Novel guanidine derivatives targeting leukemia as selective Src/Abl dual inhibitors: Design, synthesis and anti-proliferative activity

Abstract

A new series of benzene-sulfonamide derivatives 3a-i was designed and synthesized via the reaction of N-(pyrimidin-2-yl)cyanamides 1a-i with sulfamethazine sodium salt 2 as dual Src/Abl inhibitors. Spectral data IR, ¹H-, ¹³C- NMR and elemental analyses were used to confirm the structures of all the newly synthesized compounds 3a-i and 4a-i. Crucially, we screened all the synthesized compounds 3a-i against NCI 60 cancer cell lines. Among all, compound 3b was the most potent, with IC₅₀ of 0.018 μM for normoxia, and 0.001 μM for hypoxia, compared to staurosporine against HL-60 leukemia cell line. To verify the selectivity of this derivative, it was assessed against a panel of tyrosine kinase EGFR, VEGFR-2, B-raf, ERK, CK1, p38-MAPK, Src and Abl enzymes. Results revealed that compound 3b can effectively and selectively inhibit Src/Abl with IC₅₀0.25 μM and Abl inhibitory activity with IC₅₀0.08 μM, respectively, and was found to be more potent on these enzymes than other kinases that showed the following results: EGFR IC₅₀0.31 μM, VEGFR-2 IC₅₀0.68 μM, B-raf IC₅₀0.33 μM, ERK IC₅₀1.41 μM, CK1 IC₅₀0.29 μM and p38-MAPK IC₅₀0.38 μM. Moreover, cell cycle analysis and apoptosis performed to compound 3b against HL-60 suggesting its antiproliferative activity through Src/Abl inhibition. Finally, molecular docking studies and physicochemical properties prediction for compounds 3b, 3c, and 3 h were carried out to investigate their biological activities and clarify their bioavailability.

Keywords: Antiproliferative activity; Apoptosis; Di-substituted guanidine; HL-60 cell line; Hypoxia; Src / Abl inhibitory activity.