Synthesis and cyclooxygenase inhibitory properties of novel (+) 2-(6-methoxy-2-naphthyl)propanoic acid (naproxene) derivatives.

Halomethylation of naproxene (1) occurs regioselectively in position 5 and subsequently--in situ or on treatment with silver nitrate--leads to naproxene-"dimers" with two naproxene units, 5,5'-connected through a ethenylene (3) and a methylene (4) bridge, respectively. Two of the new naproxene derivatives were screened for their cyclooxygenase inhibitory properties relative to naproxene. Both 5-chloromethyl naproxene (2) and 2-(5-((carboxyethyl)-2-methyloxynaphthyl)-6-methoxy-2-naphthyl)propanoic acid (4) were inactive in the concentration range of 0.1-10 mumole against both COX-1 and COX-2, indicating that bulky substituents in position 5 in naproxene are unfavourable for both COX-1 and COX-2 inhibition.

2,4-Disubstituted thiazoles, Part III. Synthesis and antitumor activity of ethyl 2-substituted-aminothiazole-4-carboxylate analogs.

The synthesis of several new ethyl 2-substituted-aminothiazole-4-carboxylate analogs is described. The prepared compounds were tested for their in vitro antitumor activity against 60 human tumor cell lines by the National Cancer Institute (NCI) and showed potential anticancer activity. Ethyl 2-[3-(diethylamino)-propanamido]-thiazole-4-carboxylate (14) exhibited remarkable activity against RPMI-8226 leukemia cell line with GI50 value of 0.08 microM, and a broad spectrum activity against all the tumor cell lines used with GI50 (MG-MID) value of 38.3 microM. The detailed synthesis and antitumor screening data are reported.

Synthesis, antitumor and antitubercular evaluation of certain new xanthenone and acridinone analogs.

6-Chloro-4-substituted methyl-4-xanthenones and 2,4-dichloro-1-substituted amino-9-(10 H)-acridinones were synthesized as tricyclic planar analogs and tested for their in vitro antitumor and antitubercular activity. The obtained derivatives were also evaluated for two biochemical, mechanism-based screens to explore their ability to inhibit the cell cycle control proteins cdc2 kinase and cdc25 phosphatase as molecular targets which may account for their antitumor activity. 4-(N1-Amidino)-sulphanilamidomethyl-6-chloro-9-xanthenone (10) proved to be the most active member of these derivatives exhibiting a broad spectrum antitumor potency against a wide range of human tumor cell lines with full panel median growth inhibition (GI50), total growth inhibition (TGI) and median lethal concentration (LC50) mean graph midpoint (MG-MID) values of 3.2, 12.7 and 21.8 mumol l-1, respectively. Meanwhile, compound 4-(N1-Acetyl)sulphanilamidomethyl-6-chloro-9-xanthenone (9) showed GI50, and TGI (MG-MID) values of 25.6 and 87.6 mumol l-1, respectively with a moderate selectivity for leukemia cell lines at the GI50 level. Compound 9 exhibited a weak in vivo growth inhibitory effect against many human tumor cells cultivated in hollow fibers and implanted into the intraperitoneal or subcutaneous physiologic compartments in mice. In addition, compounds 15, 20, 23-25 showed potential activity against mycobacterium strain H37Rv at 12.5 micrograms ml-1 concentration. The detailed synthess, spectroscopic and biological data are reported.

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.

3-Cyano-4,6-disubstituted-2(1H)-imino or oxopyridines: new antineoplastic agents with high selectivity towards leukemia cell lines.

Two series of 3-cyano-2(1H)-oxopyridine and 3-cyano-2(1H)-iminopyridine derivatives carrying various aryl substituents at position 4 and (4-((7-chloro or trifluoromethylquinol-4-yl)amino)phenyl) substituent at position 6 were synthesized and evaluated for their antitumor activity. Compounds 3f and 6d showed high selectivity towards leukemia cell lines with full panel median growth inhibition GI50 average sensitivity towards all cell lines (MG-MID) at 7.9 and 19.7 microM and leukemia subpanel GI50 average sensitivity towards leukemia cell lines (MG-MID) at 1.74 and 2.9 microM, respectively, also they exhibited full panel total growth inhibition TGI (MG-MID) at 34.8 and 59.0 microM and leukemia subpanel TGI (MG-MID) at 5.3 and 13.5 microM, respectively.

5-substituted 2-bromoindolo[3,2-b]quinoxalines. A class of potential antitumor agents with cdc25 phosphatase inhibitory properties.

Several derivatives of 5-substituted 2-bromoindolo[3,2-b]quinoxaline were synthesized and characterized. The synthesized compounds were evaluated for their antitumor activity using the National Cancer Institute-in vitro-disease oriented antitumor screen and two biochemical mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Compound 19 showed broad spectrum antitumor activity with full panel (MG-MID) GI50. TGI, and LC50 of 14.2, 31.6- and 66.2 microM, respectively. In addition it inhibited cdc2 kinase and cdc25 phosphatase with IC50's of 70 and 25 microM, respectively. Thus, compound 19 represents a model for compounds with potential antitumor activity and cdc25 phosphatase inhibitory properties.

Synthesis and antitumor activity of 9-anilino, phenylhydrazino, and sulphonamido analogs of 2- or 4-methoxy-6-nitroacridines.

Synthesis of several new 9-anilino, phenylhydrazino, and sulphonamido analogs of 2- or 4-methoxy-6-nitroacridine derivatives is described. The prepared compounds were tested for their in vitro antitumor activity against 60 human tumor cell lines by the National Cancer Institute (NCI) and showed a potential anticancer activity. Compounds 9-(phenylhydrazino)-2-methoxy-6-nitroacridine (8a) and 9-(4-chlorophenylhydrazino)-4-methoxy-6-nitroacridine (9b) exhibited a broad spectrum antitumor activity with full panel (MG-MID) median growth inhibition (GI50), of 16.1 and 10.9 microM and total growth inhibition (TGI) of 66.7 and 37.9 microM, respectively. Meanwhile, compounds 15a and 15b showed moderate selectivity toward leukemia cell lines. As a trial to explore the mode of action of their antitumor activity, the 6-nitroacridine analogs were evaluated for their inhibitory effect on major cell cycle control proteins cdc2 kinase and cdc25 phosphatase as possible molecular targets that may account for antimitotic potency. None of the tested compounds proved to exert their activity via this antimitotic mode of action.

Simultaneous determination of verapamil and celiprolol in human plasma.

A simple and reproducible method for the simultaneous determination of the beta 1-selective adrenergic blocker, celiprolol, and the calcium antagonist, verapamil, in human plasma is described. It involves a two-step liquid-liquid extraction and separation using a C18 column with ultraviolet detection at 237 nm. Deacetyldiltiazem is used as the internal standard. Within-day and between-day coefficients of variation are less than 10%. The lower limits of detection are 4, 2, and 4 ng/mL for celiprolol, deacetyldiltiazem, and verapamil, respectively. The assay has clinical applicability.

High-performance liquid chromatographic determination of diltiazem and two of its metabolites in plasma using a short alkyl chain silanol deactivated column.

A simple and reproducible method for the determination of diltiazem and its two major metabolites, demethyl- and deacetyldiltiazem, is presented using a new column containing a short alkyl chain silanol deactivated support. This method involves the extraction of alkalinized plasma with a hexane-isopropanol mixture (95:5, v/v) followed by back-extraction into 5 mM sulfuric acid. Reversed-phase liquid chromatography is used with ultraviolet detection at 237 nm over a concentration range of 20-400 ng/ml for the compounds. Imipramine is used as the internal standard. Within-day and between-day coefficients of variation are less than 10%. The lower limits of detection are 4, 2 and 4 ng/ml for diltiazem, deacetyl- and demethyldiltiazem, respectively. Samples can be stored for up to thirty days with no significant degradation. The assay has clinical applicability.