Chiral 2-phenyl-3-hydroxypropyl esters as PKC-alpha modulators: HPLC enantioseparation, NMR absolute configuration assignment, and molecular docking studies
Articolo
Data di Pubblicazione:
2021
Citazione:
Chiral 2-phenyl-3-hydroxypropyl esters as PKC-alpha modulators: HPLC enantioseparation, NMR absolute configuration assignment, and molecular docking studies / P. Linciano, R. Nasti, R. Listro, M. Amadio, A. Pascale, D. Potenza, F. Vasile, M. Minneci, J. Ann, J. Lee, X. Zhou, G.A. Mitchell, P.M. Blumberg, D. Rossi, S. Collina. - In: CHIRALITY. - ISSN 1520-636X. - 34:3(2021 Dec), pp. 498-513. [10.1002/chir.23406]
Abstract:
Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous
cellular functions, making them extensively studied and highly attractive
drug targets. In our previous work, we identified in racemate 1–2, based on the
2-benzyl-3-hydroxypropyl ester scaffold, two new potent and promising PKCα
and PKCδ ligands, targeting the C1 domain of these two kinases. Herein, we
report the resolution of the racemates by enantioselective semi-preparative
HPLC. The attribution of the absolute configuration (AC) of homochirals
1 was performed by NMR, via methoxy-α-trifluoromethyl-α-phenylacetic acid
derivatization (MTPA or Mosher's acid). Moreover, the match between the
experimental and predicted electronic circular dichroism (ECD) spectra confirmed
the assigned AC. These results proved that Mosher's esters can be properly
exploited for the determination of the AC also for chiral primary alcohols.
Lastly, homochiral 1 and 2 were assessed for binding affinity and functional
activity against PKCα. No significative differences in the Ki of the enantiopure
compounds was observed, thus suggesting that chirality does not seem to play
a significant role in targeting PKC C1 domain. These results are in accordance
with the molecular docking studies performed using a new homology model
for the human PKCαC1B domain.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
P. Linciano, R. Nasti, R. Listro, M. Amadio, A. Pascale, D. Potenza, F. Vasile, M. Minneci, J. Ann, J. Lee, X. Zhou, G.A. Mitchell, P.M. Blumberg, D. Rossi, S. Collina
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