1,2,3Triazole tethered β-lactam-Chalcone bifunctional hybrids: Synthesis and anticancer evaluation (original) (raw)
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Bioorganic & Medicinal Chemistry Letters, 2011
In the chalcone scaffold, it is thought that the double bond is an important structural linker but it is likely not essential for the interaction with tubulin. Yet, it may be a potential site of metabolic degradation and interaction with biological nucleophiles. In this letter, we have replaced this olefinic portion of chalcones with two metabolically stable and chemically inert heterocyclic rings, namely triazole or tetrazole. Yet, our biologic data suggest that, unlike in other antitubulinic structures, the olephinic ring might not be merely a structural linker.
Molecules, 2019
By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine-and quinidinederived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted-and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidineand (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.
Synthesis and characterization of new 1,2,4-triazole anticancer scaffold derivatives: In Vitro study
Egyptian Journal of Chemistry
Four Schiff bases were obtained via one direct click reaction between 3-amino-1H-1,2,4-triazole and different substituted benzaldehyde. The synthesized compounds were characterized on the basis of their spectral data including IR spectra, mass spectroscopy and 1 HNMR. The synthesized compounds were tested against three human cancer cell lines to evaluate their in vitro anticancer activity, and also tested on Vero cells extracted from African green monkey kidney to investigate their side effect. The screening showed that the Schiff bases TB-NO2 and TB-OCH3 produced an effective anticancer activity against HEPG2, HCT-116, and MCF-7 cell lines. Further investigations had been conducted to determine the apoptotic and antifibrotic ability of TB-NO2 and TB-OCH3 on MCF-7 cells by determining the expression of Bax, Bcl-2, CTGF, and PDGF. Results of Bax/Bcl-2 ratio for TB-NO2 and TB-OCH3 confirmed the apoptotic effect of these compounds on MCF-7 cells. The reduction in CTGF and PDGF genes expression confirmed the regulatory effect of these compounds on MCF-7 cells growth.
Molecules
In an effort to improve and achieve biologically active anticancer agents, a novel series of 1,2,3-triazole-containing hybrids were designed and efficiently synthesized via the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of substituted-arylazides with alkyne-functionalized pyrazole-[1,2,4]-triazole hybrids. The structure geometry of these new clicked 1,2,3-triazoles was explored by density functional theory (DFT) using the B3LYP/6-311++G(d,p) level; also, the potential activity of the compounds for light absorption was simulated by time-dependent DFT calculations (TD-DFT). The antitumor impacts of the newly synthesized compounds were in vitro estimated to be towards the human liver cancer cell line (HepG-2), the human colon cancer cell line (HCT-116), and human breast adenocarcinoma (MCF-7). Among the tested compounds, conjugate 7 was the most potent cytotoxic candidate towards HepG-2, HCT-116, and MCF-7, with IC50 = 12.22, 14.16, and 14.64 µM, respectively, in comparis...
In the present study, two important starting materials and 18 new 1,2,4-triazole compounds with mono ring system have been synthesized and characterized. The mono system showed 16 compounds of a Schiff base moiety attached to the triazole ring which was prepared from the corresponding starting material 5(AeB) or piperidinium salt system 6(AeB). All these compounds were characterized using Fourier Transform Infrared (FT-IR) and Nuclear Magnetic Resonance (NMR) spectroscopy and carbon hydrogen nitrogen (CHN) elemental analysis. The compounds were selected for in vitro anticancer study to test the therapeutic cytotoxic potential against cancer cells. The MTT test was conducted against human breast (MCF-7) and colorectal (HCT-116) cancer cells. Among all the compounds tested, 7A-i demonstrated more pronounced in vitro anticancer effect against MCF-7 and HCT-116 cells with IC 50 of 38 and 19.2 mM, respectively, comparable to that of the standard reference drugs, tamoxifen and 5fluorouracil, respectively. Compound 7A-vi showed a considerable cytotoxic effect with IC 50 53 and 41.2 mM against MCF-7 and HCT-116 cells, respectively. Compounds 7A-ii, 7A-iii and 7A-v exhibited moderate cytotoxicity with IC 50 68, 91 and 85 mM, respectively against MCF-7 cells and also 59.3, 81.7 and 137.1 mM against HCT-116 cells, respectively. However, all other compounds tested in this study showed poor cytotoxicity against both the cell lines. Cellular morphological analysis revealed that the cytotoxicity induced by the compounds could probably due to autophagy. It can be concluded that 1,2,4-triazole derivatives can be promising therapeutic agents. Further studies will be done to investigate the antitumor efficacy of the 1,2,4-triazole derivatives using suitable preclinical models.
Synthesis of chalcone-amidobenzothiazole conjugates as antimitotic and apoptotic inducing agents
Bioorganic & Medicinal Chemistry, 2012
A series of chalcone-amidobenzothiazole conjugates (9a-k and 10a,b) have been synthesized and evaluated for their anticancer activity. All these compounds exhibited potent activity and the IC 50 of two potential compounds (9a and 9f) against different cancer cell lines are in the range of 0.85-3.3 lM. Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phase in A549 cell line leading to caspase-3 dependent apoptotic cell death. The tubulin polymerization assay (IC 50 of 9a is 3.5 lM and 9f is 5.2 lM) and immuofluorescence analysis showed that these compounds effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Further, Annexin staining also suggested that these compounds induced cell death by apoptosis. Moreover, docking experiments have shown that they interact and bind efficiently with tubulin protein. Overall, the current study demonstrates that the synthesis of chalcone-amidobenzothiazole conjugates as promising anticancer agents with potent G2/M arrest and apoptotic-inducing activities via targeting tubulin.
Biointerface Research in Applied Chemistry, 2021
1,2,3-triazole skeleton is a privileged building block for the discovery of new promising anticancer agents. In this report, new 1,4-disubstituted 1,2,3-triazoles with the bioisoster triazole moiety were straightforwardly prepared under copper-catalyzed azide-alkyne [3+2] cycloaddition reactions (CuAAC) regime using a variety of both functional organic azides and terminal alkynes. The resulting functional 1,4-disubstituted 1,2,3-triazole compounds were fully characterized and subsequently tested for their antiproliferative activity against four different cancer cell lines. The cytotoxicity tests carried out with these 1,2,3-triazole derivatives show average IC50 values ranging from 15 to 50 µM by comparison with the standard reference drug, namely doxorubicin. The phosphonate 1,2,3-triazole derivative was found to exhibit the best antiproliferative activity among the studied compounds against the HT-1080 cell lines. It was chosen to evaluate its mode of action in these cancer cell l...
Journal of Applied Pharmaceutical Science, 2018
New hybrids of tetrazole moiety with different chalcone derivatives were synthesized. The reaction of these chalcones with hydrazine hydrate resulted in the formation of tetrazole-pyrazoline hybrids. Evaluation of the in vitro antiproliferative activity of all newly synthesized hybrids against three cancer cell lines and Vero-B normal cell line, using MTT-based assay, was performed. Most of the chalcone derivatives exerted superior activity against colon HCT-116 and prostate PC-3 cell lines, in comparison with cisplatin (IC 50 = 20 and 5 µg/ml) and 5-FU (IC 50 = 17.3 and 21.4 µg/ml), respectively. Compound 5a was found to be the most active antiproliferative agent against colon HCT-116 and prostate PC-3 cell lines (IC 50 = 0.6 and 1.6 µg/ml) with high selectivity indices (SI = 6.66 and 2.50), respectively. Compound 8f, in particular, displayed a wider spectrum of activity that included, in addition, excellent effect against breast MCF-7 cell lines with SI = 2.75. The available docking results revealed a good binding of 5b with HDAC2 and CYP17A1 that endorses the in vitro biological activity against the tested colon and prostate cell lines.
Bioorganic & medicinal chemistry letters, 2016
A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ∼6-10μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10μM) that was supported by the docking studies (PLP score 87-94) in silico.