Loading...
Synthesis and Biological Evaluation of Analogues of AKT (Protein Kinase B) Inhibitor-IV
Sun, Qi Wu, Runzhi Cai, Sutang Lin, Yuan Sellers, Llewlyn Sakamoto, Kaori He, Biao Peterson, Blake R.
Sun, Qi
Wu, Runzhi
Cai, Sutang
Lin, Yuan
Sellers, Llewlyn
Sakamoto, Kaori
He, Biao
Peterson, Blake R.
Citations
Altmetric:
Abstract
Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl4-catalyzed cyclization of 1,2-arylenediamines with α,β-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells, and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold.
Description
Date
2011-03-10
Journal Title
Journal ISSN
Volume Title
Publisher
American Chemical Society
Collections
Research Projects
Organizational Units
Journal Issue
Keywords
Citation
Sun, Q., Wu, R., Cai, S., Lin, Y., Sellers, L., Sakamoto, K., … Peterson, B. R. (2011). Synthesis and Biological Evaluation of Analogues of AKT (Protein Kinase B) Inhibitor-IV. Journal of Medicinal Chemistry, 54(5), 1126–1139. http://doi.org/10.1021/jm100912b