New Paracyclophanylthiazoles with Anti-Leukemia Activity : Design, Synthesis, Molecular Docking, and Mechanistic Studies

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Aly , A A , Bräse , S , Hassan , A A , Mohamed , N K , Abd El-Haleem , L E , Nieger , M , Morsy , N M & Abdelhafez , E M N 2020 , ' New Paracyclophanylthiazoles with Anti-Leukemia Activity : Design, Synthesis, Molecular Docking, and Mechanistic Studies ' , Molecules , vol. 25 , no. 13 , 3089 . https://doi.org/10.3390/molecules25133089

Title: New Paracyclophanylthiazoles with Anti-Leukemia Activity : Design, Synthesis, Molecular Docking, and Mechanistic Studies
Author: Aly, Ashraf A.; Bräse, Stefan; Hassan, Alaa A.; Mohamed, Nasr K.; Abd El-Haleem, Lamiaa E.; Nieger, Martin; Morsy, Nesrin M.; Abdelhafez, Elshimaa M. N.
Contributor: University of Helsinki, Department of Chemistry
Date: 2020-07
Language: eng
Number of pages: 30
Belongs to series: Molecules
ISSN: 1420-3049
URI: http://hdl.handle.net/10138/318499
Abstract: A new series of methyl 2-(2-(4 '-[2.2]paracyclophanyl)-hydrazinylidene)-3-substituted-4-oxothiazolidin-5-ylidene)acetates3a-fwere synthesized from the reaction of paracyclophanyl-acylthiosemicarbazides2a-fwith 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 compounds3a-fwere screened against 60 cancer cell lines. They displayed anticancer activity against a leukemia subpanel, namely, RPMI-8226 and SR cell lines. The activity of compound3awas 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 GI(50)and total growth inhibition (TGI) levels, respectively. Accordingly, compound3aunderwent 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 mu M against RPMI-8226 and SR cell lines, respectively. It also revealed a remarkable tubulin inhibitory activity, compared to colchicine with IC50 = 4.97 mu M/mL. Caspase-3, BAX, and Bcl-2 assays for3ausing 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 beta-tubulin indicate that most of the tested compounds illustrated good binding at the colchicine binding site of the enzyme, especially for compound3a, which made several interactions better than that of the reference colchicine.
Subject: paracyclophanes
NMR
X-ray
NCI-60
cancer cell lines
mechanism
docking
CELL-CYCLE
HETEROCYCLES
DERIVATIVES
DISCOVERY
THIAZOLE
TUBULIN
CANCER
116 Chemical sciences
1182 Biochemistry, cell and molecular biology
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