Abstract
The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes.
Highlights
Notoincisol A [1] is a natural product recently isolated from the roots and rhizomes of Notopterygium incisum Ting ex H.T
The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported
Within a multidisciplinary research program8 aimed at the identification of novel natural products displaying antiinflammatory activity,9,10 we became interested in the synthesis of polyeneynes such as 1 to confirm the absolute configuration of this natural product as well as to investigate the prospects of further developing this structural lead
Summary
Recruits coactivators, necessary for its transactivation activity. PPARγ was recognized as a potential anti-inflammatory target in 1998, when it was shown that activation of the receptor leads to the inhibition of NF-κB (nuclear factor “kappa-lightchain-enhancer” of activated B cells), a transcription factor regulating the expression of pro-inflammatory target genes.−. Synthesis of Enantioenriched Alkynes R-14 and S-15a aReaction conditions: (a) Ni(OAc)2·4H2O, NaBH4, (CH2NH2), MeOH, rt, 3 h; (b) IBX, DMSO/CH2Cl2, rt, 2 h; (c) TMS acetylene, n-BuLi, THF, −78 °C to rt, 2.5 h, 60% over three steps; (d) amano lipase PS, MTBE, vinyl acetate, rt, 36 h, 48%, ee > 99% for R-14, 45%, ee > 99% for S15 Both synthons were isolated with ee’s of >99% (Table 1). Additional control experiments for the absolute chemistry determination were carried out (see Supporting Information) Both compounds R-14 and S-15 were subjected to basic hydrolysis, yielding the enantiomerically enriched primary alkynes R-16 and S-16 in 85% and 81% yields, respectively. Deprotection of TBS Groupsa aReaction conditions: (a) HF·pyridine, THF, 0 °C to rt
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