title: Synthesis and biological evaluation of analogues of AKT (protein kinase B) inhibitor-IV.
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 ZrCl(4)-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.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66047, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.forename: Runzhi
authors.initials: R
authors.lastname: Wu
authors.forename: Sutang
authors.initials: S
authors.lastname: Cai
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.forename: Llewlyn
authors.initials: L
authors.lastname: Sellers
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Biao
authors.initials: B
authors.lastname: He
authors.forename: Blake R
authors.initials: BR
authors.lastname: Peterson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D019907:Mycobacterium fortuitum / Q000187:drug effects / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D020545:Respiratory Mucosa / Q000166:cytology; D019213:Rubulavirus / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014132:Trachea / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001562:Benzimidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; D051057:Proto-Oncogene Proteins c-akt