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-d]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 3a–e had the highest ability to inhibit the proliferation of different cancer cell lines. Moreover, the hybrids 3c–e were selected for five-dose analyses to demonstrate a broad spectrum of antitumor activity without apparent selectivity. Interestingly, series I compounds (Z)-N-substituted-4,9-dihydronaphtho[2,3-d]thiazol-3(2H)-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 3c and 3e on the healthy, normal unaffected SK-MEL-5 cell line indicated their relative safety. Compound 3c 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 3c revealed a remarkable downregulation of phospho-Tyr15 with a level (7.45 pg/mL) close to the reference. 3c 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 3c 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.

Thiazole Ring—A Biologically Active Scaffold

“…Based on the data from the literature [138][139][140] as well as on their previous results [141], Aly et al [142] designed and synthesized a novel series of derivatives incorporating three bioactive entities such as 1,4 dihydronapthoquinone, thiazole, and [2.2] In order to elucidate the potential mechanism of action of synthesized compounds, the docking studies were carried out against three potential targets, protein kinases CLK1 (5 × 8I), EGFR (2J5F), and tubulin (1SA0). The best docking score was found against CLK1 and binding energy (−9.264 to −8.794 kcal/mol) and was in accordance with anticancer activity.…”

“…Based on the data from the literature [138][139][140] as well as on their previous results [141], Aly et al [142] designed and synthesized a novel series of derivatives incorporating three bioactive entities such as 1,4 dihydronapthoquinone, thiazole, and [2.2] paracyclophane in the frame of one molecule 88a-e, 89a-d, 90 (Figure 35). Compounds 88a-e displayed the highest inhibition of proliferation of different cancer cell lines, showing a broad spectrum of anticancer activity against nine tumor subpanels in an in vitro five dose full NCI 60-cell panel assay.…”

Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets

“…The ability of a bioactive compound to quench activities that lead to abnormal cell growth has been applied in the treatment of inflammatory-related diseases. Five highly reactive naphthoquinones ( 89 – 93 ) investigated by Aly et al showed promising anti-tumor activity via cell cycle arrest in the pre-G1 and G2/M phases and downregulation of cyclin-dependent kinases (CDK) [ 136 ]. Three of them, 91 – 93 were found to be strong inhibitors of cyclic dependent kinases with 91 being the most potent.…”

“…Three of them, 91 – 93 were found to be strong inhibitors of cyclic dependent kinases with 91 being the most potent. Compound 91 attenuated eight isoforms of CDK and phosphor-tyr15 and also induced apoptosis and cell cycle arrest by downregulating pre-G1 and G2/M phases, respectively [ 136 ].…”

Efficient Synthesis of Various Substituted (Thio)Ureas, Semicarbazides, Thiosemicarbazides, Thiazolidones, and Oxadiazole Derived from [2.2]Paracyclophane

“… 6 Among the following three assigned series I − III of the synthesized paracyclophanyl-heterocycles ( Figure 1 ), series I having 1,4-dihydronaphthoquinone, was found as more active as antiproliferative agents than their naphthalene-containing congeners (series II and III) toward the SK-MEL-5 melanoma cell line. 6 …”