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Abstract: A series of 5-(pyridin-2-yl)thiazoles (14a–l and 15a–l) has been synthesized and evaluated for their ALK5 inhibitory activity in cell-based luciferase reporter assays. Among them, 3-[[5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)thiazol-2-ylamino]methyl]benzamide (15i) and 3-[[5-(6-ethylpyridin-2-yl)-4-(quinoxalin-6-yl)thiazol-2-ylamino]methyl]benzamide (15k) showed more than 95% inhibition at 0.1μM in luciferase reporter assays using HaCaT cells transiently transfected with p3TP-luc reporter construct and ARE-luciferase reporter construct. [Copyright &y& Elsevier]

A potent inhibitor of β-galactosidase (EC 3.2.1.23), 2-phenylethyl 1-thio-β-d-galactopyranoside (PETG), was radioiodinated for noninvasive imaging of LacZ gene expression. In order to introduce radioiodine to the phenyl ring of PETG, 2-(4-bromophenyl)ethanethiol was prepared and attached to the C-1 position of β-d-galactose pentaacetate under conditions that resulted in the exclusive formation of the β anomer. The bromo group of PETG was converted to the tributylstannyl group where radioiododemetallation was carried out. Radioiodine-labeled PETG tetraacetate was purified by HPLC, which can be used as a prodrug for biological evaluation or hydrolyzed to 2-(4-[123I/125I]iodophenyl)ethyl 1-thio-β-d-galactopyranoside ([123I/125I]7) under basic conditions. The resulting radioiodine-labeled PETG was obtained in overall 62% radiochemical yield (decay-corrected) and with specific activity of 46–74 GBq/μmol. [Copyright &y& Elsevier]

A series of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles, 7a–c, 11a–h, and 16a–h has been synthesised and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Incorporation of a quinoxalin-6-yl moiety and a methylene linker at the 4- and 2-position of the imidazole ring, respectively, and a m-CONH2 substituent in the phenyl ring generated a highly potent and selective ALK5 inhibitor 11e. Docking model of ALK5 in complex with 11e showed that it fitted well in the ATP-binding pocket with favourable interactions. [ABSTRACT FROM AUTHOR]

Wrinkle formation and abnormal pigmentation are major clinical alterations associated with skin aging. As the aim of our study was to investigate the effects of palmitoyl-KVK-L-ascorbic acid on skin aging, the anti-wrinkle and depigmentation effects of palmitoyl-KVK-L-ascorbic acid were evaluated by measuring collagen expression in dermal fibroblast cells and inhibition of melanogenesis in B16F1 cells, respectively. The anti-aging effect of palmitoyl-KVK-L-ascorbic acid cream was also evaluated against a placebo cream in a clinical trial. Our results confirmed that the expression of type Ι collagen in dermal fibroblast cells treated with palmitoyl-KVK-L-ascorbic acid (0.1-4 μg/mL) increased in a dose-dependent manner. In B16F1 cells, treatment with 20 μg/mL palmitoyl-KVK-L-ascorbic acid reduced the melanin content by approximately 20% compared to alpha-melanocyte stimulating hormone treatment. In the clinical trial, application of palmitoyl-KVK-L-ascorbic acid cream led to an improvement in skin roughness and lightness in 12 and 8 weeks, respectively. Our data show that palmitoyl-KVK-L-ascorbic acid is an effective anti-aging agent that reduces wrinkles and abnormal skin pigmentation. [ABSTRACT FROM AUTHOR]