Styryl-N-phenyl-N′-(2-chloroethyl)ureas and styrylphenylimidazolidin-2-ones as new potent microtubule-disrupting agents using combretastatin A-4 as model

Abstract

Combretastatin A-4 (CA-4) is a well-studied and attractive molecular template to develop new antimitotics. Several thousand of modifications were performed on the ring B and the ethenyl bridge of CA-4 but only a few involved the trimethoxyphenyl moiety (TMP, ring A) often considered essential to the antiproliferative and antimicrotubule activities. In this study, we described the design, the preparation, the characterization and the biological evaluation of three new series of CA-4 analogs namely styryl-N-phenyl-N'-ethylureas (SEUs), styryl-N-phenyl-N'-(2-chloroethyl)ureas (SCEUs) and styrylphenylimidazolidin-2-ones (SIMZs) bearing a 3-Cl (series a), 3,5-Me (series b) and TMP (series c) substituents, respectively. All SCEU and SIMZ Z-isomers were active in the high and the low nanomolar range, respectively. Conversely to SEUs and their E-isomers that were significantly less active or inactive. Interestingly, the TMP moiety is giving rise to derivatives exhibiting the lowest antiproliferative activity in the SCEU series (10c) and the most active compound in the SIMZ series (12c). Moreover, SIMZ Z-isomers bearing either a 3-Cl (12a) or a 3,5-Me (12b) exhibited antiproliferative activities that are also in the same order of magnitude as 12c. All SCEU and SIMZ Z-isomers also arrested the cell cycle progression in G2/M phase, bound to the colchicine-binding site and disrupted the cytoskeleton of cancer cells. In addition to the promising and innovative microtubule-disrupting properties of SCEUs and SIMZs, these results show that the TMP moiety is not essential for the cytocidal activity of these new CA-4 analogs.

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

“…In order to evaluate whether 28 directly binds to tubulin at the colchicine binding site, we carried out a competition assay with N , N ′-ethylene-bis(iodoacetamide) (EBI) in MGC-803 cells as described in a previously published paper 47 . EBI was an alkylating agent that cross-links the Cys239 and the Cys354 residues of β -tubulin involved in the colchicine-binding site, forming a EBI: β -tubulin adduct 48 .…”

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

“…Gagné-Boulet et al obtained novel derivatives of 1-(4-(phenylthio)phenyl)imidazolidin-2-one [ 129 ]. The imidazolidin-2-one scaffold was selected based on previous studies, and the sulfonate moiety from previous studies was replaced with a thioether linker [ 130 ]. Compound (54) exhibited the highest activity against melanoma cell line M21 with an IC 50 = 0.2 ± 0.1 µM.…”

Novel Trifluoromethylcoumarinyl Urea Derivatives: Synthesis, Characterization, Fluorescence, and Bioactivity

“…Ureas are very important compounds in organic chemistry because of their extensive applications in medicine and agriculture. The substituted ureas exhibit diversified medicinal activities such as antimicrobial [ 1 ], antiviral [ 2 ], anti-HIV [ 3 ], anti-AIDS [ 4 ], anti-malaria [ 5 ], anti-proliferative [ 6 ], antitumor [ 7 ], anticancer [ 8 ], anti-inflammatory [ 9 ], anti-ulcerogenic [ 10 ], anticonvulsant [ 11 ], anti-nociceptive [ 12 ], antihypertensive [ 9 ], antidepressant [ 13 ], complement inhibition [ 14 ], HDL-elevating [ 15 ], and inhibition of nitric oxide [ 16 ]. Urea compounds also possess a broad spectrum of pesticidal activities, such as benzoylurea type insecticides (Diflubenzuron, Chlorbenzuron, etc.)…”