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Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety ( 16a – g and 17a – p ) were designed, synthesized and evaluated for the IC 50 values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds ( 17f and 17n ) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC 50 values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC 50 values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series ( 17a – p ) showed more active than the first series ( 16a – g ). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity. [ABSTRACT FROM AUTHOR]

Two series of sorafenib derivatives ( N -methylpicolinamide-4-oxy) chalcones ( 5a – o , 7a – e ) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR and BRAF kinases. The results indicated that all the compounds showed moderate to good antitumor activity, and the compound 5c showed well cytotoxic activity against HepG2, MCF-7 and PC-3 cell lines with IC 50 values of 0.56 ± 0.83 μM, 3.88 ± 1.03 μM and 3.15 ± 0.81 μM, which were 1.03–6.14-fold more active than sorafenib (3.44 ± 1.50 μM, 3.18 ± 1.43 μM, 3.24 ± 0.45 μM), respectively. The compound 5b showed good activity on VEGFR-2/KDR kinase, and its IC 50 value was 0.72 μM. Structure–activity relationships (SARs) and docking studies indicated that replacement of urea group of sorafenib by chalcone ketones improved the cytotoxic activity, and the results suggested that halogen [3-Br, 4-F] and methoxy (substituted on C-3,4,5 or C-2,3,4 position) substitution was benefit for the activity. [ABSTRACT FROM AUTHOR]

Four series of phenylpyrimidine-carboxamide derivatives bearing 1 H -pyrrolo[2,3- b ]pyridine moiety ( 14a – e , 15a – g , 16a – e and 17a – g ) were designed, synthesized and evaluated for the IC 50 values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds ( 15e , 16a – b and 17a ) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC 50 valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC 50 values of 0.14 ± 0.08 μM, 0.24 ± 0.07 μM and 0.02 ± 0.01 μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What’s more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity. [ABSTRACT FROM AUTHOR]

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC 50 = 1.21/2.15 nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure–activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity. [ABSTRACT FROM AUTHOR]

A series of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 4 cancer cell lines (HT-29, A549, MCF-7, and PC-3) in vitro. Most compounds showed moderate to excellent potency, with the most promising analog 34 showing a c-Met IC 50 value of 1.68 nM. Structure–activity relationship studies indicated that electron-withdrawing groups (X = CF 3 , R 1 = F, R 2 = 4-F) were required to decrease the higher electron density on the 5-atom linker to a proper degree to improve the inhibitory activity. [ABSTRACT FROM AUTHOR]

Two series of thienopyrimidine derivatives ( 10a – k , 16a – j ) bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC 50 values against mTOR kinase, PI3Kα kinase and two cancer cell lines. Some of the target compounds exhibited moderate to excellent mTOR/PI3Kα kinase inhibitory activity and cytotoxicity. The most promising compound 16i showed good inhibitory activity against mTOR/PI3Kα kinase and good antitumor potency for H460 and PC-3 cell lines with IC 50 values of 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 μM, >10 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds. Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency. [ABSTRACT FROM AUTHOR]

A series of 7,8-dihydro-5 H -thiopyrano[4,3- d ]pyrimidine derivatives ( 7a – q , 10a – q ) were designed, synthesized and their chemical structures were confirmed by 1 H NMR, 13 C NMR, MS and HRMS spectrum. All the compounds were evaluated for the inhibitory activity against mTOR kinase at 10 μM level. Five selected compounds ( 7b , 7e , 7h , 10b and 10e ) were further evaluated for the inhibitory activity against PI3Kα at 10 μM level, and the IC 50 values against mTOR kinase and two cancer cell lines. Twelve of the target compounds exhibited moderate antitumor activities. The most promising compound 7e showed strong antitumor activities against mTOR kinase, H460 and PC-3 cell lines with IC 50 values of 0.80 ± 0.15 μM, 7.43 ± 1.45 μM and 11.90 ± 0.94 μM, which were 1.28 to 1.71-fold more active than BMCL-200908069-1 (1.37 ± 0.07 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3- d ]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of aryl group at C-4 position had a significant impact on the antitumor activities, and 4-OH substitution produced the best potency. [ABSTRACT FROM AUTHOR]