Total synthesis and absolute stereochemistry of the proteasome inhibitors cystargolides A and B

Abstract

The absolute stereochemistry of the cystargolides was determined by total synthesis. Evaluation of synthetic cystargolides and derivatives showed that the natural (2S,3R) stereochemistry is essential for activity. Moreover, benzyl esters (−)-10 and (−)-15 were found to be about 100 times more potent, and to selectively kill MCF-7 cancerous cells.

Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors

“…Cystargolides A and B (CysA and CysB, Scheme 1a), were isolated from the actinomycete Kitasatospora cystarginea, and these compounds have been described to block human proteasome activity in the μΜ range [21]. Recently, our group accomplished the first total synthesis and determined the absolute stereochemistry for both CysA and CysB [22]. This work identified the benzyl ester 1 (Scheme 1a) as a potent analog that inhibited the proteasome at low nanomolar concentrations.…”

“…This work identified the benzyl ester 1 (Scheme 1a) as a potent analog that inhibited the proteasome at low nanomolar concentrations. Interestingly, 1 also displayed low micromolar cytotoxicity against MCF7 breast cancer cells [22], warranting further investigations of the cystargolide scaffold as a peptidic PI like the belactosins.…”

A total synthesis of (−)-hortonone C

“…4 [α] 20 D +74 ( c 4.4, CHCl 3 )}, therefore, the absolute stereochemistry of natural hortonone C must be described as (6 S ,7 S ,10 S ), in agreement with the Minehan report. 5 Evaluation of cytotoxicity using the MTT assay as described previously 29 demonstrated that synthetic hortonone C (−)- 1 was not active (IC 50 >100 μM) against MCF-7 breast cancer cells, indicating that the absolute stereochemistry of the natural product is essential for activity…”

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

“…176 Cystargolides A (66) and B (67) exhibited inhibition towards the ChT-L site of the 20S proteasome with IC 50 values of 0.36 AE 0.017 mM and 0.93 AE 0.032 mM, respectively. The total syntheses and absolute stereochemistry of cystargolides A and B were later successfully achieved by Tello-Aburto et al 177 Wolf et al were also able to access the cystargolides and belactosins using biosynthetic methods. The stereochemistry of these natural products is integral to inhibitory activity: maintaining the (2R,3S) absolute stereochemistry contributes to potency of inhibitors.…”

“…178 Benzylation of the N-terminus also improved inhibitory potency 100-fold, as evidenced by analogues 68 (IC 50 : 9.2 AE 0.59 nM) and 69 (IC 50 : 9.0 AE 1.4 nM). 177 Subsequent optimization of the cystargolide scaffold was achieved in 2018: benzyl ether 70 inhibits the hb5 subunit of Jurkat cell lysate with an IC 50 value of 3.1 AE 0.2 nM as compared to cystargolide B (IC 50 : 0.90 AE 0.11 mM), and is also cytotoxic against MCF-7 and RPMI-8226 cells. 179…”