C-terminal trans,trans-muconic acid ethyl ester partial retro-inverso pseudopeptides as proteasome inhibitors

Figures & data

Figure 1.  Structure of the C-terminal retro-inverso pseudotripeptide 16 and hypothetical pockets of the proteasomal substrate binding catalytic site that are occupied by the pharmacophore, residue side chains and N-terminal function.

Scheme 1.  Synthesis of new trans,trans-muconic acid ethyl ester derivatives 1–16.

Table 1.  Analytical data and physicochemical properties of C-terminal retro-inverso peptides 1–16.

No.	Compound	HPLC		^a[α]D^20	M.P. (°C)	M + H^+
		K′ (a)	K′ (b)
1	H-Leu-gLeu-MEE	>10	>10	−23.4	138–142	368.25
2	H-Ser-gLeu-MEE	>10	>10	−31.8	129–131	342.20
3	HMB-Leu-gLeu-MEE	>10	>10	−17.9	120–124	502.29
4	HMB-Ser-gLeu-MEE	>10	>10	−20.5	115–118	476.24
5	Z-NH-(CH2)5-CO-Leu-gLeu-MEE	>10	>10	−13.3	Oil	615.37
6	Z-NH-(CH2)5-CO-Ser-gLeu-MEE	>10	>10	−14.8	Oil	589.32
7	Z-NH-(CH2)7-CO-Leu-gLeu-MEE	>10	>10	−9.7	Oil	643.40
8	Z-NH-(CH2)7-CO-Ser-gLeu-MEE	>10	>10	−12.1	Oil	617.35
9	H-Leu-Leu-gLeu-MEE	>10	>10	−11.6	97–100	581.39
10	H-Val-Ser-gLeu-MEE	>10	>10	−15.8	145–148	441.27
11	HMB-Leu-Leu-gLeu-MEE	>10	>10	−9.3	101–105	615.37
12	HMB-Val-Ser-gLeu-MEE	>10	>10	−9.9	105–108	575.30
13	Z-NH-(CH2)5-CO-Leu-Leu-gLeu-MEE	>10	>10	−6.5	Oil	728.46
14	Z-NH-(CH2)5-CO-Val-Ser-gLeu-MEE	>10	9.40	−7.4	Oil	687.39
15	Z-NH-(CH2)7-CO-Leu-Leu-gLeu-MEE	>10	>10	−5.5	Oil	756.49
16	Z-NH-(CH2)7-CO-Val-Ser-gLeu-MEE	>10	8.37	−7.3	Oil	715.42

^ac = 1, MeOH.

Table 2.  Inhibition of proteasome subunits and metabolic stability of butadienyl ethyl ester derivatives.

No.	Compound	Isolated enzyme LCL ^aIC50 (µM)			Half-life (min)Human plasma
		ChT-L	T-L	PGHP
1	H-Leu-gLeu-MEE	>10	>10	>10
2	H-Ser-gLeu-MEE	>10	>10	>10
3	HMB-Leu-gLeu-MEE	>10	>10	>10
4	HMB-Ser-gLeu-MEE	>10	>10	>10
5	Z-NH-(CH2)5-CO-Leu-gLeu-MEE	>10	>10	>10
6	Z-NH-(CH2)5-CO-Ser-gLeu-MEE	>10	>10	>10
7	Z-NH-(CH2)7-CO-Leu-gLeu-MEE	>10	>10	>10
8	Z-NH-(CH2)7-CO-Ser-gLeu-MEE	>10	>10	>10
9	H-Leu-Leu-gLeu-MEE	>10	>10	>10
10	H-Val-Ser-gLeu-MEE	>10	>10	>10
11	HMB-Leu-Leu-gLeu-MEE	>10	>10	>10
12	HMB-Val-Ser-gLeu-MEE	>10	>10	8.79 ± 0.9	>360
13	Z-NH-(CH2)5-CO-Leu-Leu-gLeu-MEE	>10	>10	>10
14	Z-NH-(CH2)5-CO-Val-Ser-gLeu-MEE	>10	9.40 ± 0.9	3.32 ± 0.5	>360
15	Z-NH-(CH2)7-CO-Leu-Leu-gLeu-MEE	>10	>10	>10
16	Z-NH-(CH2)7-CO-Val-Ser-gLeu-MEE	>10	8.37 ± 0.7	2.67 ± 0.3	>360

^aThe values reported are the average of three independent determinations.