NK cell’s killing is a tightly regulated process under the control of specific cytoskeletal proteins. This includes Wiskott-Aldrich-Syndrome protein, Wiskott-Aldrich-Syndrome protein-interacting protein, cofilin, Munc13-4, and nonmuscle myosin IIA (NMIIA). These proteins play a key role in controlling NK-mediated cytotoxicity either via regulating the attachment of lytic granules to the actin-based cytoskeleton or via promoting the cytoskeletal reorganization that is requisite for lytic granule release. UNC-45A is a highly conserved member of the UNC-45/CRO1/She4p family of proteins that act as chaperones for both conventional and nonconventional myosin. Although we and others have shown that in lower organisms and in mammalian cells NMIIA-associated functions, such as cytokinesis, cell motility, and organelle trafficking, are dependent upon the presence of UNC-45A, its role in NK-mediated functions is largely unknown. In this article, we describe UNC-45A as a key regulator of NK-mediated cell toxicity. Specifically we show that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation. Furthermore, we show that UNC-45A is disposable for NK cell immunological synapse formation and lytic granules reorientation but crucial for lytic granule exocytosis. Lastly, loss of UNC-45A leads to reduced NMIIA binding to actin, suggesting that UNC-45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes.

A new class of pentacyclic diquinoid compounds has been synthesized with a facile one-pot reaction of two molecules of 2-hydroxynaphthoquinone and 1-bromoalkanes in the presence of ferrocene. These molecules were isolated as enol tautomers that exhibit intramolecular hydrogen bond and extended electronic conjugation as proved by the intense absorption spectrum with a broad band between 400 and 600 nm. The spectroscopic and electrochemical characterization of this new class of compounds has been performed. One of the synthesized diquinoid derivatives showed a significant cytotoxicity with IC 50 values of 25−50 μM against Cisplatin-Resistant SKOV3 and colon carcinoma SW480 cell lines. The results of our study provide a valuable tool to a one-pot synthesis of highly conjugated polyquinones, analogous to important biological systems, with significant antitumoral activity. ■ INTRODUCTIONNaphthoquinone-based molecules are ubiquitous in plants, having key roles in several transformations.1 Vitamin K derivatives, for example, are naphthoquinones involved in biological processes such as the catalysis of the cyclic photophosphorylation pathways 2 and the decarboxylation of glutamic acid.3 Moreover, in the photosynthetic system, quinones act as the final electron acceptors in reaction centers after sunlight harvesting process. The understanding of the photosynthetic mechanism has stimulated the synthesis of artificial mimicking models, based on electron transfer processes. Accordingly, the donor and acceptor moieties used in such models are mainly inspired by the pigments found in photosynthetic reaction centers.4 Therefore, quinones have often been used as acceptor moieties together with easily oxidizable compounds, such as porphyrin or ferrocene derivatives, in donor−acceptor dyads mimicking natural photosynthesis. 5In this paper we described a new and unexpected synthesis of highly coniugated pentacyclic diquinoid compounds. Although our initial aim was not the diquinones formation, we studied these products because of their interesting absorption properties and in view of their relevance in many fields, and in particular in medical applications. 6For example, a quinoid tricyclic derivative with antibiotic properties, the hipposudoric acid (Chart 1a), was isolated from the skin secretion of hippopotamus after a sequence of extraction processes. 7 The chemical synthesis of hypposudoric acid is possible, but only with a difficult, time-consuming multistep route, 7b as usually occurs for the synthesis of natural poliquinonoid compounds.8 Due to its absorption spectrum in the visible region, hipposudoric acid appears to be produced to

Tat deeply alters the programming and functionality of CD8⁺ T lymphocytes.

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A small library of pentacyclic quinoid compounds, called KuQuinones (KuQs), has been prepared through a one-pot reaction. KuQuinones complex structure is made up by two naphthoquinone units connected by a five-membered ring. Due to KuQs structural features, keto-enol tautomerization in solution likely occurs, leading to the generation of four different species, i.e., the enol, the enolate, the external enol and the diquinoid species. The interchange among KuQ tautomers leads to substantial spectral variations of the dye depending on the experimental conditions used. The comprehension of tautomeric equilibria of this new class of quinoid compounds is strongly required in order to explain their behavior in solution and in biological environment. UV-vis, H NMR spectroscopies, and DFT calculations resulted appropriate tools to understand the nature of the prevalent KuQuinone species in solution. Moreover, due to the structural similarity of KuQuinones with camptothecin (CPT), a largely used anticancer agent, KuQs have been tested against Cisplatin-resistant SKOV3 and SW480 cancer cell lines. Results highlighted that KuQs are highly active toward the analyzed cell lines and almost nontoxic for healthy cell, indicating a high specific activity.