Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders.

Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.

Design, synthesis and biological evaluation of novel 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives as potent mTOR inhibitors.

The mammalian target of rapamycin (mTOR) has been proved to be an effective target for cancer therapy. Two kinds of mTOR inhibitors, the rapalogs and mTOR kinase inhibitors (TORKi), have been developed and clinically validated in several types of malignancies. Compared with rapalogs, TORKi can exert better antitumor activity by inhibiting both mTORC1 and mTORC2, but the clinical development of current TORKi candidates has been relative slow, more TORKi with novel scaffold need to be developed to expand the current pipelines. In this study, a series of 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives were designed, synthesized and biological evaluation. Most of these compounds exhibited good mTOR kinase inhibitory activity and selectivity over PI3Kα. Subsequent antiproliferative assay allowed us to identify the lead compound 15i, which display nanomolar to low micromolar IC50s against six human cancer cell lines. 15i could induce cell cycle arrest of MCF-7, PC-3 and A549 cells at the G0/G1 phase and suppress the migration and invasion of these cancer cells by suppressing the phosphorylation of AKT and P70S6 kinase. It could also regulate autophagy-related proteins to induce autophagy. Therefore, 15i would be a starting point for the development of new TORKi as anticancer drug.

Density functional study of the stability of various α-Bi2O3 surfaces.

Bi(2)O(3) is an important metal oxide in catalysis. In this paper we employed density functional theory and slab model to investigate the surface energies and structures of various α-Bi(2)O(3) surfaces. We first studied ten different terminations along [100] direction which has both polar and nonpolar terminations due to alternating stacking of Bi layers and O layers. Our calculated surface free energies show that the stoichiometric symmetric terminations are most stable at both high and low oxygen pressures, followed by the T(2O)/T(4O) terminations at low/high oxygen pressures. In the low Miller index planes, the (010) plane is the most stable whereas the (110) plane is the least stable. Analyses reveal that relaxation may change the surface structures significantly and there is a nice linear relationship between the surface density of broken short Bi-O bonds and the surface energy before relaxation.

Design, synthesis, and biological evaluation of dinuclear bismuth(III) complexes with Isoniazid-derived Schiff bases.

Four dinuclear bismuth(III) Schiff-base complexes bearing Schiff-base ligands have been synthesized and structurally characterized by single-crystal X-ray diffraction, elemental analysis, and spectral techniques (FT-IR, NMR and MS). The analytical data reveal the bismuth(III) complexes possess 1:1 metal-ligand ratios. In vitro biological studies have revealed that bismuth(III) complexes displayed much higher antibacterial and antitumor activities than their parent ligands, which involves two gram-negative (S. aureus, B. subtili) and two gram-positive (E. coli, P. aeruginosa) bacteria, and human gastric cancer SNU-16 cells. The power-time curves of S. pombe exposed to tested compounds were detected by bio-microcalorimetry. Some thermokinetic parameters (k, Pmax,tG and Qtotal) were derived based on the metabolic power-time curves, and their quantitative relationships with the concentrations (c) were further discussed.