Design, synthesis and bioactivity evaluation of selenium-containing PI3Kδ inhibitors.

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 µM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.

Discovery of Novel, Potent, and Selective Small-Molecule Menin-Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups.

Introduction of the N,N-dimethylaminoethoxy group to pyrido[3,2-d]pyrimidine led to the discovery of menin-mixed lineage leukemia (MLL) interaction inhibitor C20. C20 showed strong binding affinity to menin protein and achieved sub-micromolar potency in cell growth inhibition. C20 had good selectivity for the inhibition of the interaction between menin and MLL in the kinase profile evaluation. Pharmacokinetic studies demonstrated that C20 possessed good stability and low clearance rate in liver microsomes and acceptable bioavailability in rats. Subsequent oral administration of C20 showed potent antitumor activity in the MV4;11 subcutaneous xenograft models of MLL-rearranged leukemia. The docking study showed that C20 bound highly with menin, and the N,N-dimethylaminoethoxy group occupied the F9 pocket of menin. This study proved that introducing a hydrophilic group into the F9 pocket of menin would be a new strategy for the design of menin-MLL interaction inhibitors with potent binding affinity and improved physical properties.

Small molecule selenium-containing compounds: Recent development and therapeutic applications.

Selenium (Se) is an essential micronutrient of organism and has important function. It participates in the functions of selenoprotein in several manners. In recent years, Se has attracted much attention because of its therapeutic potential against several diseases. Many natural and synthetic organic Se-containing compounds were studied and explored for the treatment of cancer and other diseases. Studies have showed that incorporation of Se atom into small molecules significantly enhanced their bioactivities. In this paper, according to different applications and structural characteristics, the research progress and therapeutic application of Se-containing compounds are reviewed, and more than 110 Se-containing compounds were selected as representatives which showed potent activities such as anticancer, antioxidant, antifibrolytic, antiparasitic, antibacterial, antiviral, antifungal and central nervous system related effects. This review is expected to provide a basis for further study of new promising Se-containing compounds.