Synthesis and Anti-inflammatory Evaluation of (R)-, (S)-, and (±)-Sanjuanolide Isolated from Dalea frutescens

Abstract

The known chalcone (±)-sanjuanolide (1) can be isolated from Dalea f rutescens. This study presents a convergent strategy for the first total synthesis of (R)-, (S)-, and (±)-sanjuanolide (1). The key step for synthesizing (R)-and (S)-1 was a Corey−Bakshi−Shibata enantioselective carbonyl reduction to construct the C-2″ configuration. (R)-1 efficiently inhibited the lipopolysaccharides (LPS)-induced expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), while (S)-1 produced no significant anti-inflammatory effect. (R)-1 also effectively inhibited the mRNA expression of several inflammatory cytokines after the LPS challenge in vitro. The synthesis and biological properties of these compounds have confirmed (R)-sanjuanolide and (±)-sanjuanolide as promising new leads for developing anti-inflammatory agents.

Discovery, total syntheses and potent anti-inflammatory activity of pyrrolinone-fused benzoazepine alkaloids Asperazepanones A and B from Aspergillus candidus

“…Pro-inflammatory cytokines, such as IL-6 and TNF-α, have been recognized as critical regulators in inflammatory diseases 41 such as rheumatoid arthritis 42 , inflammatory bowel disease 43 , asthma 44 , and diabetic complications 45 . Inhibiting the release of pro-inflammatory cytokines is an important mode of action for anti-inflammatory drugs 46 .…”

Synthesis and Cytotoxic Evaluation of Sanjoseolide and Representative Analogues

“…By the Claisen–Schmidt condensation reaction under alkaline conditions, compound 6 successfully yields chalcone 7a . Finally, the reaction of the bis-MOM-protected chalcone intermediates with hydrochloric acid in methanol and THF at 55 °C provided natural product sanjoseolide ( 1 ) in 8.6% yield over six steps . In a hydrogen atmosphere, reduction of the sanjoseolide (1) provided derivatives 11 in 8.0% yield over seven steps.…”

“…Finally, the reaction of the bis-MOM-protected chalcone intermediates with hydrochloric acid in methanol and THF at 55 °C provided natural product sanjoseolide (1) in 8.6% yield over six steps. 17 In a hydrogen atmosphere, reduction of the sanjoseolide (1) provided derivatives 11 in 8.0% yield over seven steps. The other derivatives (7a, 10, 8b−8e) were synthesized similarly and the overall yields ranged from 4.5 to 13.9%.…”

Progress of isolation, chemical synthesis and biological activities of natural chalcones bearing 2-hydroxy-3-methyl-3-butenyl group

“…According to the report of Fang et al, (R)-Sanjuanolide efficiently inhibited the lipopolysaccharides-induced expression of tumor necrosis factor alpha and interleukin-6 (IC 50 = 1.1 μM), but (S)-Sanjuanolide didn′t showed significant antiinflammatory effect. Furthermore, (R)-Sanjuanolide effectively inhibited the mRNA expression of several inflammatory cytokines after the lipopolysaccharides challenge in vitro (Fang et al, 2019).…”

“…At the same time, Fang et al completed the total synthesis of (±)-Sanjuanolide (Scheme 8B) in 15 steps with overall yield of 3.8%. In addition, (S)-Sanjuanolide and (R)-Sanjuanolide were also prepared in 17 steps with overall yields of 7.3% and 4.2%, respectively (Fang et al, 2019) (Scheme 8C).…”