New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors

Abstract

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

Vanillin-Based Indolin-2-one Derivative Bearing a Pyridyl Moiety as a Promising Anti-Breast Cancer Agent via Anti-Estrogenic Activity

“…Vanillin or alkylated vanillin derivatives reacted with different oxindole derivatives, yielding compounds 5a–c and 6a–o , respectively. The resulted compounds were a mixture of E and Z isomers and used without separation as the previous literature reported that the E isomer is mainly the major isomer − with the possibility of interconversion between the two isomers in methanol within 2 days. , Compounds’ identities were confirmed by comparing mp and NMR data to those we had previously reported …”

Indole derivatives targeting colchicine binding site as potential anticancer agents

“…The biological findings suggest compounds 61 and 62 are suitable leads for development of novel therapeutics for colon cancer, along with improved physicochemical and pharmacokinetic features. [68] 2.20 Mechanistic investigations showed that 63 substantially reduced tubulin polymerization, dose-dependently triggered cell death, and arrested cell division in the G2/M phase. Since 63 was a microtubule polymerization inhibitor, the outcomes of molecular docking and bioactive activities were comparable with those of colchicine.…”

“…The biological findings suggest compounds 61 and 62 are suitable leads for development of novel therapeutics for colon cancer, along with improved physicochemical and pharmacokinetic features. [ 68 ]…”

Discovery of oxindole‐based FLT3 inhibitors as a promising therapeutic lead for acute myeloid leukemia carrying the oncogenic ITD mutation

“…Compounds were mixtures of E and Z isomers (see Supporting Information: S1). No separation was made since previous literature reported that the E isomer is mainly the major isomer [24][25][26] and acknowledged the interconversion between the two isomers in methanol within 2 days. [21,27] 2.2 | Pharmacology/biology 2.2.1 | One-dose screening against FLT3 ITDmutated MV4-11 and FLT3 WT THP-1 acute myeloid leukemia cells…”