Diastereoselective Synthesis of 4-Hydroxy-2-quinolinones via Formal [2 + 4] Cycloaddition Reactions Using α-Diazo Pyrazoleamides as C2 Synthons.

A rhodium-catalyzed highly stereoselective formal [2 + 4]-cycloaddition reaction of α-diazo pyrazoleamides and 2-aminophenyl ketones that produces 4-hydroxy-2-quinolinones in good yields with excellent diastereoselectivities has been developed. A pyrazolium ylide species that is generated from α-diazo pyrazoleamides is used as a C2 synthon for this cycloaddition. This protocol offers an efficient approach to a variety of 4-hydroxy-2-quinolinones featuring sequential quaternary centers.

Discovery and Optimization of Novel Biphenyl Derivatives Bearing Cyclopropyl Linkage as Potent Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Inhibitors.

A series of novel compounds bearing a cyclopropyl linkage were designed, synthesized, and evaluated as programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. An optimized compound (1,2)- showed potent inhibitory activity against the PD-1/PD-L1 interaction (IC = 0.029 μM) with a selected binding affinity with PD-L1 ( = 1.

Design, synthesis and biological evaluation N-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD 'head' as potential ALK inhibitors.

Aiming to develop promising ALK inhibitors, two series of N-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives (22a-x and 23a-d) were designed according to scaffold hopping and bioisosterism principles. All compounds were efficiently synthesized by concise reactions and anti-proliferative activities on ALK-addicted H2228, Karpas299 cells and EGFR-expressive A549 cell were evaluated by MTT assay. Several compounds exhibited potential cytotoxic activities with IC values below 0.

Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine derivatives as novel ATX and EGFR dual inhibitors.

In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC values of 18.

Synthesis, biological evaluation and molecular modeling of imidazo[1,2-a]pyridine derivatives as potent antitubulin agents.

Two series of novel 5,7-diarylimidazo[1,2-a]pyridine-8-carbonitrile derivatives (3a-3q and 7a-7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h-7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC values in double-digit nanomolar degree.

Discovery and Optimization of Novel 5-Indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrile Derivatives as Potent Antitubulin Agents Targeting Colchicine-binding Site.

Aiming at development of potent antitubulin agents targeting colchicine-binding site, a series of novel 5-indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrilederivatives (5a-5v and 7a-7h) were designed based on bioisosterism and hybridization strategies. All these compounds were concisely synthesized via a three-step process and examined against five human cancer cell lines (HT-29, A549, MKN-45, MDA-MB-231 and SMMC-7721) along with a normal human cell (L02) in vitro. A structure-activity relationships (SARs) study was carried out and optimization towards this series of compounds in cellular assay resulted in the discovery of 5k, which displayed similar or better antitumor potency against the tested cancer cells with IC value ranging from 0.

Design, synthesis and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives as selective c-Met inhibitors.

Two novel series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives bearing 1H-imidazole-4-carboxamido or (E)-3-hydrosulfonylacrylamido motifs (16-31 and 32-42) were designed, synthesized and evaluated for their in vitro cytotoxic activity. Most of the compounds exhibited moderate to excellent potency against tested three cell lines, and fifteen compounds were further examined for their inhibitory activity against c-Met kinase. The most promising compound 16 (c-Met kinase [IC]=1.