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Research Article

Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents

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Pages 111-122 | Received 29 Feb 2016, Accepted 05 May 2016, Published online: 02 Jun 2016

Figures & data

Figure 1. Structures of SB203580, Encorafenib (LGX818), and rationale design to the target compounds 1a–l and 2a–l.

Figure 1. Structures of SB203580, Encorafenib (LGX818), and rationale design to the target compounds 1a–l and 2a–l.

Scheme 1. Reagents and conditions: (a) (i) triethylamine, CH2Cl2, 0 °C, RT, overnight; (ii) N-ethyl ethylenediamine, C5H5N, reflux, 3 h; (iii) benzyloxycarbonyl chloride, TEA, CH2Cl2, 0 °C; (iv) methanesulfonyl chloride, TEA, CH2Cl2, 0 °C; (v) IV, NaH (60% dispersion in mineral oil), DMF; (vi) H2/Pd-C, MeOH, RT, 1 h; (b) (CH3)2SO4, K2CO3, acetone, reflux, 3 h; (c) KMnO4, C5H5N, H2O, 50 °C, 24 h, then RT, 13 h; (d) acetyl chloride, CH3OH, RT, 15 h; (e) 4-methyl-2-(methylthio)pyrimidine, LiHMDS, THF, −78 °C, 2 h then RT, overnight; (f) (i) DMF-DMA, 80 °C, 3 h; (ii) phenylhydrazine, C2H5OH, RT, overnight; (g) oxone, MeOH, H2O, RT, 16 h; (h) 3a–l, diisopropylethylamine, DMSO, 80 °C, 16 h; (i) BBr3, CH2Cl2, −78 °C, 1 h; RT, overnight.

Scheme 1. Reagents and conditions: (a) (i) triethylamine, CH2Cl2, 0 °C, RT, overnight; (ii) N-ethyl ethylenediamine, C5H5N, reflux, 3 h; (iii) benzyloxycarbonyl chloride, TEA, CH2Cl2, 0 °C; (iv) methanesulfonyl chloride, TEA, CH2Cl2, 0 °C; (v) IV, NaH (60% dispersion in mineral oil), DMF; (vi) H2/Pd-C, MeOH, RT, 1 h; (b) (CH3)2SO4, K2CO3, acetone, reflux, 3 h; (c) KMnO4, C5H5N, H2O, 50 °C, 24 h, then RT, 13 h; (d) acetyl chloride, CH3OH, RT, 15 h; (e) 4-methyl-2-(methylthio)pyrimidine, LiHMDS, THF, −78 °C, 2 h then RT, overnight; (f) (i) DMF-DMA, 80 °C, 3 h; (ii) phenylhydrazine, C2H5OH, RT, overnight; (g) oxone, MeOH, H2O, RT, 16 h; (h) 3a–l, diisopropylethylamine, DMSO, 80 °C, 16 h; (i) BBr3, CH2Cl2, −78 °C, 1 h; RT, overnight.

Table 1. Structures of the target compounds 1a–l and 2a–l, their yield percentage, and melting points.

Table 2. Mean percentage growth of the 53 cancer cell line panel after treatment with the tested target compounds (10 μM concentration).

Figure 2. Percentage inhibition expressed by compounds 1d (a), 1h (b), and 2f (c) at 10 μM concentration over all cell lines of the NCI cancer cell line panel of nine different cancer types. The inhibition percentages are calculated by subtracting the growth percentages from 100.

Figure 2. Percentage inhibition expressed by compounds 1d (a), 1h (b), and 2f (c) at 10 μM concentration over all cell lines of the NCI cancer cell line panel of nine different cancer types. The inhibition percentages are calculated by subtracting the growth percentages from 100.

Table 3. IC50 (μM) results exerted by the compound 1d and staurosporine against HL-60 leukemia cell line, HT29 colon cancer cell line, and MRC-5 lung fibroblasts.

Table 4. Percentage inhibition and IC50 (μM) results exerted by the most potent compounds over the selected kinases.

Supplemental material

IENZ_1190715_Supplementary_Material.pdf

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