α‐Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results in the production of a variety of pro‐inflammatory and immunomodulatory cytokines. Herein, we report the synthesis and biological evaluation of photochromic derivatives of KRN‐7000, the activity of which can be modulated with light. Based on established structure–activity relationships, we designed photoswitchable analogues of this glycolipid that control the production of pro‐inflammatory cytokines, such as IFN‐γ. The azobenzene derivative α‐GalACer‐4 proved to be more potent than KRN‐7000 itself when activated with 370 nm light. Photolipids of this type could improve our mechanistic understanding of cytokine production and could open new directions in photoimmunotherapy.

Sinoracutine is a recently isolated alkaloid with unusual stereochemical and biological properties. It features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to a cyclopentenone. Interestingly, both enantiomers of sinoracutine have been independently isolated from the same plant, yet the molecule does not appear to occur as a racemate. Here, we present a short synthesis of (-)-sinoracutine that relies on a highly diastereoselective Pauson-Khand reaction and a Mandai-Claisen reaction to install the quaternary stereocenter. Our work establishes the absolute configuration of the levorotatory isomer and suggests that the optical purity of sinoracutine varies in nature due to its gradual racemization. Experimental evidence supports this proposal, and a plausible mechanism for the racemization is provided.

The natural product jasplakinolide is a widely used tool compound to stabilize F-actin and influence actin dynamics. We have previously introduced photoswitchable jasplakinolides (optojasps) that are activated with violet light and deactivated with blue light. Based on insights from cryo-electron microscopy and structure-activity relationship (SAR) studies, we now developed a new generation of functionally superior optojasps that are better suited for biological investigations. These compounds are procured through chemical total synthesis and feature rationally designed red-shifted azobenzene photoswitches. Our new optojasps can be activated with longer wavelengths in the visible range (e.g. 440-477 nm) and rapidly return to their inactive state through thermal relaxation. This has enabled the reversible control of F-actin dynamics, as shown through live-cell imaging and cell migration, as well as cell proliferation assays. Brief sub-cellular activation with blue-green light resulted in highly localized F-actin clusters that gradually dissolved in the dark. Our light-responsive tools can be useful in diverse fields to study actin dynamics with outstanding spatiotemporal precision.