Synthesis and activity of proteasome inhibitors

Figures & data

Figure 1. Structures of compounds 1 and 2.

Scheme 1. Reagents and conditions: (a) for compound 3: compound 2, MeO–NH₂·HCl, pyridine, room temperature to 80 °C, 1 h, 70%; (b) for compound 4: compound 2, H₂NC(=O)–NH–NH₂·HCl, Na-acetate, ethanol–water, room temperature, overnight, 60%.

Table 1.  Biological data for compounds.*.

Compound	R^1	n	X	P	R^2	Y	IC50 nM†
2	CN	8	Cyclopentyl	CHMe2	CHO	NO2	6
3	CN	8	Cyclopentyl	CHMe2	CH=N–OMe	NO2	700
4	CN	8	Cyclopentyl	CHMe2	CH=N–NH–CONH2	NO2	100
5	CN	8	Cyclopentyl	CHMe2	CHO	PMC‡	20
6	CN	8	Cyclopentyl	Ph	COCH2F	NO2	>1000
10	CF3SO2NH	8	Cyclopentyl	CHMe2	CHO	NO2	8
15	COOMe	7	Cyclopentyl	CHMe2	CHO	NO2	5
16	COOMe	7	Cyclopentyl	CHMe2	CHO	PMC‡	10
17	COOMe	7	H	CHMe2	CHO	NO2	40
18	COOMe	6	Cyclopentyl	CHMe2	CHO	NO2	40

*All compounds except 17 were tested as a mixture of diastereomers at pseudo-P₃ site.

†Average of two experiments, done in triplicate.

‡PMC = 

Scheme 2. Reagents and conditions: (a) BOP, HOBt, NMM and DMF, 0 °C to room temperature, 2 h, 60%; (b) Dess–Martin reagent, CH₂Cl₂, 0 °C to room temperature, 2 h, 70%.

Scheme 3. Reagents and conditions: (a) hydrazine monohydrate, MeOH, heat, 1 h; (b) CF₃SO₂Cl, Et₃N, CH₂Cl₂, −10 °C to room temperature, 2 h, 60% over two steps; (c) H₂ gas, catalytic 10% Pd–C (50% water content), MeOH, 42–26 psi, 2 h, 80%; (d) (S)-leucinol, BOP, HOBt, NMM, DMF, 0 °C to room temperature, 2 h, 70%; and (e) Dess–Martin reagent, CH₂Cl₂, 0 °C to room temperature, 2 h, 80%.