scholarly journals Discovery of 2-(1-(3-(4-Chloroxyphenyl)-3-oxo- propyl)pyrrolidine-3-yl)-1H-benzo[d]imidazole-4-carboxamide: A Potent Poly(ADP-ribose) Polymerase (PARP) Inhibitor for Treatment of Cancer

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1901 ◽  
Author(s):  
Rui Min ◽  
Weibin Wu ◽  
Mingzhong Wang ◽  
Lin Tang ◽  
Dawei Chen ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Anticancer Activities ◽  
Reference Drug ◽  
Structure Activity ◽  
Ic50 Values ◽  
Proliferation Assays ◽  
Parp 1

A series of benzimidazole carboxamide derivatives have been synthesized and characterized by 1H-NMR, 13C-NMR and HRMS. PARP inhibition assays and cellular proliferation assays have also been carried out. Compounds 5cj and 5cp exhibited potential anticancer activities with IC50 values of about 4 nM against both PARP-1 and PARP-2, similar to the reference drug veliparib. The two compounds also displayed slightly better in vitro cytotoxicities against MDA-MB-436 and CAPAN-1 cell lines than veliparib and olaparib, with values of 17.4 µM and 11.4 µM, 19.8 µM and 15.5 µM, respectively. The structure-activity relationship based on molecular docking was discussed as well.

Synthesis and Antitumor Activity Evaluation of New Phenanthrene-Based Tylophorine Derivatives

2019 ◽  
Vol 16 (6) ◽  
pp. 462-467
Author(s):  
Songtao Li ◽  
Hongling Zhao ◽  
Zhifeng Yin ◽  
Shuhua Deng ◽  
Yang Gao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Antitumor Activities ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Structure Activity ◽  
Human Carcinoma Cell ◽  
Ic50 Values ◽  
Relationship Of

A series of new phenanthrene-based tylophorine derivatives (PBTs) were synthesized in good yield and their structures were characterized by 1H-NMR spectroscopy and ESI MS. In vitro antitumor activity of these compounds against five human carcinoma cell lines, including HCT116 (colorectal), BGC-823 (gastric), HepG-2 (hepatic), Hela (cervical) and H460 (lung) cells, was evaluated by MTT assay. Among these PBTs, compound 6b showed the highest antitumor activities against HCT116 and HepG-2 cell lines with IC50 values of 6.1 and 6.4 μM, respectively, which were comparable to that of adriamycin hydrochloride. The structure-activity relationship of these compounds was also discussed based on the results of their antitumor activity.

scholarly journals Structurally Simple Phenanthridine Analogues Based on Nitidine and Their Antitumor Activities

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 437
Author(s):  
Shu-Qin Qin ◽  
Lian-Chun Li ◽  
Jing-Ru Song ◽  
Hai-Yun Li ◽  
Dian-Peng Li
Keyword(s):  
Anticancer Agents ◽  
Human Cancer ◽  
A549 Cells ◽  
Anticancer Activities ◽  
Human Cancer Cell Lines ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Diphenyl Tetrazolium Bromide ◽  
Conjugated Compounds

A series of novel structurally simple analogues based on nitidine was designed and synthesized in search of potent anticancer agents. The antitumor activity against human cancer cell lines (HepG2, A549, NCI-H460, and CNE1) was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro. The results showed that some of them had good anticancer activities, especially derivatives with a [(dimethylamino)ethyl]amino side chain in the C-6 position. Planar conjugated compounds 15a, 15b, and 15c, with IC50 values of 1.20 μM, 1.87 μM, and 1.19 μM against CNE1 cells, respectively, were more active than nitidine chloride. Compound 15b and compound 15c with IC50 values of 1.19 μM and 1.37 μM against HepG2 cells and A549 cells demonstrated superior activities to nitidine. Besides, compound 5e which had a phenanthridinone core displayed extraordinary cytotoxicity against all test cells, particularly against CNE1 cells with the IC50 value of 1.13 μM.

Preclinical study of a PARP inhibitor in neuroblastoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9570-9570
Author(s):  
Anissa Addioui ◽  
Assila Belounis ◽  
Sonia Cournoyer ◽  
Carine Nyalendo ◽  
Rose- Marie Brito ◽  
...  
Keyword(s):  
Cell Survival ◽  
Synergistic Effects ◽  
Parp Inhibitor ◽  
Chemotherapeutic Agents ◽  
Tumor Initiating Cells ◽  
Apoptotic Pathway ◽  
Western Blots ◽  
Optimal Drug ◽  
Parp 1

9570 Background: Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In spite of many therapeutic improvements, only 60% survive long term despite aggressive combinations of multi-agent chemotherapy. In previous studies, we have demonstrated that tumor initiating cells (TIC) expressing CD133 (CD133high) in NB are more resistant to chemotherapy. Moreover, these cells express higher levels of PARP-1, a central protein involved in DNA repair. PARP-1 expression is significantly lower in NB usually showing spontaneous regression than in standard NB, suggesting an implication of PARP-1 in NB progression. The objective of this study is to determine the efficacy in vitro of AG-014699 (AG), a PARP- inhibitor, used in monotherapy or in combination to cisplatine (CP) and doxorubicine (DR), classical chemotherapeutic agents used in NB treatment, on NB cell survival. Methods: Six NB cell lines (parental or CD133high purified by flow cytometry (FACS)) were treated with AG alone or in association to CP or DR. PARP-1 ELISA protein assay was used to determine the optimal drug concentration needed to inhibit the protein. Cell survival was measured by MTT test. Western Blots were done to evaluate any apoptotic or autophagic pathway modulations. Quantification of DNA damage in treated cell was done by immunofluorescence of H2A-X protein. Results: We showed that a 4µM concentration of AG is sufficient for PARP-1 inhibition. One third of celllines presented a sensitivity to AG when used in monotherapy with an IC50 lower than 5µM. However, AG demonstrated synergistic effects when associated to DR, decreasing the IC50 by half, although none is observed when combined to CP. Sentitivity of the TIC did not appear to be more important than the bulk cells. With increasing concentration of AG, our WB showed no increase in cleaved Caspase-3 suggesting no modulation of the apoptotic pathway. However, autophagy seemed to be upregulated confirmed by an increase in cleaved LC3 II protein. Double strand breaks increased 2.5 folds when 4µM AG is added to the IC50 of DR. Conclusions: AG used in combination at potentially therapeutic doses shows promising results in NB. These results will allow for the improvement of NB treatments by introducing a new therapeutic strategy.

scholarly journals Potential Antileishmanial Activity of Essential Oils of Native Species from Southern Brazil

2016 ◽  
Vol 6 (4) ◽  
pp. 18 ◽  
Author(s):  
Carla Kauffmann ◽  
Eduardo M. Ethur ◽  
Barbara Buhl ◽  
Talita Scheibel ◽  
Gerzia M. C. Machado ◽  
...  
Keyword(s):  
Essential Oils ◽  
Native Species ◽  
Neglected Tropical Diseases ◽  
Antileishmanial Activity ◽  
Reference Drug ◽  
Ic50 Values ◽  
Brazilian Flora ◽  
South Of Brazil ◽  
Antileishmanial Activities

Leishmaniasis are a neglected tropical diseases that affecting 98 countries on three continents. Every year, 1.3 million of people are infected with the disease and 50.000 persons die because of this. The aim of this work was to evaluate antileishmanial activities in vitro from native species of South of Brazil belonging to the Myrtaceae family. The essential oils from leaves of Calyptranthes grandifolia, Calyptranthes tricona, Eugenia anomala, Eugenia arenosa, Eugenia pyriformis, Myrrhinium atropurpureum and Psidium salutare were analyzed in vitro for antileishmanial activity against promastigotes of Leishmania amazonensis, employed MTT assay. The essential oils from leaves of C. grandifolia, C. tricona, E. arenosa and E. pyriformis presented IC50 values of 31.27 ± 6.40 µg/mL, 26.13 ± 8.60 µg/mL, 13.72 ± 8.65 µg/mL and 19.73 ± 5.40 µg/mL, respectively, and not are statistically different from pentamidine (IC50 = 23.22 ± 9.04 µg/mL), the reference drug. The results show the potential of essential oils from leaves of C. grandifolia, C. tricona, E. arenosa and E. pyriformis as antileishmanial, as well as the importance of continuing studies to in order to advance in the search and development of new therapeutic options from of brazilian flora sources.

Effect of inhibition of poly-(ADP ribose) polymerase on gemcitabine and radiation-induced cytotoxicity of pancreatic cancer cells.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 203-203
Author(s):  
R. Tuli ◽  
A. Surmak ◽  
A. Blackford ◽  
A. Leubner ◽  
E. M. Jaffee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Pancreatic Cancer Cells ◽  
Synergistic Mechanism ◽  
Radiation Induced ◽  
Parp 1

203 Background: Poly-(ADP ribose) polymerases (PARPs) are DNA-binding proteins involved in DNA repair. PARP inhibition has resulted in excellent antitumor activity when used with other cytotoxic therapies. ABT-888 is a promising PARP inhibitor with excellent potency against the PARP-1/2 enzymes and good oral bioavailability. We attempt to determine whether PARP-1/2 inhibition alone, or in combination with gemcitabine, will enhance the effects of irradiation (RT) of pancreatic cancer cells. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were treated with ABT-888, gemcitabine, RT, or combinations thereof. RT was delivered with a 137-Cs Gammacell in a single fraction. Cells were pre-treated once with ABT-888 and/or gemcitabine 30 minutes prior to RT. Viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3/7 activity using a luminescent assay. PARP activity was determined using a chemiluminescent PAR elisa. Results: The half maximal inhibitory concentration (IC50) of RT was 5 Gy; IC10 for ABT-888 and gemcitabine were 10 uM and 5 nM, respectively. Treatment with ABT-888 (10 uM), gemcitabine (5 nM), or combinations of the two with RT led to increasingly higher rates of cell death 8 days after treatment (p<0.001). RT dose enhancement factors were 1.5, 1.82 and 2.36 for 1, 10 and 100 uM ABT-888, respectively. Minimal cytotoxicity was noted when cells were treated with ABT-888 alone up to 100 uM. Caspase activity was not significantly increased when treated with ABT-888 (10 uM) alone (1.28 fold, p=0.077), but became significant when RT (2 Gy) was added (2.03 fold, p=0.006). This difference was further enhanced by the addition of gemcitabine (2.95 fold, p=0.004). Conclusions: ABT-888 is a potent radiosensitizer of pancreatic cancer cells with minimal cytotoxicity when used alone. Cell death is further potentiated by cotreatment with gemcitabine. Radiation-induced apoptosis was significantly enhanced by ABT-888 and gemcitabine, suggesting a synergistic mechanism of interference with DNA repair. These data are currently being validated in an orthotopic pancreatic cancer mouse model. No significant financial relationships to disclose.

PARPi in PCa results in decreased availability of DNA repair factors.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 301-301
Author(s):  
Matthew Joseph Schiewer ◽  
Karen E. Knudsen
Keyword(s):  
Dna Repair ◽  
Enzymatic Activity ◽  
Disease Progression ◽  
Target Genes ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Clinical Trial Data ◽  
Parp Inhibition ◽  
Transcriptional Regulatory ◽  
Parp 1

301 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions in cancer, including regulating NFkB and HIF function. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of AR function PCa, and assists in regulating AR-driven, PCa-associated phenotypes, including castrate-resistant AR function, tumor growth, and transition to CRPC. Additionally, recent clinical trial data of PARP inhibition as a single agent in advanced cancers has been promising. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARP inhibitor action in PCa may yield markers of response and/or rationale for precision medicine. Methods: Hormone therapy-sensitive and CRPC models were transcriptionally profiled in response to PARP inhibition. Pathways were nominated for validation. Bioinformatics approaches were used to compare the PARP-1-sensitive transcritome with publicly available data sets. ChIP-qPCR was performed to examine the effect of PARPi on target genes of the nominated pathways. Patient specimen TMAs were utilized for PAR IHC. PARP inhibition reduced AR and E2F1 target gene expression, as well as significantly decreased expression of DNA repair genes. Both PARP enzymatic activity and the PARP-1-dependent transcriptional program are increased as a function of disease progression. Results: These data indicate that:(1) The PARPi-sensitive transcriptome holds major transcriptional regulatory events beyond AR signaling. (2) E2F1-regulated genes are sensitive to PARP-1 function. (3) The PARPi-sensitive E2F-regulated transcriptome is enriched for DNA repair factors. (4) PARP enzymatic and transcriptional functions are increased during disease progression. Conclusions: Taken together, this study demonstrates that the transcriptional roles of PARP-1 may contribute to the clinical response to PARP-1 inhibitors as single agents. This work was supported by a PCF YI award (to MJS).

scholarly journals Involvement of Poly(ADP-Ribose) Polymerase 1 and Poly(ADP-Ribosyl)ation in Regulation of Centrosome Function

2003 ◽  
Vol 23 (7) ◽  
pp. 2451-2462 ◽  
Author(s):  
Masayuki Kanai ◽  
Wei-Min Tong ◽  
Eiji Sugihara ◽  
Zhao-Qi Wang ◽  
Kenji Fukasawa ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Chromosomal Instability ◽  
Regulatory Mechanism ◽  
Parp Inhibitor ◽  
Daughter Cells ◽  
P53 Tumor Suppressor Protein ◽  
Centrosomal Proteins ◽  
Parp 1

ABSTRACT The regulatory mechanism of centrosome function is crucial to the accurate transmission of chromosomes to the daughter cells in mitosis. Recent findings on the posttranslational modifications of many centrosomal proteins led us to speculate that these modifications might be involved in centrosome behavior. Poly(ADP-ribose) polymerase 1 (PARP-1) catalyzes poly(ADP-ribosyl)ation to various proteins. We show here that PARP-1 localizes to centrosomes and catalyzes poly(ADP-ribosyl)ation of centrosomal proteins. Moreover, centrosome hyperamplification is frequently observed with PARP inhibitor, as well as in PARP-1-null cells. Thus, it is possible that chromosomal instability known in PARP-1-null cells can be attributed to the centrosomal dysfunction. P53 tumor suppressor protein has been also shown to be localized at centrosomes and to be involved in the regulation of centrosome duplication and monitoring of the chromosomal stability. We found that centrosomal p53 is poly(ADP-ribosyl)ated in vivo and centrosomal PARP-1 directly catalyzes poly(ADP-ribosyl)ation of p53 in vitro. These results indicate that PARP-1 and PARP-1-mediated poly(ADP-ribosyl)ation of centrosomal proteins are involved in the regulation of centrosome function.

Two New Oxovanadium(IV) Compounds Containing Amino Acid Schiff Base and 1,10-Bathophenanthroline Ligands: Syntheses, Crystal Structures, and In Vitro Evaluation of the Anticancer Activities

2017 ◽  
Vol 70 (5) ◽  
pp. 608 ◽  
Author(s):  
Yaping Cao ◽  
Hongmei Liu ◽  
Zeli Yuan ◽  
Gang Wei
Keyword(s):  
Schiff Base ◽  
Anticancer Agents ◽  
High Resolution Mass Spectrometry ◽  
Hepatoma Cell ◽  
A549 Cells ◽  
Molar Conductance ◽  
Anticancer Activities ◽  
Human Hepatoma Cell ◽  
Ic50 Values

Two new oxovanadium(iv) compounds containing 1,10-bathophenanthroline (Bphen) and amino Schiff base derivatives [VO(hnd-napha)(Bphen)] (1) and [VO(o-van-met)(Bphen)] (2) were synthesised (where hnd-napha and o-van-met are N-Schiff bases derived from the reaction of 2-hydroxy-1-naphthaldehyde with 3-(1-naphthyl)-l-alanine and o-vanillin with l-methionine, respectively). These compounds were characterised by elemental analysis, infrared spectroscopy, high-resolution mass spectrometry, and single-crystal X-ray diffraction (XRD). Both compounds showed low molar conductance values, indicating that they are non-electrolytes. The XRD results showed that the VIV atoms in both compounds existed in the VO3N3 coordination geometry with Schiff base and Bphen ligands. The in vitro anticancer activities of compounds 1 and 2 were evaluated against A549 human lung carcinoma and HepG2 human hepatoma cell lines using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the results revealed that both compounds were cytotoxic with half maximal inhibitory concentration (IC50) values in the range of 8.22 ± 1.0 to 94.89 ± 3.2 μmol L−1. Notably, compound 2 exhibited much better anticancer activity in vitro against A549 cells (8.22 ± 1 μmol L−1) than [VO(acac)2] (24 ± 6 μmol L−1) or any of our previously reported oxovanadium(iv) compounds, making it comparable in activity to cisplatin (3.1 ± 0.5 μmol L−1). These results therefore suggest that compound 2 could be used as a promising lead for the development of anticancer agents for the treatment of lung cancer.

scholarly journals Development and In Vitro Evaluation of 2-Methoxyestradiol Loaded Polymeric Micelles for Enhancing Anticancer Activities in Prostate Cancer

Polymers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 884
Author(s):  
Nabil A. Alhakamy ◽  
Osama A. A. Ahmed ◽  
Usama A. Fahmy ◽  
Shadab Md
Keyword(s):  
Prostate Cancer ◽  
Polymeric Micelles ◽  
Research Work ◽  
Entrapment Efficiency ◽  
Tween 80 ◽  
Tumor Biomarkers ◽  
Anticancer Activities ◽  
Ic50 Values ◽  
Optimum Formula

The present study aimed to formulate and optimize 2ME-loaded PMs (2ME-PMs) for enhancing the anticancer activity of 2ME in prostate cancer (PC). The 2ME-PMs were formulated using PEG-PLGA (PL), Tween 80 (TW80), and alpha-lipoic acid (ALA). The optimization was carried out using a Box-Behnken design with the PL, TW80, and ALA as the independent variables and particle size (PS) as the response. The formulation was optimized for the lowest possible PS, and the software suggested optimum formula with 100.282 mg, 2%, and 40 mg for PL, TW80, and ALA, respectively. The optimized PMs had spherical morphology with PS of 65.36 ± 2.2 nm, polydispersity index (PDI) of 0.273 ± 0.03, and entrapment efficiency of 65.23 ± 3.5%. The in vitro drug release was 76.3 ± 3.2% after 24 h. The cell line studies using PC-3 cells showed IC50 values of 18.75 and 54.41 µmol for 2ME-PM and 2ME, respectively. The estimation of tumor biomarkers was also carried out. The tumor biomarkers caspase-9 (17.38 ± 1.42 ng/mL), tumor protein P53 (p53) (1050.0 ± 40.9 pg/mL), nitric oxide (NO) (0.693 ± 0.03 pg/mL), interleukin-1β (IL-1β) (25.84 ± 2.23 pg/mL), nuclear factor kappa B (NF-kB) (0.719 ± 0.07 pg/mL), interleukin-6 (IL-6) (2.53 ± 0.16 folds), and cyclooxygenase-2 (COX-2) (3.04 ± 0.5 folds) were determined for 2ME-PMs and the results showed that these values changed significantly compared to those of 2ME. Overall, the results showed that the formulation of 2ME to 2ME-PMs enhances the anticancer effect. The exploration of the combined advantages of PEG, PLGA, ALA, and PMs in cancer therapy and the delivery of 2ME is the major importance of this research work. PEG reduces the elimination of 2ME, PLGA enhances 2ME loading, ALA has an inherent apoptotic effect, and PMs can efficiently target tumor cells.

scholarly journals Design, Synthesis and Biological Screening of Novel 1,5-Diphenyl-3-(4-(trifluoromethyl)phenyl)-2-pyrazoline Derivatives

2020 ◽  
Vol 67 (4) ◽  
pp. 1139-1147
Author(s):  
Fatih Tok ◽  
Bedia Koçyiğit-Kaymakçıoğlu
Keyword(s):  
Inflammatory Activity ◽  
Antidiabetic Activity ◽  
Spectroscopic Methods ◽  
Design Synthesis ◽  
Reference Drug ◽  
Ic50 Values ◽  
Adme Properties ◽  
Anti Inflammatory ◽  
In Vitro Antioxidant Activity

1-Phenyl-5-substituted-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole derivatives were synthesized from chalcone derivatives. The structures of compounds were characterized by IR, 1H NMR spectroscopic methods and elemental analysis. All compounds were evaluated for their in vitro antioxidant activity using DPPH and ABTS methods, anti-inflammatory activity using lipoxygenase inhibitory method and antidiabetic activity using the α-glucosidase inhibitory method. Especially, pyrazoline derivatives exhibited stronger anti-inflammatory activity than the reference drug indomethacin (IC50: 50.45 μM) and their IC50 values were in the range of 0.68 and 4.45 μM. In addition, the ADME properties of all chalcone and pyrazoline derivatives were calculated by Lipinski’s and Veber’s rules.

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