Design, synthesis and biological evaluation of pyrimidine base hydroxamic acid derivatives as dual JMJD3 and HDAC inhibitors.

The Jumonji domain-containing protein demethylase 3 (JMJD3) and histone deacetylase (HADC) are related to various cancers and regard as antitumor targets for drug discovery. In this study, based on rational drug design strategy, we designed and synthesized a series of pyrimidine derivatives with hydroxamic acid as novel dual JMJD3 and HDAC inhibitors for synergistic cancer treatment. Compound A5b exhibited inhibitory potency against JMJD3 and HDAC1/6 simultaneously and favorable cytotoxicity against human cancer cells such as A549 and U937. Furthermore, mechanistic studies showed that A5b treatment in A549 cells increased the hypermethylation of histone H3K27 and hyperacetylation of H3K9, suppressed clonogenicity, migration and invasion of cancer cells. Besides, A5b induced apoptosis via the cleavage of caspase-7 and PARP, and G1 cell cycle arrest via upregulated p21 expression. All these results suggested that A5b was the first dual inhibitor against JMJD3 and HDAC and can be a potential compound for cancer therapy.

Deformation Behavior and Tensile Properties of the Semi-Equiaxed Microstructure in Near Alpha Titanium Alloy.

The tensile deformation and fracture behavior of a particular semi-equiaxed microstructure (S-EM) in a near alpha titanium alloy TA19 are investigated by an in situ method. In the S-EM, the thin ß lamellae grow through the equiaxed αp phase (αp), and the original αp/ßtrans interface in the bimodal microstructure largely disappears, forming a blurry interface between the semi-equiaxed αp phase (equiaxed αp phase that is grew through by the thin ß lamellae) and the transformed ß microstructure (ßtrans). The formation of dense slip bands inside the semi-equiaxed αp phase in the S-EM is inhibited by the thin ß lamellae during the tensile deformation. The special characteristics of the S-EM reduce the stress concentration at the interface, and the crack initiation probability in the blurry semi-αp/ßtrans interface decreased compared to the distinct αp/ßtrans interface in a conventional equiaxed microstructure (EM). Moreover, the ultimate tensile strength of the S-EM is higher than that of the EM with a slight loss of plasticity.