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The new pyrrolo[3,4-c]pyridines have been synthesized. 4-Methyl-6-phenyl-1H-pyrrolo[3,4-cpyridine-1,3-dione (1) was the key intermediate for the synthesis of the novel derivatives of various chemical structures. In the first step, the pyrrolo[3,4-c]pyridine-1,3-dione 1 was alkylated to the corresponding N-alkyl-4- methyl-6-phenyl-IH-pyrrolo[3,4-c]pyridine-1,3-dione derivatives 2a-f. The Mannich bases 3a-j were synthesized by treating pyrrolo[3,4-c]pyridine-1,3-dione 1 with appropriate amines and formaldehyde. Hydrolysis of ester 2a gave the appropriate acid 5. Next, amides 4a-e have been obtained. The structures of the new compounds were confirmed by elemental analysis, IR and NMR spectra. The antitumor and antimicrobial activities in vitro of the obtained derivatives were examined. Mannich bases 3c and 3g showed activity against C. albicans and S. aureus.

Novel 5H-indolo[2,3-b]quinoline O-aminoglycosides were synthesized in order to check the hypothesis that the construction of hybrids composed of the active 5H-indolo[2,3-b]quinoline chromophore and daunosaminyl or acosaminyl moiety may result in the cytotoxic activity of the obtained derivatives that is much higher than the one of the parent DIMIQ (5,11-dimethyl-5H-indolo[2,3-b]quinoline) and 6H-indoloquinoline analogs. Actually, 5H-indolo[2,3-b]indoloquinoline O-aminoglycosides showed the anti-proliferative activity in vitro against human lung adenocarcinoma A549, breast cancer MCF-7, melanoma Hs294T, promyelocytic leukemia HL-60, uterine sarcoma MES-SA and colon cancer LoVo cell lines, which was 10 times higher than that of the 6H-analogs and comparable to the one of the referential DIMIQ. Unexpectedly, it appeared that except for HL-60/MX2 (P-gp-independent and topoisomerase II-dependent resistance), other MDR tumor cell lines (LoVo/DX. P-gp-dependent, MRP-, LRP-dependent multidrug resistance) and MES-SA/DX5 (P-gp-dependent resistance to doxorubicin) are also resistant to the 5H-indolo[2,3-b]indoloquinoline O-aminoglycosides tested. This is surprising because 6H-analogs, in general, 10 times less active against non-MDR tumor cell lines, as well as the DIMIQ itself, are able to overcome drug resistance in all MDR cell lines examined. The cytotoxicity of the tested compounds against tumor cell lines and against normal cells (mice fibroblasts BALB/3T3) was comparable.

A new class of Mannich bases 9-26, derivatives of 2-amino-1H-benzimidazole, were obtained in the condensation of Schiff bases 1-4 or 2-benzylaminobenzimidazoles 5-8 with selected secondary amines: morpholine, piperidine, N-methylpiperazine, N-phenylpiperazine, 1-(2-pyridyl)piperazine, 1(2-methoxyphenyl)piperazine, 1-(2-pyrimidinyl)piperazine and formaldehyde in ethanol. The pyrimido[1,2-albenzimidazole derivatives 27-29 have been synthesized in the reactions of Schiff base 2 with selected compounds containing active methylene group: acetylacetone, benzoylacetone and malononitrile. The structures 1-29 were confirmed by the results of elementary analysis and their IR, 1H- and 13C-NMR spectra. The products 1-29 are of interest for biological studies and can be substrates for further synthesis. All compounds were screened against the cells of MV4-11 human leukemia and then the most active of them 5, 7, 9-16, 24-26, 28, 29 were tested towards human T47D breast and A549 lung cancer cells as well as normal mouse fibroblasts (BALB/3T3). The most active compound against the cancer cell lines was 4-amino-3-cyano-2-(4-hydroxyphenylene)-1,2-dihydropyrimi-do[1,2-a]benzimidazole (29) (IC50 0.23 ± 0.05 µg/mL against MV4-11 cells) showing in parallel very low cytotoxicity towards mouse fibroblasts. Cisplatin was the control drug.

A series of novel N,N-cyclic-2,4-dihydroxythiobenzamide derivatives is described. Test compounds were formed by the reaction of the commercially available reagents with sulfinylbis[(2,4-dihydroxyphenyl)methanethione] (STB). The chemical structures were confirmed by IR, 1H NMR, 13CNMR, EI-MS, and elemental analysis. For the estimation of potential activity in vitro, the MIC values against strains of Candida were determined. Antifungal properties of selected compounds under in vitro conditions against five phytopathogenic fungi were estimated. Furthermore, the antiproliferative activity against the HCV29T cancer cell lines has been studied. These compounds exhibited antiproliferative activity in the range of 33.98-10.51 µg/mL.

Two series of 2-thioxoimidazo[4,5-b]pyridine derivatives have been synthesized from 2,3-diaminopyridine (1) and 5-halogenosubstituted-2,3-diaminopyridines 2, 3. Mannich bases 7 - 12 and 24 - 29, derivatives of 1-arylamino-6-halogeno-2-thioxoimidazo[4,5-b]pyridine were obtained with selected secondary amines: morpholine, piperidine, 2-methoxyphenylpiperazine, pyrimidyn-2-yl-piperazine and formaldehyde in ethanol. The structures 7 - 12 and 24 - 29 were confirmed by the results of elementary analysis and their IR, 1H-NMR and MS spectra. All given structures 7 - 12 have been optimized to get the most stable low energy conformers. Synthesized compounds were of interest for biological studies or can be substrates for further synthesis. The selected compounds 7 - 10, 12- 17, 22, 25, 27 - 29 were screened for their antiproliferative activity in vitro against human cancer and normal mouse fibroblast cell lines.

A library of artificial receptors formed by the self-organization of N-lipidated peptides attached to the cellulose via m-aminophenylamino-1,3,5-triazine was used for differentiation of metabolites in urine of healthy and cancer bearing mice. The interactions of urine metabolites with the receptors were visualized by using competitive adsorption-desorption of an appropriate reporter dye. Analysis of the binding pattern (fingerprint) of urine metabolites from healthy and from cancer suffering mice showed that there were several structures among 120-elements molecular receptors which were able to differentiate bonded ligands depending on the healthy state. For all three tested types of cancers two structures: Lipid-Pro-Ala-NH-C6H4-NH-DMT-cellulose and Lipid-Arg-Pro-NH-C6H4-NH-DMT-cellulose were selected as diagnostic.

A series of new prodrugs: [bis(2-chloroethylamino)phosphoryloxy]methyl acetate, [bis(2-chloroethylamino)phosphoryloxy]methyl pivalate and [bis(2-chloroethylamino)phosphoryloxy]methyl benzoate, was obtained in the reaction of isophosphoramide mustard (iPAM) with the corresponding acyloxymethyl halides. The cytotoxic activity of these new compounds is also shown. All compounds were highly active in the inhibition of cancer cell proliferation against the human lung (A594), prostate (PC-3) and breast (MCF-7) cancer cell lines.

A novel series of esters 8-10 and hydrazones 4-6 was synthesized from 4-aryl-2-phenacylidene-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepine (1-3). Subsequent treatment of hydrazone 4 with p-chlorbenzaldehyde furnished azine 7. Long-standing heating of ester 8 with hydrazine hydrate afforded 3-[1-(p-chlorophenylene)-2-(5-phenyl-1H-pyrazol-3-yl)-ethyl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one (11). The structures of 4-6 and 8-10 were identified by the results of elemental analysis and their IR, 1H-NMR and MS spectra. Additionally, the structure of 11 was confirmed by X-ray diffraction method. Compounds 8-10 and 11 were examined for their antiproliferative activity in vitro against the cells of 5 human cancer cell lines, using SRB or MTT technique. Among tested compounds, only 11 revealed cytotoxic activity in vitro against all cell lines applied with ID50 (inhibitory dose 50%) values lower than 4 microg/mL, which is an international activity criterion for synthetic compounds. All compounds inhibit the proliferation of HL-60 human promyelocytic leukemia cell line.

A number of new 1-substituted-6H-pyrido[4,3-b]carbazole derivatives have been synthesized. Nine of the newly obtained compounds were subjected to preliminary in vitro cytostatic activity screening against murine leukemia (L1210), human lung cancer (A549) and human colon cancer (HT29) cell lines. One particular compound 6f exhibited over 20 times better activity against L1210 tumor cell line than the reference ellipticine.

The number of 3'- and 4'-substituted 1-phenyl-6H-pyrido[4,3-b]carbazole derivatives have been synthesized and tested biologically. Eleven of the newly obtained compounds were subjected to the preliminary cytostatic screening for their activity against L1210 (murine leukemia), A498 (human kidney cancer), A549 (human lung cancer) and HT29 (human colon cancer) cell lines. Eight of tested derivatives exhibited significant biological activities, which only weakly depended on side chain length and position of the substituent.

The synthesis of several new 2-, 3- or 4-substituted pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines is described. The obtained compounds were tested for their antiproliferative activity in vitro. Two of them: 3-chloro-2-methylpyrido[2',3':3,4]pyrazolo[1,5-a] pyrimidin-4-one [X] and 2,3-cyclopentylpyrido [2',3':3,4] pyrazole[1,5-a]pyrimidin-4-one [XII] revealed weak cytotoxic activity against the cells of human bladder cancer cell lines: LoVo, MCF-7, MES-SA and HCTV29T. The structures of the products II - XII were established on the basis of elemental analysis and spectral data (IR, 1H NMR and MS).

The synthesis of 3-aminoisoxazolo[5,4-b]pyridine [III] and of several new 3-substituted aminoisoxazolo[5,4-b]pyridines is described. 3-Aminoisoxazlo[5,4-b]pyridine [III] was subjected to reactions with the acid halides and substituted aromatic aldehydes, leading to the production of the corresponding amides IV-VII, IX, XI-XVI and new tricyclic pyridoisoxazolopyrimidine VIII and Schiff bases XX-XXIV. 4-Chlorobutyroamide IX cyclized into 3-(pyrrolidinon-1-yl)isoxazolo[5,4-b]pyridine [X]. 3-Chloroacetylaminoisoxaxolo[5,4-b]pyridine [V] in reaction with secondary amines gave 3-aminoacetylaminoisoxazolo[5,4-b]pyridines XVII-XIX. The structures of the products II-XXIV were established on the basis of elemental analysis and spectral data IR, 1H NMR and MS. Selected compounds were tested for their antiproliferative activity in vitro. Two of them: 3-chloroacetyl-[V] and 3-2-bromo-propionylaminoisoxazolo[5,4-b]pyridine [VI] revealed cytotoxic activity against the cells of 8 various human or mouse tumor cell lines applied. Their ID50 (inhibitory dose 50%) values are in the range of the international activity criterion for synthetic agents (4 microg/ml).

Dibenzylphosphorobenzyl and phosphorobenzyl analogues of isophosphoramide mustard, an active metabolite of ifosfamide were synthesized. Phosphorobenzyl analogue posseses stronger cytotoxic activity than isophosphoroamide mustard against the cells of several cancer cell lines suggesting the possibility of the use of this compound in Gene-Directed Enzyme-Prodrug Therapy (GDEPT).

A systematic investigation into the impact of the substituents introduced into the indolo[2,3-b]quinoline system is described. The findings clearly demonstrate that the compounds bearing a methyl group or a longer aliphatic chain at the N-6 position are inactive against prokaryotic and eukaryotic cells. The introduction of alkyl-amino-alkyl substituent at the N-6 position of indolo[2,3-b]quinoline accounts for the appearance of the antimicrobial and.cytotoxic properties. The cytotoxicity against oral epidermoid carcinoma KB (ID50) is in the range from 2.0 to 9.0 microM, and the antimicrobial activity (MIC) falls between 0.03 and 0.50 mM. The structural relation within 6H-indolo[2,3-b]quinolines, concerning their antimicrobial and cytotoxic activity, corresponds well with their ability to bind DNA and to inhibit topoisomerase II activity.

The synthesis of several new 3-substituted aminopyrazolo[3,4-b]pyridines is described. The obtained compounds were tested for their antiproliferative activity in vitro. Two of them: 3-chloroacetylaminopyrazolo[3,4-b]pyridine [II] and 3-(2-bromopropionyl-amino)pyrazolo[3.4-b]pyridine [III] revealed cytotoxic activity against the cells of 5 human tumor cell lines applied. Their ID50 values were in the range of the international activity criterion for synthetic agents (4 microg/ml). The structures of the products II-XVII were established on the basis of elemental analysis and spectral data (IR, 1H NMR and MS).

Genistein has been shown to be an inhibitor of tumor growth as well in vitro as in vivo. In addition to its antitumor effect, genistein reveals the antimetastatic and antiangiogenic properties. In this paper we described the results of our studies on the antimetastatic activity of genistein alone or combined with cyclophosphamide (CY) in mice which before this treatment were exposed to surgical excision of the primary tumor. Three transplantable subcutaneously growing mouse tumors were applied: Lewis lung cancer (LL2), B16F-10 melanoma and 16/C mammary cancer. The antitumor and antimetastatic effect was evaluated by the estimation of a number of lung colonies and a number of primary tumor recurrence as compared to the control mice exposed to the s.c. tumor extirpation only. Twenty days after the surgery, an average of 52 lung tumor colonies per mouse were detected in control mice bearing LL2 cancer. The treatment with genistein resulted in the reduction of the lung colonies to 24 per mouse. The treatment with CY reduced the number of lung colonies to 12 (p < 0.05) and combined treatment with both agents to 4 (p < 0.05). The percentage of primary tumor recurrence was 25, 86, 67 and 80% in the control, genistein treated, CY treated, and genistein + CY treated mice, respectively. Twenty days after the surgery, no lung metastases in the control mice bearing B16F-10 melanoma were observed. The percentage of primary tumor recurrence in the control, genistein treated, CY treated and genistein + CY treated mice was: 86, 29, 57 and 67% respectively. Two different protocols of the treatment with genistein were applied in 16/C mammary cancer model. In the first one genistein was injected before and in the other after surgical excision of tumor. The histological examination revealed the presence of lung metastases in all, untreated and treated, according to both protocols groups of mice. The percentage of primary tumor recurrence in the control mice, genistein treated according to the protocol I, and II was: 100, 40, and 40%, respectively.

5-Ethoxalyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin -2-one [I] was treated with some selected secondary amines (dimethyl-, diethyl-, dipropyl-, disobutylamine or with morpholine) and methyl-hydrazine. Amides II-IV and hydrazide VII were obtained. Compounds II, IV and VI were tested for their psychotropic activity; they showed a weak toxicity. Compounds II and VI showed an anxiolytic activity. Compounds I, II, IV, VI and VII were screened for their cytotoxic (anti-proliferative) activity in vitro by using different human cancer cell lines. None of them revealed any inhibiting effect against the tumor lines used.