Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

Abstract

A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…Im‐1 has a high density of aromatic rings and high lipophilicity resulting in partial solubility only in neutral aqueous media. The free‐base Im‐1 was utilized as a model system for evaluating the biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity) . Some of the excess aromatic systems were substituted with sp 3 structural motifs, including BCP and cubane moieties, which add increased three‐dimensionality and rigidity.…”

“…Benzene bioisosteres have been investigatedm ost extensively in the literature, but several examples of bioisosteres for ethynyl, cyclohexane rings, adamantane,a nd tert-butyl and methyl groups have also been reported. Linear-aliphatic-rigid linkersa re ideal replacements for these functional groups as they can maintain the structure of the drug that is often crucial to activity,o ffer metabolic stability when enzymatic action dramatically reducest he half-life of ad rug, and increase the lipophilicity of ad rug that may be required to cross the bloodbrain-barrier.M oreover,B CP has been shown to increaset he aqueous solubility of ad rug, [336] and, alongside cubane [337] and BCO, has been proven to increaset he selectivity and potency for specific receptors.…”

Carbopalladation of C–C σ-bonds enabled by strained boronate complexes

“…In addition to their occurrence in numerous medicinally-relevant natural products and pharmaceuticals, 26 − 28 cyclobutanes are useful synthetic intermediates 29,30 and are of increasing interest in medicinal chemistry since they can act as rigid carbon scaffolds 31 and as sp 3 -carbon rich bioisosteres of aromatic rings. 32,33 Indeed, the European Lead Factory, 34 which has been established to identify promising starting points for drug discovery, is searching for unique, synthetically tractable compound classes featuring rigid, non-planar scaffolds with two or more diversifiable regions, and substituted cyclobutanes have been identified as fulfilling these criteria. 35…”

Suppression of carboxylesterases by imatinib mediated by the down‐regulation of pregnane X receptor

“…As the most prominent example of selective inhibitors of TKIs, IM has led to the development of novel TKIs in the treatment of a wide range of haematological malignancies and solid tumours, to overcome drug resistance and achieve better therapeutic effects (Haouala et al, ). Novel IM analogues are synthesized by constructing a number of non‐aromatic structural motifs in place of the original phenyl moiety (Nicolaou et al, ). In this study, we demonstrate that the PXR‐targets, DMEs and P‐gp, are suppressed by IM (Figures A–F, A–D, A–E).…”