Abstract
The synthesis, cytotoxicity and inhibition of CDK8 by thirteen analogs of cortistatin A are reported. These efforts revealed that the analogs with either a 6- or 7-isoquinoline or 5-indole side chain in the 17-position are the most promising anti-proliferative agents. These compounds showed potent cytotoxic effects in CEM, HeLa and HMEC-1 cells. All three compounds exhibited IC50 values < 10µM. The most interesting 10l analog exhibited an IC50 value of 0.59 µM towards the human dermal microvascular endothelial cell line (HMEC-1), significantly lower than the reference standard 2-methoxyestradiol. At a concentration at 50 nM the most potent 10h compound reduced the activity of CDK8 to 35%.
Highlights
Steroids are a class of biologically active molecules, important for an array of different physiological effects
In 2006, cortistatin A (4) was the first compound of this group of steroidal-like alkaloids to be isolated from the marine sponge Corticium simplex [9]
Human cervical carcinoma (HeLa) cells were seeded in 96-well plates at 15,000 cells/well in the presence of 5-fold dilutions of the compounds
Summary
Steroids are a class of biologically active molecules, important for an array of different physiological effects. Their affinities for various types of nuclear receptors, as well as their safe pharmacological profile have facilitated their widespread application in drug discovery and development [1]. An extensive focus on chemical modification of the steroidal structure has been seen Such modifications of the steroidal nucleus have yielded several important anticancer molecules and lead compounds. A class of compound, the cortistatins, exemplified by cortistatins A (4), see Figure 1, are examples of natural occurring steroid-like structures that have attracted great interest within anti-cancer research [7,8]. Of the interesting analogs reported so far themost amino steroid 5 two hydroxyl-groups the one. 17-position of nitrogen containing heterocycle systems, inspired by the above mentioned compounds, at the 17didehydroepiandrosterone (DHEA) (6).(DHEA) (6)
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