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

Abstract

A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI. Among them, compound 1d with p-chlorobenzenesulfonamido terminal moiety, ethylene spacer, and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10 μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1d inhibited the growth of HL-60 (TB), SR leukemia, and T-47D and MCF-7 breast cancer cell line by 135.92%, 119.44%, 95.32%, and 82.03% at 10 μM, respectively. And it inhibited the growth of COLO 205 colon, HT29 colon, BT-549 breast, and ACHN renal cancer cell lines by more than 80% at the same test concentration. However, testing compound 1d upon determining its IC against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells). Compound 1d was further tested against 12 kinases of different kinase families, and the highest inhibitory effect was exerted against RAF1, V600E-B-RAF, and V600K-B-RAF kinases.

An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors

“…M. M. Gamal El-Din et al synthesized a series of diarylamides and diarylureas containing 1,3,4-oxadiazole moiety ( 98 ) and performed their antiproliferative activities against a panel of 58 cell lines of nine different cancer types at the NCI, compared with sorafenib as a reference compound. Among of all derivatives, Compound (1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)-3 fluorophenyl) urea) ( 99 ) showed the highest sub micromolar IC 50 values of 0.67, 0.80, and 0.87 µM against PC-3 prostate cancer cell line, HCT-116 colon cancer cell line, and ACHN renal cancer cell line, respectively, as shown in Table 1 [ 111 ].…”

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

“…Diving forward into the structural analysis of small molecule B-raf inhibitors, 1,3,4-triarylpyrazole derivatives similar to encorafenib have been synthetized and evaluated as having a promising inhibitory and thus antiproliferative potential, especially those with a sulfonamide functional group [95][96][97]. Moreover, the two aryl rings at positions 3 and 4 of encorafenib's pyrazole scaffold (Figure 4) also play an important role in binding to the active kinase domain, through hydrophobicity and hydrogen bonding valences [98]. However, in another study that investigated imidazothiazole derivatives as B-raf V600E inhibitors, the strategy of replacing the hydrophobic fluoro group with the more hydrophilic nitro group managed to secure both the electrophilic and the hydrogen bond acceptor characteristics of the aromatic substituent, thus increasing the kinase binding ability, possibly revealing insights on the presence and importance of the sulfonamide Molecules 2023, 28, 5359 9 of 32 moiety (alongside the two halogen groups on the aromatic ring at position 3) in the design of encorafenib [99].…”

Evaluation of Substituted Pyrazole-Based Kinase Inhibitors in One Decade (2011–2020): Current Status and Future Prospects

“…It produced 78.04%, 74.47%, and 72.46% inhibition at 10 µM concentration against the RAF1, V600E-B-RAF, and V600K-B-RAF kinases, respectively. The SAR study showed that an ethylene linker is more optimum for activity than propylene [ 83 ].…”