The state of histone acetylation plays a very crucial role in carcinogenesis and its development by chromatin remodeling and thus altering transcription of oncogenes and tumor suppressor genes. Such epigenetic regulation was controlled by zinc-dependent histone deacetylases (HDACs), one of the major regulators. Due to the therapeutic potential of HDACs as one of the promising drug targets in cancer, HDAC inhibitors have been intensively investigated over the last few decades. Notably, there are five HDAC inhibitors already approved to the market. Vorinostat (SAHA), Belinostat (PXD-101) and Romidepsin (FK228) have been approved by Food and Drug Administration (FDA) in USA for treating cutaneous T-cell lymphoma (CTCL) or peripheral T cell lymphoma (PTCL) while Panbinostat (LBH-589) has also been approved by the FDA for the treatment of multiple myeloma. Recently, Chidamide was approved by China Food and Drug Administration (CFDA) for the treatment of PTCL. The structural feature of almost all HDAC inhibitors consists of Cap group, linker, and zinc-binding group (ZBG). The binding of ZBG groups to zinc ion plays a decisive role in the inhibition of HDAC. Therefore, we will summarize the developed HDAC inhibitors according to different ZBG groups and discuss their binding mode with zinc ion.

Histone deacetylase 6 (HDAC6) is a potential therapeutic target for treating several diseases. A recent study revealed that HDAC6 is important for NLRP3 inflammasome activation, suggesting that targeting HDAC6 could be useful for treating many inflammatory disorders. Using the proteolysis targeting chimera (PROTAC) strategy, we herein report an HDAC6 degrader with low cytotoxicity by tethering a selective HDAC6 inhibitor derived from a natural product, indirubin, with pomalidomide, a CRBN E3 ligand. Our HDAC6 degrader efficiently and selectively decreased HDAC6 levels in several cell lines, including activated THP-1 cells. Application of this HDAC6 degrader attenuated NLRP3 inflammasome activation in LPS-induced mice, which for the first time demonstrates that HDAC6 PROTAC could be a novel strategy to treat NLRP3 inflammasome-associated diseases.

Amongst the challenges currently facing synthetic chemists is the development of efficient and elegant chemical processes that allow the rapid creation of stereochemically defined molecular complexity and diversity.[1] One of the most effective ways of achieving this goal is to implement reaction cascades; these allow multiple bond-forming events to occur in a single vessel and, as a consequence, significantly increase resource efficiency for the overall process.[1] To this end, the field of asymmetric organocatalytic cascade/domino reaction development-arguably one of the most stimulating, dynamic, and synthetically powerful areas in contemporary organic synthesis-is beginning to provide genuine solutions. [2,3] Recently, organocatalytic cascade approaches to polysubstituted chiral cyclohexanes have attracted a great deal of attention, owing to the prevalence of such motifs in pharmaceutical compounds and complex natural products. [4,5] However, despite the progress that has been achieved in this field, further advances are needed, particularly with regard to the controlled preparation of different stereoisomers by routine changes to the reaction conditions and/or catalysts employed.Recently, the combination of two organocatalysts has been elegantly employed in one-pot reactions with the controlled, sequential addition of reagents and/or catalysts throughout the course of the reaction.[6] That the vessel is not necessarily charged with all reactants and catalysts from the outset of the reaction belies incompatibilities between combinations of reactants, intermediates, or catalyst-activated species with respect to the desired product outcome. Instead of controlling the outcome of the cascade through the order or rate of addition of reactants/catalysts, our aim was to employ catalysts with orthogonal, but mutually compatible, reactant activation modes. By judicious choice of catalysts and reactants, cycle specificity can be engineered into the reaction cascade such that the product of the first catalytic cycle becomes the sole substrate which then reacts with the third "spectator" reagent.Relay catalysis has been used as an efficient strategy in non-asymmetric transformations, [7] and some examples of asymmetric metal/organocatalyst relay catalysis have also been reported.[8] Covalent-bond and bifunctional base/ Brønsted acid catalysis are two fundamental activation modes in organocatalysis. [9] We envisaged that the merging of these two fields would allow desirable levels of stereocontrol and resource efficiency in an asymmetric organocatalytic relay cascade (AORC) to polysubstituted cyclohexanes.Our proposed three-step asymmetric organocatalytic relay cascade to polysubstituted cyclohexanes is shown in Scheme 1. Initially, a bifunctional base/Brønsted acid catalyst of type 7 would preferentially activate the malonate ester 1 and the nitroalkene 2, thus promoting a chemoselective and stereoselective Michael addition.[10] The Michael adduct 5 would then be poised to participate directly in the second catalytic cyc...

Carpooling is an effective means of reducing traffic. A carpool team shares a vehicle for their commute, which reduces the number of vehicles on the road during rush hour periods. Carpooling is officially sanctioned by most governments, and is supported by the construction of high-occupancy vehicle lanes. A number of carpooling services have been designed in order to match commuters into carpool teams, but it known that the determination of optimal carpool teams is a combinatorially complex problem, and therefore technological solutions are difficult to achieve. In this paper, a model for carpool matching services is proposed, and both optimal and heuristic approaches are tested to find solutions for that model. The results show that different solution approaches are preferred over different ranges of problem instances. Most importantly, it is demonstrated that a new formulation and associated solution procedures can permit the determination of optimal carpool teams and routes. An instantiation of the model is presented (using the street network of Guangzhou city, China) to demonstrate how carpool teams can be determined.

Application of indolin-3-one derivatives in a cascade reaction for efficient assembly of complex molecules is a much less explored research area. It is demonstrated that structurally interesting polysubstituted piperidino[1,2-a]indoline compounds containing four contiguous stereocenters including one tetrasubstituted carbon center can be readily obtained with good yields (up to 94% yield) and excellent enantioselectivities (up to >99% ee) by employing indolin-3-one derivatives as substrates via bifunctional catalysis.