Design,synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid

A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by ¹H NMR, ¹³C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC₅₀ values of 0.61 ± 0.07, 0.36 ± 0.05, 12.49 ± 0.08 μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.     

Design,synthesis, anticancer evaluation and docking studies of new pyrimidine derivatives as potent thymidylate synthase inhibitors

Cancer is a perplexing and challenging problem for researchers. In this study, a series of 6-aryl-5-cyano-pyrimidine derivatives were designed, synthesized and evaluated for their anticancer activity against HePG-2, MCF-7 and HCT-116 cell lines. Compounds 2, 3d, 4a-c, 5, 8 and 12 displayed high anticancer activity, comparable to that of 5-fluorouracil. Additionally, those compounds with effective anticancer activity were further assessed for their ability to inhibit thymidylate synthase (TS) enzyme. All the tested compounds demonstrated a marked TS inhibitory activity (33.66–74.98%), with IC₅₀ ranging from 3.89 to 15.74 nM. Moreover, apoptosis studies were conducted on the most potent compound 8, to evaluate its proapoptotic potential. Interestingly, compound 8 induced the level of active caspase 3, and elevated the Bax/Bcl2 ratio 44 folds in comparison to the control. Finally, a molecular docking study was conducted to detect the probable interaction between the active compounds and the thymidylate synthase active site.     

Design,synthesis and biological evaluation of matrine derivatives as potential anticancer agents

Using matrine (1) as the lead compound, a series of new 14-(N-substituted-2-pyrrolemethylene) matrine and 14-(N-substituted-indolemethylene) matrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by ¹H NMR, ¹³C NMR and ESI-MS spectral analyses. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (SMMC-7721, A549 and CNE2). The results revealed that compound A6 and B21 displayed the most significant anticancer activity against three cancer cell lines with IC₅₀ values in range of 3.42–8.05?μM, which showed better activity than the parent compound (Matrine) and positive control Cisplatin. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound A6 and B21 could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. The cell cycle analysis also revealed that compound A6 could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase.     

Design and synthesis of 21-alkynylaryl pregnenolone derivatives and evaluation of their anticancer activity

A series of novel C21-alkynylaryl derivatives of pregnenolone were synthesized and screened for anticancer activity against a panel of seven human cancer cell lines (LNCaP, A549, MCF7, HeLa, A431, HepG2, HT29). The data revealed that these compounds can be potential antitumour agents against the specific cell models. Compound 6f bearing a 2-trifluoromethylphenyl group displayed improved cytotoxicity towards all cancer cell lines used. A431 cells were the most sensitive with derivatives 6e–6h bearing electron withdrawing substituents exhibiting high potency with IC₅₀ values ranging between 2.18 and 0.54 μM and drastic inhibition of the prosurvival PI3K-Akt/PKB pathway.     

Design,synthesis and evaluation of novel levoglucosenone derivatives as promising anticancer agents

A series of levoglucosenone-derived 1,2,3-triazoles and isoxazoles featuring a flexible spacer between the heteroaromatic and anhydropyranose cores have been designed and synthesized following an hetero Michael // 1,3-dipolar cycloaddition path. The use of a design of experiments approach allowed the optimization of the oxa-Michael reaction with propargyl alcohol as nucleophile, a key step for the synthesis of the target compounds. All of the compounds were tested for their anticancer activity on MDA-MB-231 cells, featuring mutant p53. The results highlighted the importance of the introduction of the flexible spacer as well as the higher activity of oxa-Michael isoxazole-derivatives. The most prominent compounds also showed anti-proliferative activities against lung and colon cancer cell lines. The compounds showed enhanced cytotoxic effects in the presence of mutant p53, determined both by endogenous mutant p53 knock down (R280K) and by reintroducing p53 R280K in cells lacking p53 expression.     

Novel thiosemicarbazone chitosan derivatives: Preparation, characterization, and antifungal activity

Three novel thiosemicarbazone chitosan derivatives were obtained via condensation reaction of thiosemicarbazide chitosan with phenylaldehyde, o-hydroxyphenylaldehyde, and p-methoxyphenylaldehyde, respectively. Antifungal activity against the common crop-threatening pathogenic fungi Stemphylium solani weber (S. solani), Rhizoctonia solani Kühn (R. solani), Alternaria solani (A. solani), and Phomopsis asparagi (Sacc.) (P. asparagi) was tested in vitro at 0.05, 0.1, and 0.5 mg/mL. The derivatives had broad-spectrum antifungal activity that was greatly enhanced in comparison with chitosan. In fact, the highest antifungal index reached 100%. At 0.05 mg/mL, the o-hydroxyphenylaldehyde thiosemicarbazone chitosan inhibited growth of R. solani at 52.6%, and was stronger than polyoxin whose antifungal index was found to be 31.5%. The chitosan derivatives described here lend themselves to future applicative studies in agriculture.     

Design,synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity

VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC₅₀ of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 μM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI₅₀) and safety (LC₅₀) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.     

Novel nalidixic acid derivatives targeting topoisomerase II enzyme; Design,synthesis, anticancer activity and effect on cell cycle profile

AimDesign and synthesis of novel nalidixic acid derivatives of potent anticancer and topoisomerase II inhibitory activities were our major aim.Materials & methodsAll the newly synthesized nalidixic acid derivatives were submitted to the National Cancer Institute (NCI), Bethesda, USA and were accepted for single dose screening. Further investigation via IC₅₀ determination of the most potent compound 6a against K-562 and SR leukemia cell lines. Finally, the topoisomerase II inhibitory activity, the cell cycle analysis and molecular docking of 6a were performed in order to identify the possible mechanism of the anticancer activity.ResultsCompound 6a showed interesting selectivity against leukemia especially K-562 and SR subpanels with IC₅₀ 35.29 µM and 13.85 µM respectively. Moreover, compound 6a revealed potent topoisomerase IIα and topoisomerase IIβ inhibitory activity compared with known topoisomerase inhibitors such as doxorubicin and topotecan with IC₅₀ 1.30 µM and 0.017 µM respectively. Cell cycle analysis indicated that compound 6a induced cell cycle arrest at G2-M phase leading to inhibition of cell proliferation and apoptosis. Molecular modeling demonstrated that the potent topoisomerase inhibitory activity of 6a was due to the interaction with the topoisomerase II enzyme through coordinate bonding with the magnesium ion Mg²⁺, hydrogen bonding with Asp 545 and arene cation interaction with His 759.     

Synthesis,anticancer activity and DNA-binding properties of novel 4-pyrazolyl-1,8-naphthalimide derivatives

A novel series of 4-pyrazolyl-1,8-naphthalimide derivatives have been designed and facilely synthesized. For anticancer activity in vitro, most of the compounds were found to be more toxic against human mammary cancer cells (MCF-7) than human cervical carcinoma cells (Hela) and human lung cancer cells (A549). Compounds 4i, 4h, 4b and 4a showed improved cytotoxic activity against MCF-7 cells over amonafide, in particular compounds 4i and 4h, the IC₅₀ values of which against cell lines of MCF-7 were 0.51 μM and 0.79 μM, respectively. The DNA-binding properties of 4i were investigated by UV–vis, fluorescence, and Circular Dichroism (CD) spectroscopies and thermal denaturation. The results indicated that compound 4i as the DNA-intercalating agent exhibited middle binding affinity with CT-DNA.     

Synthesis and anticancer activity of novel amide derivatives of non-acetal deoxoartemisinin

Novel amide derivatives of C-12 non-acetal deoxoartemisinin were synthesized. Some of the derivatives had potent in vitro anticancer activity against major human cancer cell lines. The deoxoartemisinin amide trimer had potent in vivo antiangiogenic activity, according to the mouse matrigel plug assay.     

A novel monoterpenoid indole alkaloid with anticancer activity from Melodinus khasianus

A novel monoterpenoid indole alkaloid with unprecedented 6/5/6/4/6 fused rings, khasuanine A (1), was isolated from the roots of Melodinus khasianus. The structure was determined by extensive analysis of its HR-MS, 1D-, and 2D-NMR spectra. Khasuanine A markedly inhibited the proliferation of PC3 cell with IC₅₀ value of 0.45 μM. Further study showed that khasuanine A was able to induce the apoptosis of PC3 cells by activation of caspase 3 and p53, and by inhibition of Bcl-2.     

Design, synthesis and anticancer activity of novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivatives

On the basis of the chemical structures of psorospermin with a xanthone template and acronycine derivatives with an acridone template, rac-1 and rac-2 constructed on an 1,2-dihydrobenzofuro[4,5-b][1,8]naphthyridin-6(11H)-one scaffold were designed and synthesized as potential anticancer agents. Their anticancer activities were evaluated against five human cancer cell lines. Rac-2 showed similar anticancer activity to doxorubicin and rac-1 exhibited even higher anticancer activity against LNCaP (IC(50)=0.14 μM), DU145 (IC(50)=0.15 μM), PC3 (IC(50)=0.30 μM) and MCF-7 (IC(50)=0.26 μM) cancer lines than doxorubicin and rac-2. Also, rac-1 revealed very potent anticancer activity (IC(50)=0.15 μM) against MCF-7/ADR cell (doxorubicin-resistant breast cancer cell) lines and induced G2/M phase arrest of the cell cycle in MCF-7/ADR cells.     

Design,synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers

Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR^WT; and the most active compounds that showed promising IC₅₀ values against EGFR^WT were tested in vitro for their inhibitory activities against mutant EGFR^T790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC₅₀ values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 µM comparable to that of erlotinib (IC₅₀ ranging from 4.99 ± 0.09 to 13.914 ± 0.36 µM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G₂/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFR^WT and EGFR^T790M.     

Design,synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents

In trying to develop new anticancer agents, a series of 1H-pyrazolo[3,4-b]pyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).     

Synthesis and anticancer activity of novel 9,13-disubstituted berberine derivatives

Novel berberine derivatives with disubstituents on positions C9 and C13 were synthesized and evaluated for antiproliferative activities against human prostate cancer cell lines (PC3 and DU145), breast cancer cell line (MDA-MB-231) and human colon cancer cell lines (HT29 and HCT116). All compounds showed significantly enhanced antiproliferative activities compared with berberine. Notably, compound 18e exhibited the strongest cytotoxicity against PC3 cells with an IC₅₀ value of 0.19 μM, and the highest selectivity index (SI^PC3 > 20). Further studies showed that 18e could arrest the cell cycle at G1 phase, and significantly inhibit tumor cell colony forming and migration even at low concentrations. Interestingly, 18e could significantly induce cytoplasmic vacuolation, suggesting a different mode of action from berberine.     

Design,synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents

In search of new compounds with strong antiproliferative activity and simple molecular structure, we designed a novel series of agents based on the 2-amino-3-alkoxycarbonyl/cyano-5-arylethylthiophene scaffold. The presence of the ethyl spacer between the 2′,5′-dimethoxyphenyl and the 5-position of the thiophene ring, as well as the number and location of methoxy substitutents on the phenyl ring, played a profound role in affecting the antiproliferative activity. Among the synthesized compounds, we identified the 2-amino-3-cyano-[2-(2,5-dimethoxyphenyl)ethyl] thiophene 2c as the most promising derivative against a wide panel of cancer cell lines (IC₅₀ = 17–130 nM). The antiproliferative activity of this compound appears to correlate well with its ability to inhibit tubulin assembly and the binding of colchicine to tubulin. Moreover 2c, as determined by flow cytometry, strongly induced arrest in the G2/M phase of the cell cycle, and annexin-V and propidium iodide staining indicate that cell death proceeds through an apoptotic mechanism that follows the intrinsic mitochondrial pathway.     

Synthesis of novel anticancer iridoid derivatives and their cell cycle arrest and caspase dependent apoptosis

Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery programme on Indian medicinal plants, we isolated arbortristoside-A (1) and 7-O-trans-cinnamoyl 6β-hydroxyloganin (2) from the seeds of N. Arbortristis, which exhibited moderate in vitro anticancer activity. Chemical transformation of 2 led to significant improvement in the activity in derivative 8 and 15 against HepG2 (human hepatocellular carcinoma), MCF-7 (breast adenocarcinoma) cell lines. The compounds 8 and 15 were also capable of cell cycle arrest and caspase dependent apoptosis in HepG2 cell lines. These iridoid derivatives hold promise for developing safer alternatives to the marketed drugs.     

Design,synthesis and biological evaluation of 3,5-diaryl isoxazole derivatives as potential anticancer agents

The present study was carried out in the attempt to synthesize a new class of potential anticancer agents comprising eleven compounds (24–34) sharing the 3,5-diarylisoxazole as a core. The chemical structure of the new synthesized compounds was established by IR, ¹H NMR, ¹³C NMR and elemental analysis. Their biological potential towards prostate cancer was evaluated by using cancer PC3 cells and non-tumorigenic PNT1a cells. Interestingly, compound 26 distinguished from others with a quite high selectivity value that is comparable to 5-FU. The binding mode of 26 towards Ribosomal protein S6 kinase beta-1 (S6K1) was investigated at a molecular level of detail by employing docking simulations based on GLIDE standard precision as well as MM-GBSA calculations.     

Design and synthesis of aminocoumarin derivatives as DPP-IV inhibitors and anticancer agents

DPP-IV “a moonlighting protein” has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100 µM concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC₅₀ value 24 ± 0.1 nM against A549 cell line.     

Design,synthesis, in silico and in vitro evaluation of thiophene derivatives: A potent tyrosine phosphatase 1B inhibitor and anticancer activity

A series of novel methyl 4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate derivatives were designed against the active site of protein tyrosine phosphatise 1B (PTP1B) enzyme using MOE.2008.10. These molecules are also subjected for in silico toxicity prediction studies and considering their corresponding drug scores, it implied that, the molecules are promising as anticancer agents. The designed compounds were synthesized by using suitable methods and characterized. They were subjected to inhibitory activity against PTP1B and in vitro anticancer activity by MTT assay. Most of the tested compounds showed potent inhibitory activity against PTP1B, among the compounds tested, compound 5b exhibited the highest activity (IC₅₀ = 5.25 µM) and remarkable cytotoxic activity at 0.09 µM of IC₅₀ against the MCF-7 cell line. In addition to this, compound 5c also showed potential anticancer activity at 2.22 µM of IC₅₀ against MCF-7 and 0.72 µM against HepG2 cell lines as well as PTP1B inhibitory activity at IC₅₀ of 6.37 µM.