Development of New IDO Inhibitors with Coumarin Pyrimidine Scaffolds as the Potential Anti Cancer Agents

2020 ◽  
Vol 16 (8) ◽  
pp. 1172-1180
Author(s):  
Radhika Chelamalla ◽  
Ajitha Makula
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Mtt Assay ◽  
Human Cancer ◽  
Docking Studies ◽  
Cytotoxic Agents ◽  
Ongoing Research ◽  
Human Cancer Cell Lines ◽  
Ic50 Values

Background: Progress in the developments of pyrimidine-coumarin moiety as an IDO inhibitor is still continuing with an outcome of the good scaffold as pyrimidine as well as coumarin individually for anticancer activity. Hence we proposed a suitable approach for the synthesis of pyrimidinecoumarin moieties in a combined form from the results of docking studies. Objective: As part of our ongoing research towards the development of novel cytotoxic agents, the synthesis and cytotoxic activity of a series of N'-(1-(6-methyl-2-oxo/thioxo-4-sub phenyl-1,2,3,4- tetrahydropyrimidin-5-yl)vinyl)-2-oxo-2H-chromene-3-carbohydrazide derivatives are discussed in this study. Methods: N'-(1-(6-methyl-2-oxo/thioxo-4-sub phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)vinyl)-2-oxo- 2H-chromene-3-carbohydrazide derivatives were designed, synthesized and evaluated for cytotoxic activity. The structures were confirmed by IR, 1H NMR, C13NMR, Mass spectroscopy. All the synthesized compounds were evaluated using in vitro MTT assay against HeLa and HepG2 cell lines. Results: Compound 6g showed inhibitory activity against IDO with IC50 values at nanomolar range in docking studies and compounds 6g and 6f also showed significant cytotoxic activity on human cancer cell lines like HepG2 and HeLa using in vitro MTT assay. Conclusion: This work showed that the coumarin containing pyrimidine derivatives are found to be the most potent against IDO through docking studies and cytotoxic against cell lines compared with cisplatin. This might give the information for the development of new series of compounds against IDO.

Novel Pyrazolo[3,4-d]pyrimidines as Potential Cytotoxic Agents: Design, Synthesis, Molecular Docking and CDK2 Inhibition

2019 ◽  
Vol 19 (11) ◽  
pp. 1368-1381
Author(s):  
Mai Maher ◽  
Asmaa E. Kassab ◽  
Ashraf F. Zaher ◽  
Zeinab Mahmoud
Keyword(s):  
Molecular Docking ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Inhibitory Activity ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Cytotoxic Agents ◽  
Human Cancer Cell Lines ◽  
Ic50 Values

Background: Pyrazolo[3,4-d]pyrimidine scaffold was reported to possess potent cytotoxic and CDK2 inhibitory activity as analogue of roscovitine. Objective: To design and synthesize novel 1-(4-flourophenyl)pyrazolo[3,4-d]pyrimidine derivatives as bioisosters of roscovitine with potential cytotoxic and CDK2 inhibitory activity. Methods: A series of novel 1-(4-flourophenyl)pyrazolo[3,4-d]pyrimidines were designed and synthesized. Structural elucidation for all the newly synthesized compounds was achieved through performing MS, 1H NMR, 13C NMR and IR spectral techniques. Eight compounds were screened for their cytotoxic activity by National Cancer Institute (USA) against 60 different human cancer cell lines. Compounds 2a, 4, 6, 7b, 8a and 8b were further studied through the determination of their IC50 values against the most sensitive cell lines. The inhibitory activities of compounds 2a and 4 were evaluated against CDK2 enzyme. Results: Compound 4 exhibited the most prominent broad-spectrum cytotoxic activity against 42 cell lines representing all human cancer types showing growth inhibition percentages from 53.19 to 99.39. Compound 2a showed promising selectivity against several cell lines. Moreover, all the test compounds exhibited potent cytotoxic activity in nanomolar to micromolar range with IC50 values ranging from 0.58 to 8.32μM. Compound 2a showed significant cytotoxic activity against CNS (SNB-75), lung (NCI-H460) and ovarian (OVCAR-4) cancer cell lines with IC50 values 0.64, 0.78 and 1.9μM, respectively. Compound 4 showed promising potency against leukemia (HL-60) and CNS (SNB-75) cell lines (IC50 = 0.58 and 0.94μM, sequentially). Moreover, the antiproliferative activities of compounds 2a and 4 appeared to correlate well with their ability to inhibit CDK2 at sub-micromolar level (IC50 = 0.69 and 0.67μM, respectively) that were comparable to roscovitine (IC50=0.44μM). The Molecular docking results revealed that compound 4 interacted with the same key amino acids as roscovitine in the active site of CDK2 enzyme with a marked docking score (-14.1031 kcal/mol). Conclusion: 1-(4-Flourophenyl)pyrazolo[3,4-d]pyrimidine is a promising scaffold for the design and synthesis of potent cytotoxic leads.

scholarly journals Synthesis of New Simplified and Racemic Hemiasterlin Derivatives with Extremely High Cytotoxicity

2018 ◽  
Vol 13 (12) ◽  
pp. 1934578X1801301
Author(s):  
Pham The Chinh ◽  
Đang Thi Tuyet Anh ◽  
Duong Huong Quynh ◽  
Le Nhat Thuy Giang ◽  
Nguyen Ha Thanh ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Human Cancer ◽  
Microtubule Depolymerization ◽  
Antimitotic Agent ◽  
Human Cancer Cell Lines ◽  
Weak Activity ◽  
High Cytotoxicity ◽  
Chemistry Community

Hemiasterlin is a potent antimitotic agent acting through inhibition of microtubule depolymerization. For this reason, the synthesis of new hemiasterlin derivatives has attracted a lot of interest in the organic chemistry community recently. In this paper, the synthesis and evaluation of the cytotoxicity of new simplified and racemic hemiasterlin derivatives were reported. All of the synthesized analogues were evaluated in vitro for cytotoxic activity against four human cell lines (KB, Hep-G2, LU and MCF7). Most of these analogues possess a strong cytotoxic activity on two human cancer cell lines (KB and Hep-G2) and very weak activity on LU and MCF7 cell lines.

Six New neo-Clerodane Diterpenoids from Aerial Parts of Scutellaria barbata and Their Cytotoxic Activities

Planta Medica ◽  
2018 ◽  
Vol 84 (17) ◽  
pp. 1292-1299 ◽  
Author(s):  
Guo-Chun Yang ◽  
Jia-Hui Hu ◽  
Bing-Long Li ◽  
Huan Liu ◽  
Jia-Yue Wang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
In Vitro Cytotoxicity ◽  
Cytotoxic Activities ◽  
Scutellaria Barbata ◽  
Human Cancer Cell Lines ◽  
Aerial Parts ◽  
Ic50 Values ◽  
Clerodane Diterpenoids

AbstractSix new neo-clerodane diterpenoids (1–6), scutebatas X – Z, A1-C1, along with twelve known ones (7–18) were obtained via the phytochemical investigation of the aerial parts of Scutellaria barbata. Their structures were established by detailed spectroscopic analysis. The absolute configurations of 1 and 2, as the representative members of this type, were identified based on a circular dichroic exciton chirality method. Moreover, in vitro cytotoxicity of compounds 1–6 were evaluated against three human cancer cell lines (SGC-7901, MCF-7, and A-549) using the MTT method. Compound 6 showed cytotoxic activities against all the three cell lines with IC50 values of 17.9, 29.9, and 35.7 µM, respectively.

The Design and Synthesis of Novel Phenothiazine Derivatives as Potential Cytotoxic Agents

2019 ◽  
Vol 17 (1) ◽  
pp. 57-67
Author(s):  
Yepeng Luan ◽  
Jinyi Liu ◽  
Jianjun Gao ◽  
Jinhua Wang
Keyword(s):  
Cell Lines ◽  
High Efficiency ◽  
Human Cancer ◽  
Human Tumor ◽  
Cytotoxic Agents ◽  
Cancer Drug ◽  
Human Cancer Cell Lines ◽  
Incidence And Mortality ◽  
Anti Cancer

Background: Cancer incidence and mortality have been increasing and cancer is still the leading cause of death all over the world. Despite the enormous progress in cancer treatment, many patients died of ineffective chemotherapy and drug resistance. Therefore, the design and development of anti-cancer drugs with high efficiency and low toxicity is still one of the most challenging tasks. Tricyclic heterocycles, such as phenothiazine, are always important sources of scaffolds for anti-cancer drug discovery. Methods: In this work, ten new urea-containing derivatives of phenothiazine coupled with different kinds of amine motifs at the endpoint through a three carbon long spacer were designed and synthesized. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR and HRMS. All the synthesized compounds were tested for their antitumor activity in vitro against the proliferation of PC-3 cells, and the compounds with best potency entered further cytotoxicity evaluations against other 22 human tumor cell lines. Mechanism was also studied. Results: From all data, it showed that among all 10 target compounds, TTi-2 showed the best effect in inhibiting the proliferation of 23 human cancer cell lines while TTi-2 without obvious inhibitory effect on normal cell. Furthermore, our results also showed that TTi-2 could inhibit migration, invasion and colony formation of MDA-MB-231 cells. Finally, TTi-2 can induce arrest of cell cycle at G0/G1 phase and cell apoptosis by activating the caspase 3 activity. Conclusion: All these results suggested that TTi-2 might be used as a promising lead compound for anticancer drug development.

CYTOTOXIC ACTIVITY OF LUVUNGA SCANDENS AGAINST HUMAN CANCER CELL LINES

2016 ◽  
Vol 78 (10) ◽  
Author(s):  
Putri Nur Hidayah Al-Zikri ◽  
Muhammad Taher ◽  
Deny Susanti ◽  
Solachuddin Jauhari Arief Ichwan
Keyword(s):  
Cytotoxic Activity ◽  
Cell Line ◽  
Cell Lines ◽  
A549 Cell ◽  
Human Cancer ◽  
In Vitro Cytotoxicity ◽  
Breast Adenocarcinoma ◽  
Human Cancer Cell Lines ◽  
Mcf 7

Luvunga scandens belongs to the family of Rutaceae which usually inhabit tropical and moist environment. This plant is known as ‘Mengkurat Jakun’ among locals and used traditionally to treat fever and fatigue via decoction. The aim of this study was to investigate the cytotoxic activity of the leaves and stems extracts of L. scandens extract. Extracts of the leaves and stems were obtained from sequential extraction procedures by various organic solvents. All extracts were subjected to cytotoxic study by 3-(4, 5-dimethylthaizol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. In in vitro cytotoxicity assay, all L. scandens extracts exhibited cytotoxicity against human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549) cell lines. The IC50 values of dichloromethane and methanol extracts from the leaves of L. scandens against MCF-7 cell line were 62.5 µg/mL and 88.0 µg/mL, respectively, whereas IC50 of methanol extract from stem was 81.0 µg/mL. All extracts were less active against A549 cell line where IC50 value were not be determined. The present findings revealed the potential of L. scandens as a cytotoxic agent against MCF-7 cell line. However, further studies should be planned to evaluate role of the plant in cytotoxic activity.

Screening of in vitro cytotoxic activity potential of Odontobuthus doriae and bothutus Saulcyi scorpion venoms against a panel of human cancer cell lines

Toxicon ◽  
2019 ◽  
Vol 158 ◽  
pp. S49
Author(s):  
Toktam M. Kashani ◽  
Amir Salarian ◽  
Hossein Vatanpour ◽  
Farshad Shirazi ◽  
Abbas Zare ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Scorpion Venoms

The Evaluation of Potential Cytotoxic Effect of Different Proton Pump Inhibitors on Different Human Cancer Cell Lines

2020 ◽  
Vol 20 (2) ◽  
pp. 245-253
Author(s):  
Aya Qasem ◽  
Violet Kasabri ◽  
Eman AbuRish ◽  
Yasser Bustanji ◽  
Yusuf Al-Hiari ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Raw 264.7 ◽  
Human Cancer Cell ◽  
Raw 264.7 Macrophages ◽  
Human Cancer Cell Lines ◽  
Ic50 Values

Objective : To assess the differential cytotoxic activity of PPIs on different human cancer cell lines; namely A549 lung cancer, CACO-2 colorectal cancer, MCF-7 breast cancer, and PANC-1 pancreatic cancer, A375 skin melanoma. Methods: In this study, the five human cancer cell lines and human non-cancerous fibroblasts were treated with increasing concentration of PPIs Omeprazole (OMP), Esomeprazole (ESOM), and Lansoprazole (LANSO) (50-300μM), over 24h, 48h, and 72h. Cell viability was determined using 3-(4,5- Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and the IC50 values of PPIs were measured. The most sensitive cell line A375 was used for further investigation. The cytotoxic effects of LANSO on these cells were assessed using Annexin-V Propidium Iodide (AV-PI) flow cytometry. As of action mechanism; anti-inflammatory effects of each PPIs and PPIs-DOXO combination therapy on LPS-stimulated RAW 264.7 mouse macrophages were assessed. Results: Dose and time dependence cytotoxic activity of PPIs on human cancer cell lines was founded. Unlike DOXO; All PPIs had a selective cytotoxic effect in the normal fibroblasts. Unlike the equipotent OMP and ESOM; LANSO was the most potent drug with IC50 values at 72h of 99, 217, 272, 208, 181μM against A375, A549, CACO-2, MCF-7, and PANC-1, respectively. AV-PI flow cytometry revealed dose-dependent apoptotic effects of LANSO alone and substantially enhanced in DOXO-co-treatments. Interestingly unlike ESOM and OMP, LANSO proved more effective than indomethacin in LPS-stimulated RAW 264.7 macrophages. None of the tested compounds, as well as indomethacin, exerted any cytotoxicity against RAW 264.7 macrophages. PPIs-DOXO lacked potential synergistic combination antiinflammation therapies. Conclusion: This study provides the evidence that PPIs induce a direct and differential cytotoxic activity against human cancer cell line by the induction of the apoptosis. Moreover, PPIs increase cancer cell lines sensitivity to doxorubicin via apoptosis augmentation. Nevertheless, PPIs-DOXO lacked potential synergistic combination therapies in either antiproliferation or anti-inflammation.

Design, Synthesis, and Cytotoxic Activity of New Tubulysin Analogues

Synlett ◽  
2021 ◽  
Author(s):  
Anh Tuan Tran ◽  
Chien Van Tran ◽  
Hai Van Le ◽  
Loc Van Tran ◽  
Thao Thi Phuong Tran ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Cytotoxic Activities ◽  
Design Synthesis ◽  
Human Cancer Cell Lines ◽  
Ht 29

AbstractSynthesis of tubulysin analogues, containing an N-methyl substituent on tubuvaline-amide together with the replacement of either the hydrophobic N-terminal N-methyl pipecolic acid (Mep) or at both N- and C- terminal peptides with available heteroaromatic acids and an unsaturated tubuphenylalanine moiety, respectively, were described. The in vitro cytotoxic activity by SRB assay on five cancer cell lines for sixteen tubulysins was evaluated. Among them, five analogues exhibited strong cytotoxic activities against five human cancer cell lines, including human breast carcinoma (MCF7), human colorectal adenocarcinoma (HT-29), HL-60, SW-480, human lung adenocarcinoma (A459). Interestingly, one analogue showed the strongest cytotoxicity on all five tested cell lines even much higher toxicity than the reference compound ellipticine.

scholarly journals Two New Cytotoxic Steroidal Alkaloids from Sarcococca Hookeriana

Molecules ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 11 ◽  
Author(s):  
Shaojie Huo ◽  
Jichun Wu ◽  
Xicheng He ◽  
Lutai Pan ◽  
Jiang Du
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
Cytotoxic Activities ◽  
Steroidal Alkaloids ◽  
X Ray ◽  
Human Cancer Cell Lines ◽  
X Ray Crystallography ◽  
Ic50 Values ◽  
Mcf 7

Two new steroidal alkaloids, named hookerianine A (1) and hookerianine B (2) were isolated from the stems and roots of Sarcococca hookeriana Baill., along with two known compounds, sarcorucinine G (3) and epipachysamine D (4). On the basis of spectroscopic methods and by comparison with literature data, their structures were determined. As well as X-ray crystallography was performed to confirm compound 4. To identify novel antitumor inhibitors, all compounds were performed a CCK-8 assay against five human cancer cell lines SW480, SMMC-7721, PC3, MCF-7 and K562 in vitro. Compound 2 exhibited moderate cytotoxic activities to all cell lines with IC50 values in the range of 5.97–19.44 μM. Compound 3 was the most effective one against SW480 and K562 cell lines with IC50 values of 5.77 and 6.29 μM, respectively.

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