Synthesis of Either C2- or C4′-Alkylated Derivatives of Honokiol and Their Biological Evaluation for Anti-inflammatory Activity

Abstract

Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4′-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4′-alkylated derivative.

Synthesis of Bisphenol Neolignans Inspired by Honokiol as Antiproliferative Agents

“…R f 0.79 (cyclohexane:acetone 70:30). Spectroscopic data were in agreement with those reported in the literature [20].…”

“…According to the above cited report [18], the allylic chains on the bisphenolic core of honokiol are important structural requirements for antiproliferative activity; thus, we planned to investigate the effect of further allylic or O-allylic substituents. Namely, 2 was subjected to S N 2 reaction with allyl bromide to obtain the bis-O-allyl honokiol 8, whose structure was confirmed by analysis of its 1 H and 13 C-NMR data, in agreement with those previously reported [20]. As a further step, the Claisen rearrangement of 8 was planned to obtain the bis-C-allyl derivative 9.…”

“…The above-cited properties have prompted many researchers to synthesize magnolol and honokiol analogues and evaluate their biological properties to obtain new potential therapeutic agents. These efforts have afforded new bisphenol neolignans with optimized properties, among which antimicrobial [17,18], neuroprotective [19], anti-inflammatory [20], antitumor [18,21,22], and antiangiogenic activity [23]. According to some studies, the antitumor activity of honokiol, magnolol, and their analogues is related to the presence of free hydroxyl group and allylic chains on a bisphenolic moiety [18,23].…”

Honokiol ameliorates angiotensin II‐induced hypertension and endothelial dysfunction by inhibiting HDAC6‐mediated cystathionine γ‐lyase degradation

“…HNK (final 10 μmol/L), rather than cell lysates, was directly added to the plate wells coated with the unique HDAC6 affinity substrate and incubated with the purified HDAC6 control protein (160 ng; 2 hours, 37°C). Alternatively, we applied a synthetic biotin‐labelled HNK 30 . Following HAEC treatment with biotin‐labelled HNK (5 μmol/L) for 12 hours, cell lysates (0.6 mg) were mixed with 25 μL streptavidin agarose resin (#20347, Thermo Fisher Scientific) overnight at 4°C, and then, the resulting pull‐down samples were processed for immunoblot analysis.…”

“…Alternatively, we performed a pull-down assay using a biotin-labelled HNK ( Figure 5E) recently synthesized for biological applications. 30 Lysates from HAECs untreated or treated with biotin-labelled HNK were pulled down using streptavidin agarose resins. The HDAC6 immunoblot analysis confirmed the binding of biotin-labelled HNK to HDAC6 ( Figure 5F).…”