Synthesis and biological properties of C-terminal vinyl ketone pseudotripeptides

Figures & data

Figure 1.  General structure of the vinyl ketone pseudotripeptides.

Scheme 1.  Synthesis of new vinyl ketone derivatives 1–10.

Table 1.  Analytical data and physicochemical properties of the novel pseudotripeptides 1–10.

No.	Compound	HPLC		^a[α]D^20	m.p. (°C)	M + H^+
		K^I (a)	K^I (b)
1	Boc-Leu-Leu-Leu-VK	7.01	5.47	−10.9	130–133	482.35
2	H-Leu-Leu-Leu-VK	6.31	4.72	−14.9	138–140	382.55
3	HMB-Leu-Leu-Leu-VK	5.80	4.61	−9.2	128–130	516.34
4	Z-NH-(CH2)5-CO-Leu-Leu-Leu-VK	7.59	6.63	−8.5	118–121	629.42
5	Z-NH-(CH2)7-CO-Leu-Leu-Leu-VK	7.89	6.95	−8.7	140–142	657.45
6	Boc-Val-Ser-Leu-VK	6.30	5.21	−22.3	145–148	442.29
7	H-Val-Ser-Leu-VK	5.70	4.43	−11.4	141–143	342.23
8	HMB-Val-Ser-Leu-VK	5.47	3.97	−12.9	135–137	476.27
9	Z-NH-(CH2)5-CO-Val-Ser-Leu-VK	7.07	6.32	−10.67	123–125	589.36
10	Z-NH-(CH2)7-CO-Val-Ser-Leu-VK	7.22	6.54	−9.98	119–124	617.39

^ac = 1, MeOH.

Table 2.  Inhibition of proteasome subunits and metabolic stability of vinyl ketone derivatives.

N	Compound	Isolated enzyme LCL ^aIC50 (µM)			Half-life (min) human plasma
		ChT-L	T-L	PGHP
1	Boc-Leu-Leu-Leu-VK	>10	>10	>10
2	H-Leu-Leu-Leu-VK	>10	>10	>10
3	HMB-Leu-Leu-Leu-VK	>10	8.53	>10	>360
4	Z-NH-(CH2)5-CO-Leu-Leu-Leu-VK	9.13	4.22	>10	>360
5	Z-NH-(CH2)7-CO-Leu-Leu-Leu-VK	7.95	3.81	>10	>360
6	Boc-Val-Ser-Leu-VK	>10	>10	>10
7	H-Val-Ser-Leu-VK	>10	>10	>10
8	HMB-Val-Ser-Leu-VK	>10	>10	>10
9	Z-NH-(CH2)5-CO-Val-Ser-Leu-VK	8.54	8.02	>10	>360
10	Z-NH-(CH2)7-CO-Val-Ser-Leu-VK	6.41	6.65	>10	>360

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

ChT-L, chymotrypsin-like; LCL, lymphoblastoid cell lines; T-L, trypsin-like.