Design, synthesis and biological evaluation of 2-phenylaminopyrimidine derivatives as EGFR inhibitors.

In the treatment of non-small cell lung cancer (NSCLC), acquired drug resistance is a major factor that affects the efficacy of third-generation epidermal growth factor receptor (EGFR) inhibitors like Osimertinib. To overcome the L858R/T790M/C797S mutation, taking the Brigatinib as the positive control, two classes of 20 target compounds were designed and synthesized with 2-phenylaminopyrimidine as the core structure on the basis of summarizing the structure-activity relationship (SAR), following the basic principles of drug design. Representative compound I-10 potently inhibited EGFRL858R/T790M/C797S with an IC50 value of 33.26 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S cells with an IC50 value of 106.4 nM, which is 5-fold more potent than Brigatinib. Besides, the compound exhibited an inhibition rate of less than 50 % against wild-type cell (NCI-H838), which reflected its toxicity or selectivity. Furthermore, this work serves as a foundation for future studies on EGFR inhibitors.

Design, synthesis and biological evaluation of quinazoline SOS1 inhibitors.

Son of sevenless 1 (SOS1) is a vital guanine nucleotide exchange factor (GEFs) that activates rat sarcoma (Ras) protein in cells. SOS1 inhibitors can effectively inhibit the expression of downstream signaling pathways by blocking the interaction between SOS1 and Ras protein. Here, we designed and synthesized a series of quinazoline-based compounds, and conducted subsequent evaluations of their biological activities. Among them, the comparable compounds I-2 (IC50 = 20 nM, against SOS1) I-5 (IC50 = 18 nM, against SOS1) and I-10 (IC50 = 8.5 nM, against SOS1) have kinase activity equivalent to BAY-293 (IC50 = 6.6 nM, against SOS1), and I-10 also has cell activity equivalent to BAY-293, providing a theoretical reference for subsequent related researches on SOS1 inhibitors.

Novel quinoline-based derivatives: A new class of PDE4B inhibitors for adjuvant-induced arthritis.

A total of 31 quinoline-based derivatives were designed and synthesized to develop novel anti-inflammatory drugs. After the toxicity of synthetic compounds to RAW264.7 cells were evaluated in vitro, their anti-inflammatory activity was assessed by inhibiting lipopolysaccharide (LPS)-induced NO production levels in the RAW264.7 cells. Among the derivatives, compound f4 had the best anti-inflammatory activity, which could reduce the production of pro-inflammatory cytokines NO, IL-1ß, and TNF-α with corresponding IC50 values of 20.40 ± 0.94, 18.98 ± 0.21 and 23.48 ± 0.46 µM. Western blot showed that f4 could inhibit the expression of LPS-induced inflammatory mediators iNOS and COX-2. Molecular docking showed that f4 could also enter the PDE4B receptor binding pocket, and the cellular thermal shift assay method indicated that the PDE4B protein bound to f4 had increased stability. Meanwhile, the inhibitory effect of this compound on the PDE4B enzyme (IC50 = 0.94 ± 0.36 µM) was comparable to that of the positive drug rolipram (IC50 = 1.04 ± 0.28 µM). Finally, in vivo studies showed that f4 could improve the degree of foot swelling and knee joint pathology in adjuvant-induced arthritic rats and decrease the levels of serum inflammatory factors TNF-α and IL-1ß in a dose-dependent manner. Therefore, the development and design of quinoline-based derivatives for anti-inflammatory applications could be considered opportunities and challenges.

Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: Design, synthesis and biological evaluation.

As a receptor tyrosine kinase (RTK), tropomyosin receptor kinase (Trk) is a key drug target in solid tumors. However, the use of the First-generation Trk inhibitors was greatly restricted due to mutant drug resistance. Fortunately, the emergence of the Second-generation of Trk inhibitors has brought an effective solution to this mutant resistance, such as TPX-0005 (Repotrectinib). Here, we reported a series of pyrizolo[1,5-a]pyrimidine derivatives as the second-generation Trk inhibitors, and carried out the subsequent biological activity evaluation. Among them, the best compound 14h (IC50 = 1.40, 1.80 nM, against TrkA, TrkAG595R, respectively) and 14j (IC50 = 0.86, 6.92 nM, against TrkA, TrkAG595R, respectively) has a kinase activity comparable to TPX-0005, and 14j (IC50 = 350 nM against ALK) has a higher selectivity of Trk inhibition than TPX-0005, which may be of great significance for reducing toxicity.

Synthesis and biological evaluation of novel 5,6-dihydrobenzo[h]quinazoline derivatives as FLT3 inhibitors.

Fms-like tyrosine kinase 3 (FLT3) is widely expressed and often mutated in acute myeloid leukemia (AML), which makes it an important target for the treatment of AML. The structure-based synthesis and biological evaluation of 5,6-dihydrobenzo[h]quinazoline derivatives as FLT3 inhibitors have been studied in this paper. III-1a, III-1c, III-2a, III-2c, and III-4a displayed comparable inhibitory potency against FLT3-ITD and showed remarkable antiproliferative activities against MV4-11.

Pyrazolo[1,5-a]pyrimidine based Trk inhibitors: Design, synthesis, biological activity evaluation.

Tropomyosin receptor kinases (Trks), a transmembrane receptor tyrosine kinases, have attracted more and more attention as a drug target. Here we reported the structure-based synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors, which exhibited potent Trk inhibitory activities. Particularly, compounds 8a, 8f, 9a, 9b and 9f (IC50 < 5 nM) showed significant inhibitory potency against Trk.

Visible-light photocatalytic aerobic oxidation of sulfides to sulfoxides with a perylene diimide photocatalyst.

Photosensitized oxygenation has been recognised as a modern method of incorporating oxygen into a substrate, as it offers environmentally benign alternatives to several conventional synthetic procedures. A metal-free aerobic selective sulfoxidation photosensitized by a perylene diimide photocatalyst has been developed. The reaction utilizes visible light as the driving force and molecular oxygen as the oxidant. The advantages of the developed method include high efficiency and selectivity, extremely simple operation and work-up procedure, mild reaction conditions, and practical application in late-stage functionalization.

Making Nanocomposites of Hydrophilic and Hydrophobic Polymers Using Gas-Responsive Cellulose Nanocrystals.

Generally, different surface-functionalized cellulose nanocrystals (CNC) are required for use as nanofillers in hydrophilic and hydrophobic polymers. In the present study, for the first time, a kind of "universal" nanofiller for polymer composites is demonstrated by using CNC grafted with a gas-responsive polymer. CNC are functionalized with pyrene-containing poly(2-(N,N-diethylaminoethyl)methacrylate) (CNC-g-PDEAEMA-Py). The reversible transport of the nanocrystals between phase-separated water and toluene is proved by nuclear magnetic resonance (1 H NMR) and fluorescence spectroscopy. On the one hand, water-soluble poly(vinyl alcohol) (PVA) can be mixed with dispersed CNC upon CO2 bubbling for making the PVA-CNC nanocomposite. On the other hand, after the transfer of CNC into the toluene solution upon N2 bubbling, styrene-butadiene-styrene (SBS) triblock copolymer can be dissolved for the SBS-CNC nanocomposite. In both systems, CNC are well dispersed, having an effect on the mechanical and shape memory properties of SBS and PVA, respectively.

Cu-Catalyzed carbamoylation versus amination of quinoline N-oxide with formamides.

An efficient, direct carbamoylation and amination of quinoline N-oxides with formamides to access 2-carbamoyl and 2-amino quinolines has been developed through copper-catalyzed C-C and C-N bond formations via cross-dehydrogenative coupling reactions. The reaction proceeds smoothly over a broad range of substrates with excellent functional group tolerance under mild conditions. Mechanistic studies suggest that the reaction is initiated by formamide radical or decarbonylative aminyl radical formation in the presence of TBHP, according to the different substituent on the N atom of formamide.

CO2-Responsive polymer membranes with gas-tunable pore size.

We report a smart polymer membrane whose pore can be switched between the "closed" and "open" state just by passing CO2 and Ar in solution respectively. Compared with other stimuli, such as pH or temperature change, gas is an environmentally friendly and cost-effective stimulus for reversibly tuning the pore size and imparting the size selectivity of the membrane.

Photodegradable and size-tunable single-chain nanoparticles prepared from a single main-chain coumarin-containing polymer precursor.

A polyester bearing coumarin moieties in the main chain was used to prepare photodegradable single-chain nanoparticles (SCNPs) of variable sizes. While the intra-chain photodimerization of the chromophore determines the size of SCNPs, the photocleavage occurring under UV irradiation at a different wavelength breaks down the ultra-small nanoparticles.

Ruthenium-catalyzed asymmetric hydrogenation of 3-oxoglutaric acid derivatives: a study of unconventional solvent and substituent effects.

A series of 3-oxoglutaric acid derivatives have been hydrogenated in different solvents in the presence of [RuCl(benzene)(S)-SunPhos]Cl (SunPhos = (2,2,2',2'-tetramethyl-[4,4'-bibenzo[d][1,3]dioxole]-5,5'-diyl)bis(diphenylphosphine)). Unlike simple ß-keto acid derivatives, these advanced analogues can be readily hydrogenated in uncommon solvents such as THF, CH(2)Cl(2), acetone, and dioxane with high enantioselectivities. Two possible catalytic cycles have been proposed to explain the different reactivities of these 1,3,5-tricarbonyl substrates in the tested solvents. The C-2 and C-4 substituents had notable but irregular influence on the reactivity and enantioselectivity of the reactions. More pronounced solvent effects were observed: the ee values increased from around 20% in EtOH or THF to 90% in acetone. Inversion of the product configuration was observed when the solvent was changed from EtOH to THF or acetone, and a mixed solvent system can lead to better enantioselectivity than a single solvent.

Enantioselective hydrogenation of ß-ketophosphonates with chiral Ru(II) catalysts.

Highly effective asymmetric hydrogenation of ß-ketophosphonates in the presence of Ru-(S)-SunPhos as catalyst was realized; good to excellent enantioselectivities (up to 99.9% ee) and excellent diastereoselectivities (96:4) were obtained.

Ru-catalyzed hydrogenation of 3,5-diketo amides: simultaneous control of chemo- and enantioselectivity.

By modulating the chelating priorities of the different directing groups in 3,5-diketo amides with the assistance from coordinating solvent, highly chemo- and enantioselective hydrogenation of the C3-carbonyls was achieved in the presence of [RuCl(benzene)(S)-SunPhos]Cl in THF.

Ru-catalyzed highly chemo- and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-ß-keto esters under neutral conditions.

Finely-tuned ruthenium-catalyzed highly chemoselective and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-ß-keto esters at the carbonyl group was achieved under neutral reaction conditions (ee up to 97%). Both olefin and alkenyl halogen moieties, which are labile under hydrogenation conditions, remained untouched during the reaction.

Acid-labile δ-ketal-ß-hydroxy esters by asymmetric hydrogenation of corresponding δ-ketal-ß-keto esters in the presence of CaCO3.

A series of acid-labile, optically pure ε-substituted δ-ketal-ß-hydroxy esters were obtained by a Ru-SunPhos catalyzed asymmetric hydrogenation of the corresponding ε-substituted δ-ketal-ß-keto esters. CaCO(3) played a dual role in the hydrogenation reaction--removing the acid generated during the formation of the catalyst and maintaining the activity of the catalyst.

Ruthenium-catalyzed enantioselective hydrogenation of aryl-pyridyl ketones.

Various substituted aryl-pyridyl ketones were hydrogenated in the presence of Ru-XylSunPhos-Daipen bifunctional catalytic system with enantiomeric excesses up to 99.5%. Upon introduction of a readily removable ortho-bromo atom to the phenyl ring, enantiomerically enriched 4-chlorophenylpyridylmethanol was obtained by hydrogenation method with 97.3% ee, which provided an important chiral intermediate for some histamine H(1) antagonists.

Ru-catalyzed asymmetric hydrogenation of γ-heteroatom substituted ß-keto esters.

A series of enantiomerically pure γ-heteroatom substituted ß-hydroxy esters were synthesized with high enantioselectivities (up to 99.1% ee) by hydrogenation of γ-heteroatom substituted ß-keto esters in the presence of Ru-(S)-SunPhos catalyst. These asymmetric hydrogenations provide key building blocks for a variety of naturally occurring and biologically active compounds.

Ru-catalyzed asymmetric hydrogenation of 3-oxoglutaric acid derivatives via solvent-assisted pinpoint recognition of carbonyls in close chemical propinquity.

Upon comparison of hydrogenation rates of various ß-ketocarboxylic acid derivatives, ß-ketoamides were found to be hydrogenated slightly faster than ß-ketoesters in EtOH in the presence of [RuCl(benzene)(S)-SunPhos]Cl at 70 °C with 20 bar of hydrogen. In THF these differences were so sharpened that ß-ketoamides were hydrogenated even faster than in EtOH while the esters were extremely slow. Based on these findings, a series of 3-oxoglutaric acid derived with ester and amide moieties on the two ends were hydrogenated to 3-hydroxyl products with high enantioselectivities.

Synthesis of (S)-7-amino-5-azaspiro[2.4]heptane via highly enantioselective hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropanecarboxylates.

Highly effective asymmetric hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropane carboxylates in the presence of [RuCl(benzene)(S)-SunPhos]Cl was realized, and high enantioselectivities (up to 98.7% ee) were obtained. This asymmetric hydrogenation provides a key intermediate for the enantioselective synthesis of (S)-7-amino-5-azaspiro[2.4]heptane moiety of quinolone antibacterial agents.