Synthesis and biological evaluation of naphthoquinone analogs as a novel class of proteasome inhibitors

Abstract

Screening of the NCI Diversity Set-1 identified PI-083 (NSC-45382) a proteasome inhibitor selective for cancer over normal cells. Focused libraries of novel compounds based on PI-083 chloronaphthoquinone and sulfonamide moieties were synthesized to gain a better understanding of the structure activity relationship responsible for chymotrypsin-like proteasome inhibitory activity. This led to the demonstration that the chloronaphthoquinone and the sulfonamide moieties are critical for inhibitory activity. The pyridyl group in PI-083 can be replaced with other heterocyclic groups without significant loss of activity. Molecular modeling studies were also performed to explore the detailed interactions of PI-083 and its derivatives with the β5 and β6 subunits of the 20S proteasome. The refined model showed an H-bond interaction between the Asp-114 and the sulfonamide moiety of the PI-083 in the β6 subunit.

Substituted quinolines as noncovalent proteasome inhibitors

“…Our SAR study identified several domains that were found to be critical for the activity of this new lead template. Quinoline 25 was found to be the most active analogue in this series and inhibited the chymotryptic activity of the 20S proteasome with an IC 50 of 5.4 μM This potency is similar to the noncovalent proteasome inhibitors, PI-083 (IC 50 ∼ 1.0 μM), 32 5-AHQ (IC 50 ∼ 0.6–5 μM), 37 and a significant improvement over the millimolar activity of chloroquine. 36 Thus, these studies describe a novel class of quinoline-based proteasome inhibitors.…”

“…Lawrence and co-workers discovered and optimized a novel class of hydrophthoquinone derivates as nonpeptidic, noncovalent proteasome inhibitors. 31,32 These agents, exemplified by PI-083 (Fig. 1), demonstrated selectivity for cancer cells over non-transformed cells, which potentially broadens the range of anticancer activity.…”

Studies of C-terminal naphthoquinone dipeptides as 20S proteasome inhibitors

“…Recently, through library screenings, compounds bearing 2-cloronaphtoquinonic unit named PI-083 (NSC-45382), able to express a good inhibition against chymotryptic activity of the proteasome have been identified (compound a in Figure 1). These compounds showed, in vitro and in vivo, the capacity to selectively inhibit tumor cell proliferation 29 . Other non-peptide analogues with increased activity compared to the initial prototype, were also developed (general structure b in Figure 1) 30,31 .…”

“…The 2-chloronaphtoquinone (ClNafQ), which is the pharmacophoric unit able to function as a potential substrate for the threonine catalytic electrophile, is located at the C-terminal of the dipeptidic sequences. Cited studies [29][30][31] suggest the proximity of the hydroxyl group of catalytic threonine to the 2-chloronaphtoquinone unit potentially able to attack carbon 2 of the pharmacophoric unit. Our docking studies suggest the same interaction for our compounds making reasonable the nucleophilic substitution of chlorine in position 2.…”

Psoralenquinones as a Novel Class of Proteasome Inhibitors: Design, Synthesis and Biological Evaluation

“…It is noteworthy that the proposed binding mode described here (Figure 2) is quite similar to the recently reported binding mode for other benzoquinone derivatives. [32] To further demonstrate our observations, we synthesized furochromone 11, which cannot form any hydrogen bonds with Ser129, since the carbonyl group of the pyrone ring is in the gposition rather than the a-position. The biological evaluation on compound 11 revealed its inability to inhibit any proteasome catalytic activity, thus strengthening the initial hypothesis (Table 3).…”