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Lipophilic phenoxazines as potent and specific inhibitors of Akt | 4004
Drug Designing: Open Access

Drug Designing: Open Access
Open Access

ISSN: 2169-0138

+44 1223 790975

Lipophilic phenoxazines as potent and specific inhibitors of Akt signaling in rhabdomyosarcoma cells


International Conference and Expo on Drug Discovery & Designing

August 11-13, 2015 Frankfurt, Germany

Kuntebommanahalli N Thimmaiah1, B T Sridhar2 and Kanchugarakoppalu S Rangappa3

Posters-Accepted Abstracts: Drug Des

Abstract :

Phenoxazines shut down the activation of Akt/mTOR/p70S6/S6 kinase pathway and induce apoptosis to a considerable extent
at about 100 nM level in rhabdomyosarcoma cells. Compounds having propyl bridge were less potent than compounds with 4
carbon chain length. This prompted us to continue the work by increasing the alkyl chain length to (-CH2)5 or (-CH2)6 at N10-
position, hoping that the potency will be increased to a significant extent. Towards this goal, twenty one phenoxazines have been
synthesized, characterized and examined for their ability to block the phosphorylation of Akt at serine 473 in cells. Serum starved
Rh1 cells were exposed to 100 nM, 500 nM or 2000 nM phenoxazine derivatives for 4 h before stimulating with IGF-I (10 ng/m)
for 10 min. Akt or Erk-1/2 phosphorylation was detected using the phospho-specific anti-Akt antibody or anti-Erk-1/2 antibody.
The results demonstrate that out of 21 phenoxaznes tested, 10-[6’-[N-Diethyl] hexyl]-2-chlorophenoxazine (10D) and 10-[6’-[N-(β-
Hydroxyethyl)-piperazino] hexyl]-2-chlorophenoxazine (15D) at 100 nM inhibited the phosphorylation of Akt at Ser 473 without
affecting the phosphorylation of Erk-1/2. As we anticipated, the potency of the hexyl derivatives to inhibit the phosphorylation of Akt
has been increased to a significant extent. 10D or 15D did not inhibit the activity of PDK1 or SGK1 but potently inhibited the kinase
activity of recombinant Akt and Aktâ�?PH. Further, 10D or 15D blocked IGF-I stimulated nuclear translocation of Akt in Rh1 cells
and suppressed growth of Rh1, Rh18, and Rh30 cells (IC50 ≈ 100 nM) under serum-containing culture conditions at concentrations
of agent consistent with Akt inhibition. Modeling studies suggest phenoxazines may bind in the ATP-binding site.

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