Derivatives 24-34 bearing both a 4-ketone and a 27-silyl ether group were prepared from compound 23 by silylation at C-27 with different silyl chloride reagents as shown in Scheme 4 (Supporting Information, S41-S46). Scheme 4. Synthesis of 4-Oxo-withaferin A-silyl Ether Analogues 24-34 a a Reagents and conditions: (i) R 1 R 2 R 3 SiCl, imidazol, DMAP, CH 2 Cl 2 , rt.
We describe the synthesis and evaluation of Strathclyde Minor Groove Binders (S-MGBs) as selective anti-cancer agents which act through a non-alkylating mechanism.
The aim of the present study was to investigate the cytotoxicity induced by an omega-3 derivative, didocosahexaenoin (Dido) on human prostate carcinoma cells and to compare the cytotoxicity to that of docosahexaenoic acid (DHA). Different carcinoma- and non-carcinoma cells were exposed to various concentrations of omega-3 compounds at varying exposure times and the cytotoxicity was measured by MTT assay. The mechanism of Dido-induced apoptosis was investigated in prostate carcinoma cells. Dido induced stronger cytotoxicity than DHA in human prostate carcinoma cells in a dose- and time-dependent manner. Dido was also more selective and potent in inducing cytotoxicity in prostate carcinoma cells than other carcinoma cell lines tested. Pre-treatment with Dido increased the level of reactive oxygen species (ROS) in prostate carcinoma cells. Pre-treatment with various antioxidants reduced the cytotoxicity induced by Dido. Pre-treatment with Dido ≥30 μM also induced apoptosis which was suggested to involve an externalisation of phosphatidyl serine, a significant increase in the mitochondrial membrane potential (p < 0.01) and the level of activated caspase 3/7 (p < 0.05) in prostate carcinoma cells. This study is the first to show that Dido induced cytotoxicity with high selectivity and higher potency than DHA in human prostate carcinoma cells. The mechanism of action is likely to involve an increase in the level of ROS, loss in the mitochondrial membrane potential as well as externalisation of phosphatidyl serine and increase in the caspase 3/7 activity. Dido may have potential to be used for the adjuvant therapy or combination therapy with conventional chemotherapeutic drugs.
Symmetrical α,αʹ-bis(arylidene)ketones were prepared by acid-catalyzed aldol condensations between aliphatic ketones (e.g., cyclopentanone, 4-alkylcyclohexanones, tetrahydropyran-4-one, and tetrahydrothiopyran-4-one) and two equivalents of an aromatic hydroxyaldehyde (e.g., 4-hydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, vanillin, isovanillin, and 3-fluoro-4hydroxybenzaldehyde). Most of the compounds were cytotoxic towards the cisplatin-resistant human ovarian cancer cell line A2780-CP70 as well as the non-resistant line A2780.
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