Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency.

Heterozygous loss-of-function mutations in the GRN gene are a major cause of hereditary frontotemporal dementia. The mechanisms linking frontotemporal dementia pathogenesis to progranulin deficiency are not well understood, and there is currently no treatment. Our strategy to prevent the onset and progression of frontotemporal dementia in patients with GRN mutations is to utilize small molecule positive regulators of GRN expression to boost progranulin levels from the remaining functional GRN allele, thus restoring progranulin levels back to normal within the brain. This work describes a series of blood-brain-barrier-penetrant small molecules which significantly increase progranulin protein levels in human cellular models, correct progranulin protein deficiency in Grn+/- mouse brains, and reverse lysosomal proteome aberrations, a phenotypic hallmark of frontotemporal dementia, more efficiently than the previously described small molecule suberoylanilide hydroxamic acid. These molecules will allow further elucidation of the cellular functions of progranulin and its role in frontotemporal dementia and will also serve as lead structures for further drug development.

Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs.

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality that show promise to open a target space not accessible to conventional small molecules via a degradation-based mechanism. PROTAC degraders, due to their bifunctional nature, which is categorized as 'beyond the Rule of Five', have gained attention as a distinctive therapeutic approach for oral administration in clinical settings. However, the development of PROTACs with adequate oral bioavailability remains a significant hurdle, largely due to their large size and less than ideal physical and chemical properties. This review encapsulates the latest advancements in orally delivered PROTACs that have entered clinical evaluation as well as developments highlighted in recent scholarly articles. The insights and methodologies elaborated upon in this review could be instrumental in supporting the discovery and refinement of novel PROTAC degraders aimed at the treatment of various human cancers.

Enzymatic Resolution and Decarboxylative Functionalization of α-Sulfinyl Esters.

α-Sulfinyl esters can be readily prepared through thiol substitution of α-bromo esters followed by oxidation to the sulfoxide. Enzymatic resolution with lipoprotein lipase provides both the unreacted esters and corresponding α-sulfinyl carboxylic acids in high yields and enantiomeric ratios. Subsequent decarboxylative halogenation, dihalogenation, trihalogenation and cross-coupling gives rise to functionalized sulfoxides. The method has been applied to the asymmetric synthesis of a potent inhibitor of 15-prostaglandin dehydrogenase.

Palladium-Catalyzed Selective [2 + 2 + 2] Annulation of 2-(2-Enynyl)pyridines with Arynes.

The palladium-catalyzed chemo- and stereoselective [2 + 2 + 2] annulation reaction of 2-(2-enynyl)pyridines with arynes has been developed. A wide range of (E)- or (E/Z)-isomers of 2-(2-enynyl)pyridines and arynes was tolerated, providing a spectrum of (E)-phenanthrenylated 2-alkenylpyridines in good yield, together with the generation of a chiral axis between an alkene and a phenanthrene ring.

Phosphine-Catalyzed [4+2] Cycloadditions of Allenic Ketones: Enantioselective Synthesis of Functionalized Tetrahydropyridines.

Amino-acid-derived phosphine catalyzed [4+2] cycloaddition leading to chiral tetrahydropyridines, making use of α-substituted allenic ketones as "C4 synthons" and N-sulfonyl cyclic ketimines, has been developed. This asymmetric cycloaddition tolerates a wide range of α-substituted allenic ketones. A series of chiral sultam-fused tetrahydropyridines bearing a quaternary stereocenter were obtained in high yields with good enantioselectivities.

Tandem Diels-Alder/oxidation-aromatization reactions involving 2-styrylchromones and arynes.

Transition-metal-free Diels-Alder and tandem Diels-Alder/oxidation-aromatization reactions of 2-styrylchromones with arynes have been demonstrated under mild reaction conditions with a wide range of substrates. The tandem process afforded functionalized benzo[c]xanthone derivatives in moderate to good yields. This efficient protocol allows rapid access to either dihydrobenzo[c]xanthone and benzo[c]xanthone derivatives selectively by simply changing the atmosphere of the reaction.

An asymmetric Mannich reaction of α-diazocarbonyl compounds and N-sulfonyl cyclic ketimines catalyzed by complexes generated from chiral and achiral phosphines with gold(i).

An unprecedented Lewis acidic gold(i)-complex generated from chiral and achiral phosphines has been developed for the Mannich reaction of α-diazocarbonyl compounds and N-sulfonyl cyclic ketimines. A series of chiral ß-amino-α-diazoesters bearing a quaternary stereocenter were obtained in high yields with good enantioselectivities. In addition, the products could be converted to promising bioactive spirosuccinimide. Furthermore, operando IR, NMR and control experiments were carried out to gain insight into the mechanism.

Synthesis and anticancer activity evaluation of novel azacalix[2]arene[2]pyrimidines.

A series of novel azacalix[2]arene[2]pyrimidines were synthesized, and evaluated for their antiproliferative activities against A549, MCF7, SH-SY5Y and CNE human cancer cell lines in vitro by using the CCK-8 assay. A number of compounds showed low micromolar antiproliferative activities against MCF7 cell line. Compound 4j, containing a pyrrolidine moiety, exhibited the strongest inhibitory activity with an IC50 value of 0.58 µM. Furthermore, breast cancer cells were used to explore the inhibition mechanism of these azacalix[2]arene[2]pyrimidines. The results suggested these compounds were involved in inducing cell apoptosis via up-regulation of caspase-3 and caspase-9 protein expression, and the cell cycle was arrested at the S phase. Our reports here represent the first studies on the biological activities of azacalix[2]arene[2]pyrimidines.

Construction of Polycyclic Indole Derivatives via Multiple Aryne Reactions with Azaheptafulvenes.

An efficient [8 + 2]/aryl-ene tandem reaction between azaheptafulvenes and arynes has been developed, leading to the formation of cyclohepta[b]indoles in a single step with good yield. In addition, employment of excess arynes provides a [8 + 2]/aryl-ene /[6 + 2] tandem reaction to synthesize polycyclic oxacyclohepta[b]indoles. This is the first time that azaheptafulvenes have been employed in tandem reactions with arynes.