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 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.

Cp2ZrCl2-catalyzed synthesis of 2-aminovinyl benzimidazoles under microwave conditions

“…1,2-Phenylenediamines (7-12) were prepared according to the reported procedures [3]. All NMR spectra were obtained with a 400 MHz instrument with chemical shifts reported in parts per million (ppm, d) and referenced to CDCl 3 or DMSO-d 6 .…”

“…In our previous research on the synthesis of AKT inhibitor IV (ChemBridge 5233705), the unique 2-aminovinyl benzimidazole core structure posed a huge challenge to the existing synthetic methods for benzimidazoles [3]. The conventional condensation of 1,2-phenylenediamines with an N-arylated 3-aminoacrolein (1) in refluxing ethanol followed by in situ oxidation only afforded the products in low yields (<20%) [1,4].…”

“…Our attempt to promote the reaction by adding oxidants (e.g., potassium peroxymonosulfate [5], I 2 [6], MnO 2 [7], and 2,3-dichloro-5,6-dicyanop-benzoquinone (DDQ) [8]), acidic catalysts (e.g., BF 3 ÁEt 2 O [9] and polyphosphoric acid (PPA) [10]), or reducing agents (e.g., SnCl 2 [11]) according to precedent reports failed to generate the desired product. Interestingly, in our search for potential metal catalyst [12], we found that ZrOCl 2 Á8H 2 O and ZrCl 4 exhibited a dramatic catalytic effect on the reactions of 1,2-phenylenediamines with 1 and improved the yields to 50%-70% [3]. However, the understanding of this metal-catalyzed condensation/cyclization reaction is still very limited and the extension of this approach to N,N-dialkylated 3-aminoacroleins has never been explored.…”

Synthesis, Biological Activity and Recent Advancement of Benzothiazoles: A Classical Review

“…Synthesis of benzothiazole from o-aminothiophenol and substituted benzaldehyde with some modifications is common, as found in many literature reports [47,48] (Fig 38). Beside this, 2-substituted benzothiazoles have also been synthesized from substituted aldehyde and oaminothiophenol inpresence of various catalysts and reaction conditions such as montmorillonite, SiO2/graphite; under MW and p-TsOH ,diethyl bromophosphonate/t-butyl hypochlorite; acetonitrile, H2O2/HCl in ethanol, AcOH/air; MW or thermal heating and…”

Design and synthesis of benzimidazoles containing substituted oxadiazole, thiadiazole and triazolo-thiadiazines as a source of new anticancer agents

“…Benzimidazole is known to be a versatile scaffold that possess potential anticancer, antitumor and antiproliferative activities (Refaat, 2010;Gumus et al, 2009;Sun et al, 2011;Abonia et al, 2011;Ramla et al, 2006;Demirayak et al, 2002;Romero-Castro et al, 2011) along with other useful biological actions. Similarly, oxadiazole, thiadiazole, triazolo-thiadiazines and triazolo-thiadiazoles are a course group of heterocyclic compounds, which have engrossed significant attention of medicinal chemists owing to their wide range of useful pharmacological actions particularly cytotoxic activities against DNA topoisomerase I (Formagio et al, 2008;Kumar et al, 2010;Sarhan et al, 2010).…”