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

Figures & data

Figure 1. PI-083 (a), schematic structure of the naftoquinone non-peptidic compounds (b) and general structure of the naftoquinone dipeptide derivatives (c).

Scheme 1. Synthesis of naphthoquinone dipeptide molecules 1–8.

Table 1. Inhibition of the proteasome subunits by naphthoquinone dipeptides 1–8 and reference compound MG132.

Compound	ChT-L	IC50 (µM)* T-L	PGHP
1. Hmb-Leu-Leu-NH-(CH2)2-NH-ClNafQ	>100	>100	4.51 ± 0.32
2. Hmb-Phe-Leu-NH-(CH2)2-NH-ClNafQ	46.15 ± 3.15	91.40 ± 9.04	20.29 ± 1.43
3. Hmb-Ser-Leu-NH-(CH2)2-NH-ClNafQ	87.24 ± 6.54	77.49 ± 8.53	25.10 ± 2.26
4. Hmb-Asn-Leu-NH-(CH2)2-NH-ClNafQ	34.2 ± 3.02	>100	15.82 ± 0.97
5. NBz-Leu-Leu-NH-(CH2)2-NH-ClNafQ	39.40 ± 2.97	>100	0.73 ± 0.08
6. NBz-Phe-Leu-NH-(CH2)2-NH-ClNafQ	>100	>100	13.74 ± 0.77
7. NBz-Ser-Leu-NH-(CH2)2-NH-ClNafQ	74.35 ± 5.45	93.6 ± 10.67	60.28 ± 4.89
8. NBz-Asn-Leu-NH-(CH2)2-NH-ClNafQ	24.79 ± 1.98	>100	1.94 ± 0.22
MG132	0.002	1.08	>10

*The values reported are the mean ± SE of three independent determinations.

Figure 2. Effect of compounds 1, 5 and 8 on cell proliferation. MDA (panel a) and A2780 (panel b) tumor cells were cultured for 3 days in the presence or absence of the indicated concentrations of compounds 1, 5 and 8. Results are expressed as % inhibition proliferation calculated in respect to untreated cells. The means of three independent experiments performed in duplicate are shown.

Figure 3. Molecule 5 in the β1 binding pocket (a) and a schematic diagram of the inhibitor–protein interactions (b).

Figure 4. Molecule 5 in the β5 binding pocket (a) and a schematic diagram of the inhibitor–protein interactions (b).