Design, Synthesis, and Molecular Docking of Paracyclophanyl-Thiazole Hybrids as Novel CDK1 Inhibitors and Apoptosis Inducing Anti-Melanoma Agents

Abstract

Three new series of paracyclophanyl-dihydronaphtho[2,3-<i>d</i>]thiazoles and paracyclophanyl-thiazolium bromides were designed, synthesized, and characterized by their spectroscopic data, along with X-ray analysis. One-dose assay results of anticancer activity indicated that <b>3a</b>-<b>e</b> had the highest ability to inhibit the proliferation of different cancer cell lines. Moreover, the hybrids <b>3c</b>-<b>e</b> were selected for five-dose analyses to demonstrate a broad spectrum of antitumor activity without apparent selectivity. Interestingly, <b>series I</b> compounds (<i>Z</i>)-<i>N</i>-substituted-4,9-dihydronaphtho[2,3-<i>d</i>]thiazol-3(2<i>H</i>)-yl)-4'-[2.2]paracyclophanylamide) that are carrying 1,4-dihydronaphthoquinone were more active as antiproliferative agents than their naphthalene-containing congeners (series II: substituted 2-(4'-[2.2]paracyclophanyl)hydrazinyl)-4-(naphth-2-yl)-thiazol-3-ium bromide hybrids) and (series III: 3-(4'-[2.2]paracyclophanyl)amido-2-(cyclopropylamino)-4-(naphth-2-yl)thiazol-3-ium bromide) toward the SK-MEL-5 melanoma cell line. Further antiproliferation investigations of <b>3c</b> and <b>3e</b> on the healthy, normal unaffected SK-MEL-5 cell line indicated their relative safety. Compound <b>3c</b> showed an inhibition of eight isoforms of cyclin-dependent kinases (CDK); however, it exhibited the lowest IC₅₀ of 54.8 nM on CDK1 in comparison to Dinaciclib as a reference. Additionally, compound <b>3c</b> revealed a remarkable downregulation of phospho-Tyr15 with a level (7.45 pg/mL) close to the reference. <b>3c</b> mainly showed cell cycle arrest in the pre-G1 and G2/M phases upon analysis of the SK-MEL-5 cell line. The sequential caspase-3 assay for <b>3c</b> indicated a remarkable overexpression level. Finally, a molecular docking study was adopted to elucidate the binding mode and interactions of the target compounds with CDK1.