Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines

Abstract

An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called and, with an anti-proliferative effects, achieving IC values of about half that of the IC of monastrol in both cell lines. As with monastrol, flow cytometry analyses showed that the and compounds induced cell cycle arrest in the G/M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to .

Ethyl 6-Methyl-2-oxo-4-{4-[(1-phenyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylate

“…The Biginelli reaction, catalyzed by p-toluenesulfonic acid, allowed the condensation of aldehyde (2) previously prepared, ethyl acetoacetate (3), and urea (4) leading to the already reported 3,4-dihydropyrimidinone (5) [10]. Compound (5) was used as the reagent in [3+2] cycloaddition with azide (7) previously prepared from aniline (6). The target compound LaSOM ® 293 was obtained as an amorphous yellow solid in an 84% yield.…”

“…The inhibition of this enzyme leads to cell cycle arrest at the G 2 /M phase and activation of signaling ways, which leads to cellular apoptosis [4]. Recent investigations have reported that the monastrol derivatives with an aromatic ring at N1 position showed improved activity against rat and human glioma cell lines [5].…”

Ethyl 4-(2-fluorophenyl)-6-methyl-2-thioxo-1-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate

“…The purification processes involved only recrystallization in ethanol. The compound (3) 1-(4-methylphenyl)thiourea was obtained in accordance with the protocols previously published [4].…”

“…It has been recently identified that N1 substituted Biginelli compounds were able to interact with Eg5, a protein involved in chromosome separation during the cell cycle [4]. Another target for this heterocycle class is the enzyme ecto-5 -nucleotidase (5 -NT or CD73), a protein involved in the hydrolysis of adenosine monophosphate (AMP) to adenosine, a molecule that increases cancer growth through immune system suppression [5].…”

The use of isoxazoline and isoxazole scaffolding in the design of novel thiourea and amide liquid-crystalline compounds

“…They can also be synthesized in the reaction of thiourea with primary amines [6]. Another important synthetic route for substituted thioureas is a two-step approach: (i) the addition/elimination reaction of benzoyl chloride, with a thiocyanate salt, generating in situ, benzoyl isothiocyanate, and (ii) an appropriate amine reaction with benzoyl isothiocyanate, yielding the acylthiourea which may be the final product or may be hydrolyzed to obtain the monosubstituted thiourea [7,8]. An alternative and versatile route for generating isothiocyanate for the use in the preparation of disubstituted symmetrical and unsymmetrical thioureas is the reaction of carbon disulfide with either one or two different amines [9].…”