Cytotoxic 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienes mounted on alicyclic scaffolds.

The 5-aryl-1-(4-nitrophenyl)-3-oxo-1,4-pentadienyl pharmacophore was incorporated into four series of compounds 1-4. Compounds 1a-g comprised a cluster of 3-arylidene-1-(4-nitrophenylmethylene)-2-oxo-3,4-dihydro-1H-naphthalenes while the analogues 2a-g consisted of a group of 6-arylidene-2-(4-nitrophenylmethylene)cyclohexanones. Three other compounds prepared in this study were 1-(4-nitrophenylmethylene)-3-(3,4,5-trimethoxyphenylmethylene)-2-oxo-2,3-dihydro-1H-indene 3a as well as two 5-arylidene-2-(4-nitrophenylmethylene)cyclopentanones 4a,b. The compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. In general, the compounds in series 1 displayed marked cytotoxicity having IC50 values in the 1-5 microM range while the related cyclohexyl analogues in series 2 were slightly less potent (IC50 figures were mainly 5-10 microM). The relative locations of two aryl rings present in all four series were considered to contribute significantly to bioactivity and may have accounted for the virtual absence of cytotoxic properties in series 3 and 4. Most of the compounds were administered intraperitoneally to mice using doses up to and including 300 mg/kg. No mortalities were noted. The inhibiting effect of most of the compounds towards Helicobacter pylori is noteworthy. The modes of action of representative compounds include the induction of apoptosis while some compounds weakly inhibited tubulin polymerisation and human N-myristoyltransferase.

Copper(II) and manganese(III) complexes of N'-[(2-hydroxy phenyl) carbonothioyl] pyridine-2-carbohydrazide: novel therapeutic agents for cancer.

c-Src is a non-receptor tyrosine kinase which plays a significant role in the growth mediated signaling pathway impacting cellular proliferation, differentiation, mobility, survival and transformation. Myristoylation of pp60(c-src) leads to its membrane association and activation, a process catalyzed by N-myristoyltransferase (NMT). We have shown earlier increased NMT activity in the early stages of colon cancer. A novel sulfur nitrogen donor ligand and its Cu(II) and Mn(III) complexes have been prepared and characterized using various physicochemical analyses. These Cu(II) and Mn(III) complexes showed cytotoxicity against the colon cancer cell line HT29. The IC(50) for Cu(II) and Mn(III) complexes were 12.2 and 16.1 microM, respectively. HT29 cells treated with Cu(II) and Mn(III) complexes induced apoptosis and inhibited endogenous NMT activity. Furthermore, they induced higher levels of hsc70 and inhibited the expression of c-Src. Inhibition of endogenous NMT activity by metal complexes was demonstrated for the first time. This study also suggested that NMT activity is crucial for cell survival and demonstrated that cessation in activity results in apoptosis. These metal complexes may prove to be novel therapeutic agents for cancer targeting NMT.