Qiufeng Liu

Design, Synthesis, and Biological Evaluation of a Series of Benzo(de)(1,7)naphthyridin-7(8H)‑ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

Multisubstituted quinoxalines and pyrido[2,3-d]pyrimidines: Synthesis and SAR study as tyrosine kinase c-Met inhibitors.

Two series of new analogues were designed by replacing the quinoline scaffold of our earlier lead 2 (zgw-atinib) with quinoxaline and pyrido[2,3-d]pyrimidine frameworks. Moderate c-Met inhibitory activity was observed in the quinoxaline series. Among the pyrido[2,3-d]pyrimidine series, compounds 13a-c possessing an O-linkage were inactive, whilst the N-linked analogues 15a-c retained c-Met inhibitory potency. Highest activity was observed in the 3-nitrobenzyl analog 15b that showed an IC(50) value of 6.5 nM. Further structural modifications based on this compound were undergoing.

A neutron powder diffraction study of the system La2(Co1-xFex)16Ti for x=0.0, 0.2, and 0.4

The nuclear and magnetic structures of La-2(Co1-xFex)(16)Ti have been studied by neutron powder diffraction for the compositions x=0.0,0.2,0.4. The compound crystallizes with the symmetry of space group m. Site occupancy results show significant departures from a purely statistical distribution, with the Ti atoms located in sites which interact weakly with La, and with the Co atoms occupying preferentially the sites with strong La interaction. These results are consistent with the enthalpies of formation of equiatomic alloys of rare earth and 3d elements. The spin ordering at all compositions and temperatures is ferromagnetic. At room temperature the moments are aligned along the c axis for the compositions x=0.0 and x=0.2, and form an angle of about 57 degrees with c for x=0.4. This tilt angle is a function of temperature and the moment is aligned along c at 11 K, moving gradually towards the a,b plane as the temperature increases

Syntheses and magnetic properties of Rm+nCo5m+3nB2n compounds

New compounds Pr3Co13B2 and Nd5Co19B6 have been synthesized successfully. They belong to the Rm+nCo5m+3nB2n family with m = 2, n = 1 and m = 2 and n = 3, respectively. Pr3Co13B2 adopts the hexagonal La3Ni13B2-type structure with lattice parameters a = 5.0672(3) Angstrom and c = 10.6850(6) Angstrom, while Nd5Co19B6 is isostructural to Lu5Ni19B6 With a = 5.1328(3) Angstrom and c = 16.6519(5) Angstrom. Magnetic measurements indicate that Pr3Co13B2 is ferromagnetic with a Curie temperature of 360 K. Its saturation magnetic moment at 5 K is 20.0 mu(B) fu(-1). Based on the results of the saturation magnetization, two kinds of Co sites with different magnetic moments are proposed. Pr3Co13B2 exhibits large uniaxial anisotropy with an anisotropy field of 90 A m(-1) at 5 K. The Nd5Co19B6 compound is ferromagnetic with a Curie temperature of 380 K. Its saturation magnetic moment and anisotropy field are 21.5 mu(B) fu(-1) and 340 A m(-1) at 5 K, respectively. No spin reorientation was detected from the temperature dependence of the magnetization of these compounds from 5 K to their Curie temperatures, and the behaviour of magnetocrystalline anisotropy was analysed using the single-ion model.

Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure-activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.

Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors

Lipoprotein-associated phospholipase A2 (Lp-PLA2) represents a promising therapeutic target for atherosclerosis and Alzheimers disease. Here we reported the first crystal structures of Lp-PLA2 bound with reversible inhibitors and the thermodynamic characterization of complexes. High rigidity of Lp-PLA2 structure and similar binding modes of inhibitors with completely different scaffolds are revealed. It not only provides the molecular basis for inhibitory activity but also sheds light on the essential features of Lp-PLA2 recognition with reversible inhibitors.

Novel fatty acid binding protein 4 (FABP4) inhibitors: virtual screening, synthesis and crystal structure determination.

Fatty acid binding protein 4 (FABP4) is a potential drug target for diabetes and atherosclerosis. For discovering new chemical entities as FABP4 inhibitors, structure-based virtual screening (VS) was performed, bioassay demonstrated that 16 of 251 tested compounds are FABP4 inhibitors, among which compound m1 are more active than endogenous ligand linoleic acid (LA). Based on the structure of m1, new derivatives were designed and prepared, leading to the discovery of two more potent inhibitors, compounds 9 and 10. To further explore the binding mechanisms of these new inhibitors, we determined the X-ray structures of the complexes of FABP4-9 and FABP4-10, which revealed similar binding conformations of the two compounds. Residue Ser53 and Arg126 formed direct hydrogen bonding with the ligands. We also found that 10 could significantly reduce the levels of lipolysis on mouse 3T3-L1 adipocytes. Taken together, in silico, in vitro and crystallographic data provide useful hints for future development of novel inhibitors against FABP4.

Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor

c-Met/HGF overexpression has been detected in many human malignancies including tumors which are resistant to anticancer therapy. Disrupting the aberrant c-Met/HGF axis has enjoyed significant progress in both preclinical and clinical antitumor campaign. To eliminate the OCH2-related metabolic deficiency of our previously reported triazolotriazine 2, we synthesized a series of CH2-/CF2-linked triazolotriazines and assessed their c-Met activities, leading to the highly potent compound 23 with IC50 values of 0.24xa0nM of enzymatic activity in c-Met and 0.85xa0nM of cellular activity in EBC-1 cancer cell line, as well as with complete tumor regression in EBC-1 xenograft mice model at dose of 25xa0mg/kg via oral administration. Based on its potent anti-proliferative activities and favorable pharmacokinetic properties, 23 has been selected as a drug candidate for preclinical investigation.

Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors

The c-Met kinase has emerged as an attractive target for developing antitumor agents because of its close relationship with the development of many human cancers, poor clinical outcomes and even drug resistance. A series of novel c-Met kinase inhibitors have been identified with multiple workflow in this work, including virtual screening, X-ray crystallography, biological evaluation and structural optimization. The experimentally determined crystal structure of the best hit compound HL-11 in c-Met kinase domain was highly consistent with the computational prediction. Comparison of the hit compounds with different c-Met kinase inhibitory activity by molecular dynamics simulations suggested the key protein-ligand interactions for structural optimization. Based on these, structural optimization produced compound 11e with better c-Met kinase inhibitory activity and improved anti-proliferative activity. These experimental findings proved the reliability and efficiency of our in silico methods. This strategy will facilitate further lead discovery and optimization for novel c-Met kinase inhibitors.

Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimers disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.