Halo-perfluoroalkoxylation of gem-difluoroalkenes with short-lived alkali metal perfluoroalkoxides in triglyme.

Alkali metal alkoxides play a pivotal role in nucleophilic alkoxylation reactions, offering pathways for the synthesis of ethers, including the increasingly sought-after trifluoromethyl ethers. However, the synthesis of long-chain perfluoroalkyl ethers remains a substantial challenge in this field. Through the innovative use of triglyme to encapsulate potassium ions, we enhanced the stability of short-lived, longer-chain perfluoroalkoxy anions, thereby facilitating efficient nucleophilic perfluoroalkoxylation reactions. This method provides a new precedent for the halo-perfluoroalkoxylation of gem-difluoroalkenes and offers a versatile tool for the design of perfluoroalkyl ethers, including those containing complex moieties of heterocycles and drug molecules. We also demonstrated the utility of the resulting halo-perfluoroalkoxyl adducts through various chemical transformations to valuable diverse perfluoroalkyl ethers.

Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation.

Lenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4CRBN. Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs.

Src family kinases suppress differentiation of brown adipocytes and browning of white adipocytes.

Brown adipocytes and beige adipocytes can expend energy, generate heat, and increase whole-body energy expenditure. The detailed mechanisms of adipogenesis and thermogenesis of these cells are still obscure. Here, we show that Src family kinases (SFKs) regulate both brown adipogenesis and browning of white adipocytes. To identify factors involved in brown adipogenesis, we first examined the effect of several chemical inhibitors on the differentiation of brown preadipocytes isolated from mouse brown adipose tissue (BAT) and found that treatment with PP2, the specific inhibitor of SFKs, promoted the differentiation. Another inhibitor of SFKs, PP1, also promoted the brown adipogenesis, whereas an inactive analogue of PP2, PP3, did not. Moreover, over-expression of C-terminal Src kinase (CSK), the negative regulator of SFKs, also promoted brown adipogenesis. Next, we examined the effect of inhibition of SFKs on the differentiation of white preadipocytes isolated from white adipose tissue (WAT). Our results showed that either PP2 treatment or CSK-over-expression generated Ucp1-positive beige adipocytes, thus inducing browning of white adipocytes. Finally, our analysis showed that the expression levels and activity of SFKs in WAT were much higher than in BAT. These results taken together suggest that SFKs regulate differentiation and browning of fat cells in vivo.

Antagonism between the master regulators of differentiation ensures the discreteness and robustness of cell fates.

The discreteness of cell fates is an inherent and fundamental feature of multicellular organisms. Here we show that cross-antagonistic mechanisms of actions of MyoD and PPARγ, which are the master regulators of muscle and adipose differentiation, respectively, confer robustness to the integrity of cell differentiation. Simultaneous expression of MyoD and PPARγ in mesenchymal stem/stromal cells led to the generation of a mixture of multinucleated myotubes and lipid-filled adipocytes. Interestingly, hybrid cells (i.e., lipid-filled myotubes) were not generated, suggesting that these differentiation programs are mutually exclusive. Mechanistically, although exogenously expressed MyoD was rapidly degraded in adipocytes through ubiquitin-proteasome pathways, exogenously expressed PPARγ was not downregulated in myotubes. In PPARγ-expressing myotubes, PPARγ-dependent histone hyperacetylation was inhibited in a subset of adipogenic gene loci, including that of C/EBPα, an essential effector of PPARγ. Thus, the cross-repressive interactions between MyoD- and PPARγ-induced differentiation programs ensure discrete cell-fate decisions.