Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development.

Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.

Synthesis, reactivity, and characterization of sodium and rare-earth metal complexes bearing a dianionic N-aryloxo-functionalized beta-ketoiminate ligand.

The synthesis and reactivity of a series of sodium and rare-earth metal complexes stabilized by a dianionic N-aryloxo-functionalized beta-ketoiminate ligand were presented. The reaction of acetylacetone with 1 equiv of 2-amino-4-methylphenol in absolute ethanol gave the compound 4-(2-hydroxy-5-methylphenyl)imino-2-pentanone (LH2, 1) in high yield. Compound 1 reacted with excess NaH to afford the novel sodium cluster [LNa2(THF)2]4 (2) in good isolated yield. Structure determination revealed that complex 2 has the 22-vertex cage structure. Reactions of complex 2 with anhydrous LnCl3 in a 1:4 molar ratio, after workup, gave the desired lanthanide chlorides [LLnCl(DME)]2 [Ln = Y (3), Yb (4), Tb (5)] as dimers. A further study revealed that complexes 3-5 are inert for chlorine substitution reactions. (ArO)3Ln(THF) (ArO = 2,6-Bu(t)2-4-MeC6H2O) reacted with compound 1 in a 1:1 molar ratio in tetrahydrofuran (THF), after workup, to give the desired rare-earth metal aryloxides as dimers [LLn(OAr)(THF)]2 [Ln = Nd (6), Sm (7), Yb (8), Y (9)] in high isolated yields. All of these complexes are well characterized, and the definitive molecular structures of complexes 2 and 4-6 were determined. It was found that complexes 6-9 can be used as efficient initiators for L-lactide polymerization, and the ionic radii of the central metals have a significant effect on the catalytic activity.

[Effects of biochar addition into soils in semiarid land on water infiltration under the condition of the same bulk density].

Making clear the effects of biochar addition on soil water infiltration process can provide the scientific basis for the evaluation of the influence of biochar application on soil hydrology in semi-arid region. In this paper, through the soil column simulation method in laboratory, the effects of biochar of three sizes (1-2 mm, 0.25-1 mm and ≤ 0.25 mm) at 4 doses (10, 50, 100 and 150 g x kg(-1)) on the cumulative infiltration, the permeability and the stable infiltration rate of two different soils (anthrosol and aeolian sandy soil) were studied. The results showed that the infiltration capacity of the anthrosol was obviously increased compared to the control, however, the one in the aeolian sandy soil was decreased due to the biochar addition. At 100 minutes after infiltration starting, the averaged cumulative infiltration was increased by 25.1% in the anthrosol with comparison to the control. Contrarily, the averaged cumulative infiltration was decreased by 11.1% in the aeolian sandy soil at 15 minutes after infiltration starting. When the dose was the same, biochar with different particle sizes improved the infiltration for the anthrosol, but for the different dose treatments, the particle size of biochar which showed the greatest improvement was different. As for the aeolian sandy soil, the infiltration increased at the dose of 10 g x kg(-1) after the addition of biochar with different particle sizes, while decreased at the higher dose of 50, 100 and 150 g x kg(-1). The cumulative infiltration of the aeolian sandy soil was decreased with the increase in addition amount of biochar with the same particle size, while it was not so for the anthrosol. The determination coefficient fitted by the Philip infiltration model ranged from 0.965 to 0.999, suggesting this model was suitable for the simulation of soil water infiltration process after biochar application. Statistical analysis of main effects showed that the biochar particle size, the biochar addition amount, and the interactive effect had statistically significant effect on the soil permeability and stable infiltration rate in the two soils. In conclusion, the biochar had different effects on the soils with different textures, moreover, there was a positive correlation relationship between the impact and the addition amount.

Synthesis, characterization and reactivity of heteroleptic rare earth metal bis(phenolate) complexes.

The synthesis, characterization and reactivity of heteroleptic rare earth metal complexes supported by the carbon-bridged bis(phenolate) ligand 2,2'-methylene-bis(6-tert-butyl-4-methyl-phenoxo) (MBMP2-) are described. Reaction of (C5H5)3Ln(THF) with MBMPH2 in a 1:1.5 molar ratio in THF at 50 degrees C produced the heteroleptic rare earth metal bis(phenolate) complexes (C5H5)Ln(MBMP)(THF)n (Ln=La, n=3 (); Ln=Yb (), Y (), n=2) in nearly quantitative yields. The residual C5H5- groups in complexes to can be substituted by the bridged bis(phenolate) ligands at elevated temperature to give the neutral rare earth metal bis(phenolate) complexes, and the ionic radii have a profound effect on the structures of the final products. Complex reacted with MBMPH2 in a 1:0.5 molar ratio in toluene at 80 degrees C to produce a dinuclear complex (MBMP)La(THF)(micro-MBMP)2La(THF)2 () in good isolated yield; whereas complexes and reacted with MBMPH2 under the same conditions to give (MBMP)Ln(MBMPH)(THF)2 (Ln=Yb (), Y ()) as the final products, in which one hydroxyl group of the phenol is coordinated to the rare earth metal in a neutral fashion. The reactivity of complexes and with some metal alkyls was explored. Reaction of complex with 1 equiv. of AlEt3 in toluene at room temperature afforded unexpected ligand redistributed products, and a discrete ion pair ytterbium complex [(MBMP)Yb(THF)2(DME)][(MBMP)2Yb(THF)2] () was isolated in moderate yield. Furthermore, reaction of complex with 1 equiv. of ZnEt2 in toluene gave a ligand redistributed complex [(micro-MBMP)Zn(THF)]2 () in reasonable isolated yield. Similar reaction of complex with ZnEt2 also afforded complex ; whereas the reaction of complex with 1 equiv. of n-BuLi in THF afforded the heterodimetallic complex [(THF)Yb(MBMP)2Li(THF)2] (). All of these complexes were well characterized by elemental analyses, IR spectra, and single-crystal structure determination, in the cases of complexes , and -.