo[4,3-c]pyrimidines is described, starting from derivatives of 5-carboxy-2-hydroxy-4-hydrazino-6-methylpyrimidine. The 4-methyl-2,3-dihydropyrazolo[3,4-d]pyrimidine-3,6-dione was also obtained. Some of triazolo[4,3-c]pyrimidines tested for biological activity were found inactive.

Synthesis and antineoplastic effects of furo[3,4-d]pyrimidine derivatives.

Furo[3,4-d]pyrimidine was obtained in the reaction of 2-phenyl-4-phenylamino-6-methyl-5-pyrimidinecarboxylic acid with SOCl2. This compound, heated with aliphatic amines, yielded mono- and diamino-derivatives. Some of the obtained compounds exhibited a potent antineoplastic activity.

Synthesis and pharmacological properties of derivatives of isoxazolo [5,4-d]-6,7-dihydropyrimidines.

The synthesis of 4-hydroxy-4-amino substituted 5-phenylisoxazolo [5,4-d]-6,7-dihydropyrimidines was described. The compounds with alkylamine and semicarbazide substituents in position 4 showed the activity against sarcoma Sa-180, while those with heterocyclic substituents at the same position have analgesic properties.

Synthesis of p-menthane derivatives with potential biological activity.

The synthesis of amino ketones and amino alcohols in p-menthane series is presented. These compounds were obtained in Mannich reaction, starting from the unsaturated ketone p-mentha-6,8-dien-2-one and its saturated analogue p-menthan-2-one. The structures of the compounds obtained were established by means of chemical transformations and elemental and spectral (IR, 1H NMR) analysis. The compounds obtained were subjected to the pharmacological investigations.

Synthesis and antitumor properties of pyrazolo [3,4-D] pyrimidine derivatives.

Several new 5-substituted 1-phenylpyrazole [3,4-d] pyrimidine derivatives were synthesized and tested for antitumor activity. Compound 17, which has 3,4-dichlorophenyl moiety at N5 of the pyrazole pyrimidine ring, shows a strong activity against L-1210 leukemia (152%). On the other hand, compounds 15, 17 and 21 were the most active against sarcoma Sa-180. It was observed that many derivatives of pyrazole [3,4-d] pyrimidine possess different biological, especially antitumor properties [1-6, 9, 10].

Isothiazolopyrimidines--new group of anticancer agents. II.

In reactions of 5-aminoisothiazolopyrimidines 1 with glycosilisothiocyanates and phenyl isocyano- or isocyanates, N-glycosilo-N-phenylo- and N-isothiazolopyrimidinothiocarbamides type II were obtained. The same compound--5-aminoisothiazolopyrimidine 1 in reaction with glucose, arabinose and ribose bromoderivatives was converted into N-glycosiloaminoisothiazolopyrimidies type 3. Some of the newly synthetized compounds appeared effective against L-1210 leukemia and Sa-180 sarcoma.

Isothiazolopyrimidines--new group of anticancer agents. I.

Synthesis and biological properties of 27 derivatives of 5-amino-3-methylisothiazolo[5,4-d]pyrimidine-4-dione and of 3-methyl-5-semicarbazido-4-isothiazolocarboxylic acid ethyl esters are discussed. 5-Amino-3-methylisothiazolo[5,4-d]pyrimidine-4-dione was converted by reaction with aldehydes into Schiff bases, which under reduction of NaBH4, were transformed into appropriate N-methylene analogs. 3-Methyl-5-semicarbazido-4-isothiazolocarboxylic acid ethyl esters in reaction with aldehydes were converted into benzylidene derivatives. Some of the compounds obtained, especially those of Schiff base structure, displayed strong activity against L-1210 leukemia, Sa-180 sarcoma. Ehrlich carcinoma and Nemeth Kellner lymphoma.