- Development of novel amides as noncovalent inhibitors of immunoproteasomes
-
The development of immunoproteasome-selective inhibitors is a promising strategy for treating hematologic malignancies, autoimmune and inflammatory diseases. In this context, we report the design, synthesis, and biological evaluation of a new series of amide derivatives as immunoproteasome inhibitors. Notably, the designed compounds act as noncovalent inhibitors, which might be a promising therapeutic option because of the lack of drawbacks and side effects associated with irreversible inhibition. Among the synthesized compounds, we identified a panel of active inhibitors with Ki values in the low micromolar or sub-micromolar ranges toward the b5i and/or b1i subunits of immunoproteasomes. One of the active compounds was shown to be the most potent and selective inhibi-tor with a Ki value of 21 nm against the single b1i subunit. Docking studies allowed us to determine the mode of binding of the molecules in the catalytic site of immunoproteasome subunits.
- Ettari, Roberta,Cerchia, Carmen,Maiorana, Santina,Guccione, Manuela,Novellino, Ettore,Bitto, Alessandra,Grasso, Silvana,Lavecchia, Antonio,Zappalà, Maria
-
p. 842 - 852
(2019/04/01)
-
- Development of novel selective peptidomimetics containing a boronic acid moiety, targeting the 20s proteasome as anticancer agents
-
This paper describes the design, synthesis, and biological evaluation of peptidomimetic boronates as inhibitors of the 20S proteasome, a validated target in the treatment of multiple myeloma. The synthesized compounds showed a good inhibitory profile against the ChT-L activity of 20S proteasome. Compounds bearing a β-alanine residue at the P2 position were the most active, that is, 3-ethylphenylamino and 4-methoxyphenylamino (R)-1-{3-[4-(substituted)-2- oxopyridin-1(2H)-yl]propanamido}-3-methylbutylboronic acids (3 c and 3 d, respectively), and these derivatives showed inhibition constants (Ki) of 17 and 20 nM, respectively. In addition, they co-inhibited post glutamyl peptide hydrolase activity (3 c, Ki=2.57 μM; 3 d, K i=3.81 μM). No inhibition was recorded against the bovine pancreatic α-chymotrypsin, which thus confirms the selectivity towards the target enzyme. Docking studies of 3 c and related inhibitors into the yeast proteasome revealed the structural basis for specificity. The evaluation of growth inhibitory effects against 60 human tumor cell lines was performed at the US National Cancer Institute. Among the selected compounds, 3 c showed 50 % growth inhibition (GI50) values at the sub-micromolar level on all cell lines.
- Scarbaci, Kety,Troiano, Valeria,Ettari, Roberta,Pinto, Andrea,Micale, Nicola,Di Giovanni, Carmen,Cerchia, Carmen,Schirmeister, Tanja,Novellino, Ettore,Lavecchia, Antonio,Zappalà, Maria,Grasso, Silvana
-
p. 1801 - 1816
(2014/08/18)
-
- Reactions Using Micellar Systems. IV. Regioselectivity in the Photodimerizations of 2-Pyridones in Micelles and Reversed Micelles
-
Photodimerizations of N-alkyl-2-pyridones (1a-e), N-ω-carboxyalkyl-2-pyridones (1f-h),and N-2'-carboxyethyl-4-alkyl-2-pyridones (1i and 1j) in micellar and reversed micellar systems gave the following results; 1) in the reactions of 1a-e, the cis/trans ratios of dimers increased with decreasing concentration of the probes, with the octyl compound (1d) showing the highest selectivity; 2) in the case of 1f-h, the ratios increased up to 1.0 with decreasing alkyl chain length; 3) below 7.2 mM concentration, 1i gave exclusively the cis dimer, while only the trans dimer was formed when the reaction was carried out in water.The results indicate that the regio-control of the reactions was a result of the alignment effect of micelles on the substrate, and moreover, in both micellar systems, not only the distribution of amphiphilic probes between micellar and bulk (water or cyclohexane) phases but also the orientation and incorporation site of the pyridone moiety play important roles in the regioselectively for the cis dimer.Keywords - N-alkyl-2-pyridone; N-ω-carboxyalkyl-2-pyridone; N-2'-carboxyethyl-4-alkyl-2-pyridone; micelle; reversed micelle; dimer; photodimerization; regioselectivity; alignment effect; amphiphile
- Kato,Takeshi,Nakamura, Yushin,Morita, Yutaka
-
p. 2552 - 2563
(2007/10/02)
-