Synthesis of some 2-hydroxy-1-[(4-chloro-2-mercaptophenyl)sulfonyl]imidazole derivatives with potential anticancer activity

Several 2-(hydroxy or alkoxy)-1-[(4-chloro-5-R1-2-mercaptophenyl)sulfonyl]limidazoles [II-VI, IX-XI] and bis ?5-chloro-4-methyl-2-[(2-aryloxyimidazol-1-yl)sulfonyl]phenyl disulfides [XII-XV] were obtained by either the selective hydrolysis or alcoholysis of the appropriate 7-R1-8-chloroimidazo[1,2-b] [1,4,2]benzodithiazine 5,5-dioxides [Ia-d]. The structures of the products and their S-substituted derivatives [VII, VIII] were established on the basis of elemental analysis and spectral data (IR, 1H and 13C NMR). Preliminary screening data indicated that the investigated compounds [III, X, XII and XIII] exhibited weak [III, X], moderate [XII] or fairly high [XIII] activity against some human tumor cell lines (Table 1).     

Synthesis, structural characterization and biological evaluation of novel [1,2,4]triazolo [1,5-b][1,2,4]benzothiadiazine-benzothiazole conjugates as potential anticancer agents

Two series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b][1,2,4]benzothiadiazine 2-methyl/ethyl sulfanyl benzothiazole derivatives (5a-d) and 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b][1,2,4] benzothiadiazine 2-phenoxy benzothiazole derivatives (16a-c) were synthesized and their structures confirmed by NMR, MS, IR and X-ray crystallography. These compounds were evaluated for their cytotoxicity against 60 human tumour cell lines. One of the synthesized compounds (5b) exhibited significant inhibitory activity against most of the cell lines and has been further evaluated for the five-dose screening.     

Synthesis and biological evaluation of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b)pyridazines related to formycin prepared via ring closure of pyridazine precursors

All three amino-substituted 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazines (5, 19, and 20) structurally related to formycin A were prepared and tested for their antitumor and antiviral activity in cell culture. Dehydrative coupling of 4-amino-5-chloro-3-hydrazinopyridazine (7) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6) in the presence of DCC and subsequent thermal ring closure of the reaction product (8) provided 8-amino-7-chloro-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)- triazolo[4,3-b]pyridazine (9). Dehalogenation of 9, followed by debenzoylation, gave the formycin congener 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (5). Similar condensation of 5-amino-4-chloro-3-hydrazinopyridazine (13) with 6 and dehalogenation of the cyclized product (16), followed by debenzoylation, gave the isomeric 7-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (19). DCC-mediated coupling of 6 with 6-chloro-3-hydrazinopyridazine (12), followed by ammonolysis of the cyclized product (21) with liquid NH3, provided a convenient route to 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazine (20). The structural assignment of 5 was made by single-crystal X-ray diffraction analysis. Compounds 5, 19, 20, and certain deprotected nucleoside intermediates were evaluated against L1210, WI-L2, and CCRF-CEM tumor cell lines, as well as against DNA and RNA viruses in culture. These compounds did not exhibit any significant antitumor or antiviral activity in vitro.     

Synthesis and antitumor activity of some new substituted quinolin-4-one and 1,7-naphthyridin-4-one analogs

The synthesis of some new analogs of quinolin-4-one and 1,7-naphthyridin-4-one is described. The prepared compounds were tested for their in vitro antitumor and cdc2 kinase or cdc25 phosphatase inhibitory activity. Compound ethyl 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de][2,3-b]pyrido-1,4-thiazine-6-carboxylate (6b) showed antitumor activity against CNS SNB-75, breast T-47D, and lung NCI-H522 cancer cell lines with GI50 values of 8.3, 17.6, and 22.7 microM, respectively. Meanwhile, the compounds ethyl 4-oxo-8-phenylthio-1H,4H-quinoline-3-carboxylate (11a) and 4-oxo-8-phenylthio-1H,4H-1,7-naphthyridine-3-carboxylic acid (12b) have proved to be cdc25 phosphatase inhibitors at IC50 values of 11 and 5 microM, respectively.     

Design, Synthesis and Evaluation of Novel 1-(Substituted Acetyl)-4-(10-Bromo-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-B]Pyridine-11-Ylidene)piperidines as Antitumor Agents and Farnesyl Protein Transferase Inhibitors

Eight novel 1-(substituted acetyl)-4-(10-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta [1,2-b] pyridine-11-ylidene)piperidines were designed by incorporating zinc binding groups to enhance activity. The designed molecules were synthesized and were evaluated for antitumor activity in vitro in five cell lines and for farnesyl protein transferase inhibition. Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin. Compound 6e was most active with IC(50) values of <15 μM in two cell lines tested. Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 μM.     

Nigerasperones A approximately C, new monomeric and dimeric naphtho-gamma-pyrones from a marine alga-derived endophytic fungus Aspergillus niger EN-13

Three new naphtho-gamma-pyrones, 5-hydroxy-6,8-dimethoxy-2-hydroxymethyl-4H-naphtho[2,3-b]pyran-4-one (1, nigerasperone A), 3,3'-dihydro-2,2',5,5'-tetrahy-droxy-8,8',10,10'- tetramethoxy-2,2'-dimethyl-(6',9-bi-4H-naphtho[1,2-b]pyran)-4,4'-dione (2, nigerasperone B), and 3'-hydro-2',5,5',8-tetrahydroxy-6,6',8'-trimethoxy-2,2'-dimethyl-(7,10'-bi-4H-naphtho[2,3-b]pyran)-4,4'-dione (3, nigerasperone C), together with nine related known compounds were characterized from Aspergillus niger EN-13, an endophytic fungus isolated from the marine brown alga Colpomenia sinuosa. Their structures were elucidated by detailed analysis of spectroscopic data and by comparison with literature reports. In the cytotoxic assay, these compounds did not show remarkable inhibitory effects against A549 and SMMC-7721 tumor cell lines. However, 3 and several known compounds showed weak antifungal activity against Candida albicans and moderate activity on DPPH scavenging.     

Synthesis, anti-HIV and anticancer activities of new 4-(2-mercaptobenzenesulfonyl)perhydro-1,2,4-triazin-3-ones

Syntheses of N-(6-chloro-1,1-dioxo-7-R1-1,4,2-benzodithiazyn-3-yl)-N'-(2- hydroxyethyl)hydrazines (IIa-d], N-(6-chloro-1,1-dioxo-7-methyl-1,4,2-benzodithiazyn-3-yl)-N'-(2- chloroethyl)hydrazine [IV], 4-(4-chloro-5-R1-2-mercaptobenzenesulfonyl)perhydro-1,2,4-triaz in-3-ones [IIIa-d] and 5-chloro-4-methyl-2-(3-oxoperhydro-1,2,4-triazin-4- ylsulfonyl)phenylthioacetic acid [V] have been described. Preliminary screening data have indicated that compounds [IIIa-d] exhibit either a moderate or a high anti-HIV activity and a moderate anticancer activity in some human tumor cell lines.     

Synthesis and cytotoxicity testing of novel 2-(3-substituted-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl)-3-phenyl-4(3H)-quinazolinones

A new series of thirteen 2-[3-(substituted amino)-6-chloro-1,1-dioxo-1,4,2-benzodithiazin-7-yl]-3-phenyl-4(3H)-quinazolinones 4-16 were prepared in order to evaluate their cytotoxic activity against 12 human cancer cell lines. The bioassay indicated that the quinazolinone derivatives 5, 8-12, 15, and 16 possess cancer-cell growth-inhibitory properties. Compounds 5 and 12 showed a high level of selectivity for certain cell lines. The most active compounds 9, 10, 15, and 16 showed moderate antiproliferative activity and were approximately 4-fold less potent than cisplatin.     

Convenient synthesis of fused heterocyclic 1,3,5-triazines from some N-acyl imidates and heterocyclic amines as anticancer and antioxidant agents

N-Acyl imidates (2), reacting with 5-amino pyrazole (3), 2-aminobenzimidazole (4), 3-amino-1,2,4-triazole (5), 3,5-diamino-1,2,4-triazole (6), and 5-aminotetrazole (7) give pyrazolo[1,5-a][1,3,5]triazine (8), benzo[4,5]imidazo[1,2-a][1,3,5]triazine (9), [1,2,4]triazolo [2,3-a][1,3,5]triazine (10), [1,2,4]tri azolo[2,3-a][1,3,5]triazin-5-ylamine (12), and tetrazolo-[1,5-a][1,3,5]triazine (14) derivatives, respectively. The synthesized compounds were characterized on the basis of IR, (1)H-NMR, (13)C-NMR, and mass spectral data and elemental analyses results. Five of the newly synthesized compounds, 8a, 9a, 10a, 12a, and 14a, were selected by National Cancer Institute and screened for their anticancer activity against three cancer cell lines MCF7, NCI-H460, and SF-268, where 12a exhibited moderate anti-proliferation potential. 12a was, thus, further tested for anticancer activity against 60 human cancer cell lines and showed moderate growth inhibition potency. 12a showed a high growth inhibitory activity against A498 renal cancer cell line. All of the newly synthesized compounds 8-10, 12 and 14 were tested for their antioxidant capacity where they exhibited very high activity, even higher than the widely used reference antioxidants butylated hydroxytoluene and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Compound 12a also showed the highest antioxidant activity.     

Synthesis and biological evaluation of new thiazolopyrimidines

In this study, a series of 4-amino-5-cyano-3-substituted-2,3-dihydrothiazol-2-thiones (1a-c), as well as their triazolo and triazinopyrimidine derivatives such as 8-substituted-3-benzyl-5-methylthiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2-thiones (4-6, 10) and 3-benzyl-5-methyl thiazolo[5,4-e]pyrimidino[3,4-b][1,2,4]triazin-2-thiones (7a-b) were prepared as potential antimicrobial and antitumor agents. Some of the tested compounds showed promising antimicrobial activity and non of them showed any appreciable antitumor activity.     

Antitumor pyrido[3,2-d][1]benzazepines: synthesis and in vitro activity of thiophene analogs

The bioisosteric replacement of benzene elements in the antitumor lead structures 2 and 3 led to the thienyl substituted 5H-pyrido[3,2-d][1]benzazepin-6(7H)-ones 8a and 8b, the analogous thiolactams 4a and 4b, and the 4H-pyrido[2,3-d]-thieno[3,2-b]azepines 11 and 12 which represent a novel heterocyclic scaffold. The in vitro evaluation of 4a in a cell line based screening revealed a noteworthy antitumor activity and a remarkable selectivity for renal tumor cell lines. The cell line selectivity pattern of 4a differs distinctly from the pattern displayed by standard antitumor agents.     

Synthesis and antiproliferative activity in vitro of new pyrido[1,4-b]diazepine derivatives and imidazo[4,5-b]pyridine

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.     

Synthesis and cytostatic properties of some 6H-Indolo[2, 3-b][1, 8]naphthyridine derivatives

The new and efficient synthesis of the title heterocyclic ring system is described starting from suitable 2-chloro-1, 8-naphthyridines. The synthesized 6H-indolo[2, 3-b][1, 8]naphthyridine derivatives were tested in vitro on 55 tumor cell lines for their anticancer properties. The presence of the acetylamino moiety at position 3 in the main ring system proved to be crucial for the cytostatic activity of this class of compounds.     

Potential antitumor agents. 37. Synthesis and antitumor activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline

This paper reports synthesis and antitumor activity of new guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline. The compounds were tested as potential antitumor agents at the National Cancer Institute. The effect of the guanylhydrazone of 2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde (41) was investigated, and it was found to be an inhibitor of Complex III of the mitochondrial respiratory chain and is able to induce apoptosis in the cell lines HT29 and HL60.     

In-vitro anti-HIV and antitumor activity of new 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and thiadiazine analogues

A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (7-15) and the thiadiazine analogues 16-18 have been synthesized under microwave irradiation (MWI). All synthesized compounds are evaluated for their antiviral activity against the replication of HIV-1 and HIV-2 activity in MT-4. However, compounds 12 and 18 showed EC(50) = 2.11 and 1.97 mug/mL. The results suggest that these compounds can be considered as a new lead in the development of antiviral agents. Compounds 4-18 were tested in vitro against a panel of tumor cell lines. All compounds are inactive against all the tumor sub-lines, except 10 which exhibited activity against CD4(+) human acute T-lymphoblastic leukaemia of CC(50) = 64 muM.     

Neuroleptic activity of 10-(4-methyl-1-piperazinyl)-thieno[3,2-b] [1,5]benzoxazepine and benzothiazepine derivatives.

Two series of compounds, structurally related to clozapine (CAS 5786-21-0), were tested for their neuroleptic activity. The derivatives 7-chloro-10-(4-methyl-1-piperazinyl)-thieno[3,2-b][1,5]benzoxazepine and 7-chloro-10-(4-methyl-1-piperazinyl)-thieno[3,2-b][1,5]benzothiazepine at high doses were not cataleptogenic and only very weakly antagonized the amphetamine-or apomorphine-induced stereotyped behaviour in the rat, whereas at low doses they antagonized the amphetamine-induced hypermotility in mice. Thus these compounds might be efficient neuroleptics with little propensity to cause extrapyramidal side effects. On the other hand, the unsubstituted compound 10-(4-methyl-1-piperazinyl)-thieno[3,2-b][1,5]benzothiazepine appeared to be an efficient neuroleptic agent with a greater propensity to cause these side effects.     

Synthesis of 2,8-disubstituted imidazo[1,5-a]pyrimidines with potent antitumor activity

Seventeen 1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine derivatives bearing electron-withdrawing substituents were designed and synthesized by novel ring closure as potential antitumor agents. They were screened for their activities against mouse leukemia L1210 and human oral epidermoid carcinoma KB cell lines, and relationships of structure and antitumor activity in vitro are discussed. It was found that 8-thiocarbamoyl-1,2,3,4-tetrahydroimidazo[1, 5-a]pyrimidin-2(1H)-thione (8c) exhibited activity comparable to that of 5-fluorouracil against both L1210 and KB cells. The existence of both 2-thioxo and 8-substituent with a thioxo group in the molecule is crucial for the cytotoxicity against L1210 and KB cells. A novel procedure for introduction of a double bond between C-3 and C-4 in 8c was developed. Introduction of the 3,4-double bond increased the activity against L1210, but against KB cells the activity decreased by 4-fold. Cytotoxicity of compounds 8c and 8-thiocarbamoyl-1,2-dihydroimidazo[1,5-a]pyrimidin-2(1H)-thione (11c) against human solid tumor and leukemia cell lines was further evaluated. The saturation of the 3,4-double bond led to a significant increase in cytotoxicity against tumor cell lines tested.     

Benzimidazole condensed ring systems: New synthesis and antineoplastic activity of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo [4,5]imidazo[1,2-a]pyrinnidine derivatives

As part of an ongoing effort to develop new antineoplastic agents, a series of substituted 3,4-dihydro- and 1,2,3,4-tetrahydro-benzo[4,5]imidazo[1,2-a]pyrimidine derivatives (5-19) were synthesized. 1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrimidine-2-one derivatives (5-7) were prepared via one-pot two-component thermal cyclization reaction of 2-aminobenzimidazole 1 and P-substituted methyl cinnamates (2-4). Vilsmir-Haack formylation of these derivatives (5-7) afforded the 2-chloro-3-carboxaldehyde targets (8-10) followed by nucleophilic displacement of the chloro atom in the 3-carboxaldehyde compounds (8-10) to yield the remaining final targets (11-19). The structures of the synthesized derivatives (5-19) were confirmed by means of IR, 1H NMR, MS and elemental analyses. The synthesized derivatives (5-19) were subjected to the National Cancer Institute (NCI) in vitro disease human cell screening panel assay. 2-Chloro-4-phenyl-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxyaldehyde (8, NCI 722731) and 4-(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)-3,4-dihydrobenzo[4,5]imidazo [1,2-a]pyrimidine-3-carboxaldehyde (18, NCI 722739) showed a variable degree of antineoplastic activity against some of the cell lines tested. 2-Chloro-4-(4-nitrophenyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxyaldehyde (10, NCI 722743) exhibited good in vitro antineoplastic activity with subpanel disease selectivity against all the cell lines tested with log10 G150 (M), the concentration that inhibits 50% of cell growth, values ranging from -5.08 to < -8.00.     

Synthesis and in vitro anticancer and anti-HIV evaluation of new 2-mercaptobenzenesulfonamides

The reactions of 6-chloro-3-methylthio-1,4,2-benzodithiazine 1,1-dioxide derivatives with appropriate diamines were investigated. Depending on the reaction conditions 2-mercaptobenzenesulfonamide derivatives or their oxidation product disulfides were obtained. All the compounds were tested at the US National Cancer Institute (Bethesda) for their in vitro anticancer and anti-HIV activities. The highest sensibility against leukemia cell lines was found for bis[2-(6-chloro-4-phenyl-3,4-dihydroquinazolin-2-yl)aminosulfonyl-5-chloro-4-(4-R2-phenylcarbamoyl)phenyl]disulfides (R2 = H or Cl). The results of anti-HIV tests displayed moderate activity of N-(pirydo[3,2-d]imidazol-2-yl)-2-mercaptobenzenesulfonamide.