Abstract
A new series of methyl 2-(2-(4′-[2.2]paracyclophanyl)-hydrazinylidene)-3-substituted-4-oxothiazolidin-5-ylidene)acetates 3a–f were synthesized from the reaction of paracyclophanyl-acylthiosemicarbazides 2a–f with dimethyl acetylenedicarboxylate. Based upon nuclear magnetic resonance (NMR), infrared (IR), and mass spectra (HRMS), the structure of the obtained products was elucidated. X-ray structure analysis was also used as unambiguous tool to elucidate the structure of the products. The target compounds 3a–f were screened against 60 cancer cell lines. They displayed anticancer activity against a leukemia subpanel, namely, RPMI-8226 and SR cell lines. The activity of compound 3a was found as the most cytotoxic potency against 60 cancer cell lines. Consequently, it was selected for further five doses analysis according to National Cancer Institute (NCI) protocol. The cytotoxic effect showed selectivity ratios ranging between 0.63 and 1.28 and between 0.58 and 5.89 at the GI50 and total growth inhibition (TGI) levels, respectively. Accordingly, compound 3a underwent further mechanistic study against the most sensitive leukemia RPMI-8226 and SR cell lines. It showed antiproliferation with IC50 = 1.61 ± 0.04 and 1.11 ± 0.03 µM against RPMI-8226 and SR cell lines, respectively. It also revealed a remarkable tubulin inhibitory activity, compared to colchicine with IC50 = 4.97 µM/mL. Caspase-3, BAX, and Bcl-2 assays for 3a using annexin V-FITC staining revealed significant pro-apoptotic activity. Furthermore, multidrug-resistant leukemia SR cells were used to show better resistance indices (1.285 ng/mL, 1.15-fold) than the reference. Docking studies with β-tubulin indicate that most of the tested compounds illustrated good binding at the colchicine binding site of the enzyme, especially for compound 3a, which made several interactions better than that of the reference colchicine.
Highlights
IntroductionGreat deal of attention focused incorporation into heterocyclic and/or polymer chemistry
Cyclophane chemistry is rapidly growing in the field of stereoselective synthesis with its Cyclophane is and/or rapidlypolymer growingchemistry in the field ofAstereoselective synthesisis with its incorporation intochemistry heterocyclic great deal of attention focused incorporation into heterocyclic and/or polymer chemistry great deal of attention is focused on developing new synthetic tools for synthesizing functionalized [2.2]paracyclophanes
The synthesis and application of heterocycles based on [2.2]paracyclophane [10,11] can be organized into five structural application of heterocycles based on [2.2]paracyclophane can
Summary
Great deal of attention focused incorporation into heterocyclic and/or polymer chemistry. A great deal of attention is focused on developing new synthetic tools for synthesizing functionalized [2.2]paracyclophanes. Substituted [2.2]paracyclophanes can alsotools serve chiral templates and/or as [2.2]paracyclophanes. The synthesis and [2.2]paracyclophanes can serve as chiral templates and/or as auxiliaries [9]. The synthesis and application of heterocycles based on [2.2]paracyclophane [10,11] can be organized into five structural application of heterocycles based on [2.2]paracyclophane [10,11]. I), heterocycle by classes (Figure heterocycle derived by paracyclophanyl (type I), heterocycle derived by bridge II),1): heterocycle fused to ethano bridge (type III), group fused heterocycle to the benzene moiety bridgeIV),
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