Docking study, in vitro anticancer screening and radiosensitizing evaluation of some new fluorine-containing quinoline and pyrimidoquinoline derivatives bearing a sulfonamide moiety (original) (raw)
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European Journal of Medicinal Chemistry, 2010
Sulfonamide bearing compounds posses many types of biological activities and have recently been reported to show substantial antitumor activity in vitro and/or in vivo. There are a variety of mechanisms for the anticancer activity, and the most prominent mechanism is the inhibition of carbonic anhydrase (CA) isozymes. The present work reports the synthesis of twenty novel quinoline and pyrimido[4,5-b] quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for CA inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 6, 9 and 18 showed IC 50 values (72.9 mM, 72.1 mM and 71.9 mM, respectively) comparable to that of the reference drug doxorubicin (IC 50 ¼ 71.8 mM). On the other hand, compound 8 exhibited better activity than doxorubicin with an IC 50 value of 64.5 mM. Additionally, the most potent compounds 8 and 18 were evaluated for their ability to enhance the cell killing effect of g-radiation.
IOSR Journals , 2019
New classes of quinoline derivatives 2a, b, 7a, b, diazepine derivatives 3a, b, 8a, b, pyrimidine derivatives 4a, b, 5a, b; 6 had been synthesized, via reactions between visnagine carbaldehyde 1 and different reagents. The structures of the products were elucidated by spectra and elemental analyses. In the present work, the derivative products have been tested, along with reference compounds, for their cytotoxic potential against two tumor cell lines. The anticancer activity results indicated that the products 3b, 5b and 7b showed growth inhibition activity against HEPG2 cell line and products 4b, 6, and 8a showed growth inhibition activity against MCF-7. Moreover, we attempted an in-silico approach to gain insights into their binding modes against cyclin-dependent protein kinase 2 (CDK-2) which is involved in cell cycle, and receptor protein B-cell lymphoma 2 (BCL-2) which is involved in cell apoptosis. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that compound 4b was the best docked ligand against both targets, as it displayed the lowest binding energy, and critical hydrogen bonds and hydrophobic interactions with the targets.
Bioorganic & Medicinal Chemistry, 2013
Here, we investigate 28 structurally new sulfonamides and their subsequent testing for enzyme inhibition of cytosolic and tumor-associated carbonic anhydrases (CAs, EC 4.2.1.1). The compounds showed very potent inhibition of four physiologically relevant human (h) CA isoforms, namely hCA I, II, IX and XII. Interestingly, the K I values were in the nanomolar range for the tumor-associated hCA IX and hCA XII. Docking studies have revealed details regarding the very favorable interactions between the scaffolds of this new class of inhibitors and the active sites of the investigated CA isoforms. As there are reported cases of tumors overexpressing both CA II and IX, such potent inhibitors for the two isoforms as those detected in this work, may have applications for targeting more than one CA present in tumors.
European Journal of Medicinal Chemistry, 2010
It has been reported that aryl/heteroaryl sulfonamide compounds may act as anticancer agents through a variety of mechanisms and the most prominent of these mechanisms is through the inhibition of carbonic anhydrase isozymes. The present work reports the possible utility of 4-(cyclohexenylamino) benzenesulfonamide in the synthesis of some novel 4-(quinolin-1-yl)benzenesulfonamide derivatives 6aeu. The structures of these compounds were confirmed by elemental analyses, IR, 1 H NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in vitro anticancer activity. Some compounds showed interesting in vitro anticancer activities when compared with doxorubicin as a reference drug. In addition, docking of the synthesized compounds into carbonic anhydrase isozyme II (CA II) active site was performed in order to give a suggestion about the proposed mechanism of action.
Due to your efforts diligent on quinoline nucleus new series containing pyrimido [4, 5-b] quinoline were synthesized via starting with the strategic 2-aminoquinoline-3-carbonitrile (2) intermediates to afford various pyrimido [4, 5-b] quinoline via cyclization with different reagents to get compounds 3-24. Compounds 3, 6, 9a, 9b, 12, 15, 16a, 16b, 17, 21 and 24 were tested for in vitro antitumor activity against human breast carcinoma (MCF-7) cell line, We found what we were hoping for where compound 6 was found the most active member (IC50= 48.54 μM) than the Doxorubicin as a reference drug with (IC50= 71.80 μM). To understand the interaction of binding sites with the target protein receptor, the docking study was performed using topoisomerase II. The results of in vitro cancer activity and docking study revealed that the synthesized compounds have potential cancer activity and can be further optimized and developed as a lead compound.
European journal of medicinal chemistry, 2017
In order to obtain novel Human carbonic anhydrase IX (CAIX) inhibitors, a series of pyridine-thiazolidinone derivatives was synthesized and characterized by various spectroscopic techniques. The binding affinity of the compounds was measured by fluorescence binding studies and enzyme inhibition activity using esterase assay of CAIX. It was observed that compound 8 and 11 significantly inhibit the CAIX activity with the IC50 value, 1.61 μM and 1.84 μM, respectively. The binding-affinity of compound 8 and 11 for CAIX was significantly high with their KD values 11.21 μM and 2.32 μM, respectively. Docking studies revealed that compound 8 and 11 efficiently binds in the active site cavity of CA IX by forming sufficient numbers of H-bonds and van der Waals interactions with active side residues. All the compounds were further screened in vitro for anticancer activity and found that compound 8 and 11 exhibit considerable anticancer activity against MCF-7 and HepG-2 cell lines. All these fi...
Bioorganic & Medicinal Chemistry, 2010
Recent evidences suggest that cancer treatment based on combination of cytostatic and conventional chemostatic therapeutics, which are usually cytotoxic, can provide an improved curative option. On the sequence of our previous work on methotrexate (MTX) derivatives, we have developed and evaluated novel MTX analogues, containing a pteridine moiety conjugated with benzenesulfonamide derivatives, thus endowed with the potential capacity for dual inhibition of dihydrofolate reductase (DHFR) and carbonic anhydrases (CA). These enzymes are often overexpressed in tumors and are involved in two unrelated cellular pathways, important for tumor survival and progression. Their simultaneous inhibition may turn beneficial in terms of enhanced antitumor activity. Herein we report the design and synthesis of several diaminopteridine-benzenesulfonamide and-benzenesulfonate conjugates, differing in the nature and size of the spacer group between the two key moieties. The inhibition studies performed on a set of CAs and DHFR, revealed the activities in the low nanomolar and low micromolar ranges of concentration, respectively. Some inhibitors showed selectivity for the tumor-related CA (isozyme IX). Cell proliferation assays using two tumor cell lines (the non-small cell lung carcinoma, A549, and prostate carcinoma, PC-3) showed activities only in the millimolar range. Nevertheless, this fact points out the need of improving the cell intake properties of these new compounds, since the general inhibitory profiles revealed their potential as anticancer agents.
International Journal of Molecular Sciences, 2020
A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2–233 nM) and VII (KIs in the range of 2.3–350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3–1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62–0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode dr...
Design, synthesis, and docking study of new quinoline derivatives as antitumor agents
Archiv der Pharmazie, 2019
New quinolines substituted with various heterocycles and chalcone moieties were synthesized and evaluated as antitumor agents. All the synthesized compounds were in vitro screened against 60 human cancer cell lines. Compound 13 showed the highest cytotoxicity toward 58 cell lines, exhibiting distinct growth inhibition values (GI 50) against the majority of them, including SR, HL-60 (TB) strains (leukemia), and MDA-MB-435 strains (melanoma), with GI 50 values of 0.232, 0.260, and 0.300 µM, respectively. It exhibited great selectivity toward cancer cell lines, with less toxic effect against normal cells represented by skin fibroblast (BJ) and breast epithelial cell lines (MCF-10F). The enzyme inhibitory activity of compound 13 was evaluated against topoisomerase 1 (Topo 1), epidermal growth factor receptor and vascular endothelial growth factor receptor 2, where it displayed worthy Topo 1 inhibition activity with an IC 50 value of 0.278 µM compared with camptothecin as a reference drug (IC 50 0.224 µM). Docking studies were performed to investigate the recognition profile of compound 13 with the Topo 1 enzyme binding site.
Bioorganic & Medicinal Chemistry Letters, 2004
A series of benzenesulfonamide derivatives incorporating triazine moieties in their molecules was obtained by reaction of cyanuric chloride with sulfanilamide, homosulfanilamide, or 4-aminoethylbenzenesulfonamide. The dichlorotriazinyl-benzenesulfonamides intermediates were subsequently derivatized by reaction with various nucleophiles, such as water, methylamine, or aliphatic alcohols (methanol and ethanol). The library of sulfonamides incorporating triazinyl moieties was tested for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic hCA I and II, and the transmembrane, tumorassociated hCA IX. The new compounds reported here inhibited hCA I with K I s in the range of 75-136 nM, hCA II with K I s in the range of 13-278 nM, and hCA IX with K I s in the range of 0.12-549 nM. The first hCA IX-selective inhibitors were thus detected, as the chlorotriazinyl-sulfanilamide and the bis-ethoxytriazinyl derivatives of sulfanilamide/homosulfanilamide showed selectivity ratios for CA IX over CA II inhibition in the range of 166-706. Furthermore, some of these compounds have subnanomolar affinity for hCA IX, with K I s in the range 0.12-0.34 nM. These derivatives are interesting candidates for the development of novel unconventional anticancer strategies targeting the hypoxic areas of tumors. Clear renal cell carcinoma, which is the most lethal urologic malignancy and is both characterized by very high CA IX expression and chemotherapy unresponsiveness, could be the leading candidate of such novel therapies.