Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure

Abstract

The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to its chemical and enzymatic hydrolysis of the strained β-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered β-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its β-lactone carbonyl moiety and the conformational flexibility of the molecule.

From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane

“…As a result, the serotonin reuptake inhibition and N ‐methyl‐ d ‐aspartic acid (NMDA) receptor binding of milnacipran were successfully separated, and 11 showed more than 2000 times weaker serotonin reuptake inhibition than milnacipran, while retaining the NMDA receptor binding affinity. The cyclopropylic strain was also used effectively for designing histamine H 3 receptor antagonist 12 and proteasome inhibitor 13 (Figure b).…”

“… a) NMDA receptor‐selective milnacipran analog 11 based on the cyclopropylic strain. b) Other examples of cyclopropylic strain‐based conformational restriction; histamine H 3 receptor antagonist 12 and proteasome inhibitor 13 …”

A novel total synthesis of aculeatin A via a stepwise approach

“…Therefore, removal of the auxiliary by hydrolysis with LiOH and H 2 O 2 afforded the b-hydroxy acid 11. 10 However, we hardly obtained the desired b-lactone 12. To simplify the preparation of 12, we turned to the approach shown in Scheme 5; another synthetic route using acyl chloride was used to produce the intermediate 4.…”

Natural product scaffolds as inspiration for the design and synthesis of 20S human proteasome inhibitors

“…Researchers hypothesized that poor performance of belactosin analogues under biological conditions and in cell studies may be due to chemical or enzymatic hydrolysis of the reactive b-lactone moiety, 168 and thus sought to improve stability by increasing steric hindrance surrounding the b-lactone ring. 169 Analogue 62 not only contains an additional methyl group at the a-position of the lactone carbonyl carbon, but also retains the same methyl group at the C1 0 carbon adjacent to the cyclopropyl ring to lock it into the syn conformation. While analogue 62 displays lower activity towards the ChT-L site of the proteasome as compared to parent compound 60 (IC 50 : 1.3 mM and 0.0057 mM, respectively), 62 exhibited comparable growth inhibitory activity towards HCT-116 cells relative to the established inhibitor (IC 50 : 4.0 mM (62); 1.8 mM (60)).…”