Dihydroquinazolinones as Potential Antiproliferative and Tumor Inhibiting agents (original) (raw)
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European journal of medicinal chemistry, 2014
Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing copper-catalyzed Huisgen 1,3-dipolar cycloaddition ("click" reaction) between an 8-O-alkylated-quinoline containing a terminal alkyne and various aromatic or protected sugar azides. These compounds were evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar derivative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high selectivity toward ovarian cancer cells (OVCAR-03, GI50 < 0.25 μg mL(-1)); this derivative was more active than the reference drug doxorubicin (OVCAR-03, GI50 = 0.43 μg mL(-1)). In structure-activity relationship (SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calculations were performed for the α-glucosidase active site to predict the possible mechanism of action of this series of compounds.
A phenaxazone compound [5H-Benzo[a]phenoxazin-5-one (BP)] along with an aminoquinone[2-[(o-hydroxyphenyl)amino]-1,4-naphthaquinone (HAN)] derivatives were synthesized from lawsone using ultrasound irradiation technique. The structure of the compounds were characterized by elemental analysis and various spectral studies. Optoelectronic properties were studied using Schrodinger material science suit (2015). The compounds exhibit fluorescence emission in longer wave length it may find applications in photodynamic therapy. Single crystal X-ray diffraction studies reveals that the compound BP crystallizes in monoclinic space group. The antioxidant activity of HAN and BP were determined using DPPH radical scavenging assay and the results indicate that both the compounds have good antioxidant capacity, HAN having more scavenging activity than BP. Lead molecules were identified using in silico molecular docking studies as a green chemistry approach. iGEMDOCK, GOLD and Schrödinger softwares were used for these studies. The docking studies reveal that the structural modification of the parent compound gave more active compounds making them promising lead molecules. The lead molecules were subjected to in vitro studies. The cytotoxicity of BP and HAN was studied using human breast cancer (SKBR3) cell lines. The IC 50 value of HAN was found to be 19.8 M while BP was found to have cell viability, less than 10% even at 25 M concentration. The chemotherapeutic agents kill the cancer cells mainly through apoptosis. HAN and BP were subjected to apoptosis studies. BP was found to more active than HAN. Thus it can be suggested that the mechanism of cell death may be through apoptosis.
Scientific Reports, 2022
The anticancer properties of quinolones is a topic of interest among researchers in the scientific world. Because these compounds do not cause side effects, unlike the commonly used cytostatics, they are considered a promising source of new anticancer drugs. In this work, we designed a brief synthetic pathway and obtained a series of novel 8-phenyltetrahydroquinolinone derivatives functionalized with benzyl-type moieties at position 3. The compounds were synthesized via classical reactions such as nucleophilic substitution, solvent lysis, and condensation. Biological evaluation revealed that 3-(1-naphthylmethyl)-4-phenyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (4a) exhibited potent cytotoxicity toward colon (HTC-116) and lung (A549) cancer cell lines. Analysis of the mechanism of action of compounds showed that compound 4a induced cell cycle arrest at the G 2 /M phase, leading to apoptotic cell death via intrinsic and extrinsic pathways. Taken together, the findings of the study suggest that tetrahydroquinolinone derivatives bearing a carbonyl group at position 2 could be potential lead compounds to develop anticancer agents for the treatment of lung cancers. Apoptosis or programmed cell death is a basic physiological process that plays a key role in the maintenance of tissue homeostasis. It is genetically regulated as a normal physiological response to many stimuli and is associated with other processes such as aging and embryogenesis. Disorders in apoptosis mechanisms can lead to various diseases, such as cancers. The disability of cancerous cells to keep up the balance between proliferation and death results in the development of abnormal tissue and formation of solid tumors 1,2. Apoptosis is a double-track mechanism that occurs via extrinsic and intrinsic pathways. The extrinsic pathway involves transmembrane death receptor-mediated interactions, whereas the intrinsic pathway is mediated by mitochondria and starts with the binding of BAX/BAK protein to the mitochondrial membrane leading to the release of cytochrome c 3. Both pathways converge at the same point-caspases-regulated execution. The majority of cytostatic drugs used in anticancer therapy cause burdensome side effects in patients; therefore, there is a constant search for novel chemical compounds that are safe. Quinolones are a family of compounds characterized by antibacterial properties. However, research indicates that some of them exhibit potential anticancer properties, especially apoptosis activation. It has been proven that ciprofloxacin, which is the most active fluoroquinolone, can activate apoptosis in breast, bladder, and prostate cancers, colorectal carcinoma, and melanoma. At the molecular level, this chemotherapeutic causes an adverse increase in the concentration of BAX protein which results in differences in the BAX:BCL-2 ratio. It also enhances the expression of p53 protein and activation of caspases 4-8. Another fluoroquinolone, enoxacin, also works by activating apoptosis. It has been shown that programmed cell death is induced in prostate cancer by a significant increase in CASP3 mRNA and cleaved PARP expression as well as mitochondrial depolarization 9. Levofloxacin, which is also a fluoroquinolone, induces apoptosis in breast and lung cancer through a caspase-dependent pathway and mitochondrial disfunction 10. Obviously, several wellknown chemotherapeutic agents from the quinolone family display anticancer properties 11. One of the newer quinolones, voreloxin, which is currently in clinical trials for the treatment of acute myeloid leukemia, shows a high affinity to eukaryotic type II topoisomerase and induces apoptosis through double-strand DNA breaks. Because the stable quinolone core is characterized by a favorable toxicity profile, voreloxin does not generate
Anticancer Potential of 3-(Arylideneamino)-2-Phenylquinazoline-4(3H)-One Derivatives
Different quinazoline derivatives have showed wide spectrum of pharmacological activities. Some 3-(arylideneamino)-phenylquinazoline-4(3H)-ones have been reported to possess antimicrobial activity. The present study has been undertaken to evaluate the anticancer effect of these quinazolinone derivatives. The quinazolinone derivatives were synthesized as reported earlier. Compounds containing NO 2 , OH, OCH 3 , or OH and OCH 3 as substituent(s) on the arylideneamino group were named as P(3a), P(3b), P(3c), and P(3d) respectively. Out of these, P(3a) and P(3d) showed better cytotoxic activity than P(3b) and P(3c) on a panel of six cancer cell lines of different origin, namely, B16F10, MiaPaCa-2, HCT116, HeLa, MCF7, and HepG2, though the effect was higher in B16F10, HCT116, and MCF7 cells. P(3a) and P(3d) induced death of B16F10 and HCT116 cells was associated with characteristic apoptotic changes like cell shrinkage, nuclear condensation, DNA fragmentation, and annexin V binding. Also, cell cycle arrest at G1 phase, alteration of caspase-3, caspase-9, Bcl-2 and PARP levels, loss of mitochondrial membrane potential, and enhanced level of cytosolic cytochrome c were observed in treated B16F10 cells. Treatment with multiple doses of P(3a) significantly increased the survival rate of B16F10 tumor bearing BALB/c mice by suppressing the volume of tumor while decreasing microvascular density and mitotic index of the tumor cells.
Cytotoxic potential of novel 6,7-dimethoxyquinazolines
European Journal of Medicinal Chemistry, 2012
Herein, we report the synthesis and cytotoxicity of a series of substituted 6,7-dimethoxyquinazoline derivatives. The cytotoxic activity of all synthesized compounds has been evaluated against HCT116p53 þ/þ and HCT116p53 À/À colon cancer cells and a HEY ovarian cancer cell line naturally resistant to cisplatin. Nine of the tested compounds showed significant cytotoxicity in all cell lines at 10 mM. The most promising derivative (7c) showed IC 50 values of 0.7 and 1.7 mM in the two colon cancer cell lines.
Journal of Medicinal Chemistry, 2008
Experimental of Intermediates S2 Caspase activation assay (EC 50) S3 Cell growth inhibition assays (GI 50) S4 Tubulin inhibition assay S5 Colchicine binding competition assay S5 MX-1 and PC-3 tumor models S6 Determination of brain to plasma AUC S6 Appendix. Elemental analysis and HPLC for the target compounds S8 S2 Experimental of intermediates 2-Chloro-N-(4-ethoxyphenyl)quinazolin-4-amine (6c). Compound 6c was prepared from 3a and 4-ethoxyaniline and was isolated as a solid (32%). 1 H NMR (CDCl 3) 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 7.03 (m, 1H), 6.73 (m, 3H), 4.09 (q, J = 7.2, 2H), 1.49 (t, J = 7.2, 3H). 2-Chloro-N-(4-phenoxyphenyl)quinazolin-4-amine (6d). Compound 6d was prepared from 3a and 4-phenoxyaniline, and was isolated as an off white powder (95%). 1 H NMR (CDCl 3) 7.78-7.87 (m, 3H), 7.68-7.74 (m, 2H), 7.60 (s, broad, 1H), 7.56 (ddd, J = 12.0, 9.9 and 3.3, 1H), 7.33-7.39 (m, 2H), 7.03-7.16 (m, 5H). 2-Chloro-N-(3-methoxyphenyl)quinazolin-4-amine (6e). Compound 6e was prepared from 3a and 3-methoxyaniline and was isolated as a solid (80%). 1 H NMR (CDCl 3) 7.79-7.87 (m, 3H), 7.54-7.62 (m, 3H), 7.20-7.35 (m, 3H), 6.76 (dd, J = 8.4 and 2.1, 1H), 3.87 (s, 3H). 2-Chloro-N-(2-methoxyphenyl)quinazolin-4-amine (6f). Compound 6f was prepared from 3a and 2-methoxyaniline and was isolated as a solid (35%). 1 H NMR (CDCl 3) 8.76-8.79 (m, 1H), 8.50 (s, broad, 1H), 7.77-7.88 (m, 3H), 7.54-7.59 (m, 1H), 7.09-7.13 (m, 2H), 6.95-6.99 (m, 2H), 4.00 (s, 3H). 2-Chloro-N-(3,4-dimethoxyphenyl)quinazolin-4-amine (6g). Compound 6g was prepared from 3a and 3,4-dimethoxyaniline, and was isolated as an off white powder (83%). 1 H NMR (CDCl 3) 7.77-7.86 (m, 3H), 7.51-7.60 (m, 3H), 7.12 (dd, J = 8.4 and 2.4, 1H), 6.90 (d, J = 8.4, 1H), 3.94 (s, 3H), 3.91 (s, 3H). 2-Chloro-N-(2,3-dimethoxyphenyl)quinazolin-4-amine (6h). Compound 6h was prepared from 3a and 2,3-dimethoxyaniline and was isolated as solids (84%). 1 H
Synthesis of some novel dibromo-2-arylquinazolinone derivatives as cytotoxic agents
Research in Pharmaceutical Sciences, 2019
Recently the quinazoline derivatives have attracted much attention for their anticancer properties. In this study a series of new brominated quinazoline derivatives (1a-1g) were synthesized in two steps. In the first step we used N-bromosuccinimide to brominate the anthranilamid. Then in the second step we closed the quinazoline ring by different aromatic aldehydes. Our aldehydes contain different electron donating or electron withdrawing groups at different positions of the aromatic ring. The chemical structures of products were confirmed by spectroscopic methods such as IR, 1 HNMR, 13 CNMR, and mass spectroscopy. The cytotoxic activities of the compounds were assessed on three cancerous cell lines including MCF-7, A549, and SKOV3 using colorimetric MTT cytotoxic assay in comparison with cisplatin as a standard drug. Our results collectively indicated that 1f and 1g, exhibited the best anti-proliferative activities on three investigated cancerous cell lines.
Journal of Medicinal Chemistry, 2009
As a continuation of our structure-activity relationship (SAR) studies on 4-anilinoquinazolines as potent apoptosis inducers and to identify anticancer development candidates, we explored the replacement of the 2-Cl group in our lead compound 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (6b, EP128265, MPI-0441138) by other functional groups. This SAR study and lead optimization resulted in the identification of N-(4-methoxyphenyl)-N,2-dimethylquinazolin-4-amine (6h, EP128495, MPC-6827) as an anticancer clinical candidate. Compound 6h was found to be a potent apoptosis inducer with EC 50 of 2 nM in our cell-based apoptosis induction assay. It also has excellent blood brain barrier penetration, and is highly efficacious in human MX-1 breast and other mouse xenograft cancer models.
Journal of Medicinal Chemistry, 2008
Experimental of Intermediates S2 Caspase activation assay (EC 50) S3 Cell growth inhibition assays (GI 50) S4 Tubulin inhibition assay S5 Colchicine binding competition assay S5 MX-1 and PC-3 tumor models S6 Determination of brain to plasma AUC S6 Appendix. Elemental analysis and HPLC for the target compounds S8 S2 Experimental of intermediates 2-Chloro-N-(4-ethoxyphenyl)quinazolin-4-amine (6c). Compound 6c was prepared from 3a and 4-ethoxyaniline and was isolated as a solid (32%). 1 H NMR (CDCl 3) 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H), 7.03 (m, 1H), 6.73 (m, 3H), 4.09 (q, J = 7.2, 2H), 1.49 (t, J = 7.2, 3H). 2-Chloro-N-(4-phenoxyphenyl)quinazolin-4-amine (6d). Compound 6d was prepared from 3a and 4-phenoxyaniline, and was isolated as an off white powder (95%). 1 H NMR (CDCl 3) 7.78-7.87 (m, 3H), 7.68-7.74 (m, 2H), 7.60 (s, broad, 1H), 7.56 (ddd, J = 12.0, 9.9 and 3.3, 1H), 7.33-7.39 (m, 2H), 7.03-7.16 (m, 5H). 2-Chloro-N-(3-methoxyphenyl)quinazolin-4-amine (6e). Compound 6e was prepared from 3a and 3-methoxyaniline and was isolated as a solid (80%). 1 H NMR (CDCl 3) 7.79-7.87 (m, 3H), 7.54-7.62 (m, 3H), 7.20-7.35 (m, 3H), 6.76 (dd, J = 8.4 and 2.1, 1H), 3.87 (s, 3H). 2-Chloro-N-(2-methoxyphenyl)quinazolin-4-amine (6f). Compound 6f was prepared from 3a and 2-methoxyaniline and was isolated as a solid (35%). 1 H NMR (CDCl 3) 8.76-8.79 (m, 1H), 8.50 (s, broad, 1H), 7.77-7.88 (m, 3H), 7.54-7.59 (m, 1H), 7.09-7.13 (m, 2H), 6.95-6.99 (m, 2H), 4.00 (s, 3H). 2-Chloro-N-(3,4-dimethoxyphenyl)quinazolin-4-amine (6g). Compound 6g was prepared from 3a and 3,4-dimethoxyaniline, and was isolated as an off white powder (83%). 1 H NMR (CDCl 3) 7.77-7.86 (m, 3H), 7.51-7.60 (m, 3H), 7.12 (dd, J = 8.4 and 2.4, 1H), 6.90 (d, J = 8.4, 1H), 3.94 (s, 3H), 3.91 (s, 3H). 2-Chloro-N-(2,3-dimethoxyphenyl)quinazolin-4-amine (6h). Compound 6h was prepared from 3a and 2,3-dimethoxyaniline and was isolated as solids (84%). 1 H
Molecules
A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen speci...