Synthesis and Biological Evaluation of Analogs of Didehydroepiandrosterone as Potential New Anticancer Agents

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 c...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2020-07, Vol.25 (13), p.3052
Main Authors: J Solum, Eirik, Liekens, Sandra, Hansen, Trond Vidar
Format: Article
Language:English
Subjects:
Analogs
Androsterone - analogs & derivatives
Androsterone - pharmacology
anti-cancer
anti-leukemia
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Cancer
CDK8 inhibition
Cell growth
Cell Proliferation
Chromatography
cortistatin A
Cyclin-Dependent Kinase 8 - antagonists & inhibitors
Cytotoxicity
Drug Design
Drug Screening Assays, Antitumor
Endothelial cells
HeLa Cells
Humans
Indoles
Kinases
Leukemia, T-Cell - drug therapy
Leukemia, T-Cell - pathology
Microvasculature
steroids
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary: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 IC values < 10µM. The most interesting analog exhibited an IC 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 compound reduced the activity of CDK8 to 35%.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25133052