New Imatinib Derivatives with Antiproliferative Activity against A549 and K562 Cancer Cells

Abstract

Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC50 values of 7.2, 6.4, and 7.3 μM, respectively, and were all more potent than imatinib (IC50 of 65.4 μM). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 µM, showed an IC50 value of 35.8 μM (imatinib, IC50 = 0.08 μM). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer.

Recent updates in click and computational chemistry for drug discovery and development

“…Copper-catalyzed 1,3-dipolar cycloaddition (CuAAC) to form 1,2,3-triazoles is the most popular reaction in click chemistry. Recently, 1,2,3-triazole backbones with hydrogen bonds, moderate dipole moments and enhanced water solubility had been widely used to generate drug candidates of anti-tumor ( Brown et al, 2022 ; Elganzory et al, 2022 ; Mohammed et al, 2022 ; Oekchuae et al, 2022 ; Oliveira et al, 2022 ; Mironov et al, 2023 ), anti-seizure ( Bhattacherjee et al, 2022 ), anti-diabetic ( Dhameja et al, 2022 ), anti-parasitic ( Aljohani et al, 2022 ), anti-bacterial ( Daher et al, 2022 ; Mokariya et al, 2022 ; Nsira et al, 2022 ) and anti-viral ( Kutkat et al, 2022 ; Tatarinov et al, 2022 ) via CuAAC click chemistry ( Figure 1A ).…”

New nitazoxanide derivatives: design, synthesis, biological evaluation, and molecular docking studies as antibacterial and antimycobacterial agents

“…The second pathway involved propargylation of the appropriate cyclic amine, 2-mercaptobenzothiazole or isatin derivative in the presence of potassium carbonate and DMF (Scheme 1) and afforded the propargylated derivatives (4f-4q) in 76-83% yield. [64][65][66][67][68][69][70] Finally, the target 1,2,3-triazoles (5a-5q) were obtained in 76-89% yield via Cu-catalyzed click cycloaddition of 3a with the alkyne or propargylated derivatives (4f-q) under standard conditions. All 5a-q were fully characterized using IR, 1 H-NMR, 13 C-NMR, ESI-MS and elemental analyses.…”

“…Synthesis of propargylated un/5-substituted isatins (4k-p). [67][68][69] To a solution of 5-(un)substituted isatin (3.36 mmol, 1 equivalent) in DMF (3 mL) was added K 2 CO 3 (1.39 g, 10.08 mmol, 3 equivalent) and the mixture was stirred for ¼ h, then propargyl bromide (80% wt in toluene, 0.6 mL, 4.04 mmol, 1.2 equivalent) was added and the reaction mixture was stirred at room temperature for 3 h. Upon addition of H 2 O (15 mL), the propargylated isatins were precipitated, filtered, washed with H 2 O and recrystallized from EtOH/H 2 O and air dried (% yield and melting points are listed in Table 5).…”

Therapeutic potential of 1,2,3‐triazole hybrids for leukemia treatment

“…Some of the pyridine-containing 1,2,3-triazole-pyrimidine hybrids also showed decent antileukemic activity, [50,51] 2.06-27.05 µM, MTT assay) were active against stem cell-like KG-1a leukemia cells, and the SAR indicated that cyclic amino group at the C-4 position of 1,2,3-triazole was favorable to the activity. [52] In particular, hybrids 17a,b (IC 50 : 2.06 and 3.28 µM) were 4.3-and 3.0fold more potent than the parent lapatinib (IC 50 : 9.76 µM) against stem cell-like KG-1a leukemia cells, and hybrid 17a (IC 50 : 6.24 and 5.39 µM) also showed higher activity than lapatinib (IC 50 : 20.11 and 12.14 µM) against SKBR3 and SUM159 breast cancer cell lines.…”

“…Some of the pyridine‐containing 1,2,3‐triazole‐pyrimidine hybrids also showed decent antileukemic activity, [ 50,51 ] and amongst them, hybrids 16a,b (IC 50 : 1.0 and 2.3 µM, MTT assay) were active against K562 cells. The SAR revealed that the amide linker between 1,2,3‐triazole and phenyl ring was essential for the activity, and replacement by amine led to a significant loss of activity.…”