NCI in vitro and in silico anticancer screen, cell cycle pertubation and apoptosis-inducing potential of new acylated, benzylidene and isopropylidene derivatives of andrographolide

2014 ◽  
Vol 38 (2) ◽  
pp. 489-501 ◽  
Author(s):  
Charng Choon Wong ◽  
Sreenivasa Rao Sagineedu ◽  
Shariful Hasan Sumon ◽  
Shiran Mohamad Sidik ◽  
Roger Phillips ◽  
...  
Keyword(s):  
Cell Cycle ◽  
In Silico ◽  
Isopropylidene Derivatives ◽  
Derivatives Of

scholarly journals Selected Derivatives of Erythromycin B-In Silico and Anti-Malarial Studies

Materials ◽  
2021 ◽  
Vol 14 (22) ◽  
pp. 6980
Author(s):  
Pranab K. Bhadra ◽  
Rachael N. Magwaza ◽  
Niroshini Nirmalan ◽  
Sally Freeman ◽  
Jill Barber ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Bacterial Agent ◽  
Ic50 Values ◽  
Exit Tunnel ◽  
Erythromycin A ◽  
Erythronolide B ◽  
In Silico Molecular Docking ◽  
Derivatives Of

Erythromycin A is an established anti-bacterial agent against Gram-positive bacteria, but it is unstable to acid. This led to an evaluation of erythromycin B and its derivatives because these have improved acid stability. These compounds were investigated for their anti-malarial activities, by their in silico molecular docking into segments of the exit tunnel of the apicoplast ribosome from Plasmodium falciparum. This is believed to be the target of the erythromycin A derivative, azithromycin, which has mild anti-malarial activity. The erythromycin B derivatives were evaluated on the multi-drug (chloroquine, pyrimethamine, and sulfadoxine)-resistant strain K1 of P. falciparum for asexual growth inhibition on asynchronous culture. The erythromycin B derivatives were identified as active in vitro inhibitors of asexual growth of P. falciparum with low micro-molar IC50 values after a 72 h cycle. 5-Desosaminyl erythronolide B ethyl succinate showed low IC50 of 68.6 µM, d-erythromycin B 86.8 µM, and erythromycin B 9-oxime 146.0 µM on the multi-drug-resistant K1 of P. falciparum. Based on the molecular docking, it seems that a small number of favourable interactions or the presence of unfavourable interactions of investigated derivatives of erythromycin B with in silico constructed segment from the exit tunnel from the apicoplast of P. falciparum is the reason for their weak in vitro anti-malarial activities.

scholarly journals Evaluation of 2-Thioxoimadazolidin-4-One Derivatives as Potent Anti-Cancer Agents through Apoptosis Induction and Antioxidant Activation: In Vitro and In Vivo Approaches

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 83
Author(s):  
Mohamed S. Nafie ◽  
Ahmed I. Khodair ◽  
Hebat Allah Y. Hassan ◽  
Noha M. Abd El-Fadeal ◽  
Hanin A. Bogari ◽  
...  
Keyword(s):  
Cell Cycle ◽  
In Silico ◽  
Hepg2 Cells ◽  
Flow Cytometric Analysis ◽  
Apoptosis Induction ◽  
Rt Pcr ◽  
Anti Cancer ◽  
Ic50 Values

Background: Hepatocellular carcinoma (HCC) is one of the most widespread malignancies and is reported as the fourth most prevalent cause of cancer deaths worldwide. Therefore, we aimed to investigate the probable mechanistic cytotoxic effect of the promising 2-thioxoimidazolidin-4-one derivative on liver cancer cells using in vitro and in vivo approaches. The compounds were tested for the in vitro cytotoxic activity using MTT assay, and the promising compound was tested in colony forming unit assay, flow cytometric analysis, RT-PCR, Western blotting, in vivo using SEC-carcinoma and in silico to highlight the virtual mechanism of action. Both compounds 4 and 2 performed cytotoxic effects against HepG2 cells with IC50 values of 0.017 and 0.18 μM, respectively, compared to Staurosporine and 5-Fu as reference drugs with IC50 values of 5.07 and 5.18 µM, respectively. Compound 4 treatment revealed apoptosis induction by 19.35-fold (11.42% compared to 0.59% in control), arresting the cell cycle at G2/M phase. Moreover, studying gene expression that plays critical roles in cell cycle and apoptosis by RT-PCR demonstrated that compound 4 enhances the expression of the pro-apoptotic genes p53, PUMA, and Caspase 3, 8, and 9, and impedes the anti-apoptotic Bcl-2 gene in the HepG2 cells. It can also inhibit the PI3K/AKT pathway at both gene and protein levels, which was reinforced by the in silico predictions of the molecular docking simulations towards the PI3K/AKT proteins. Finally, in vivo study verified that compound 4 has a promising anti-cancer activity through activating antioxidant levels (CAT, SOD and GSH) and ameliorating hematological, biochemical, and histopathological findings.

scholarly journals Augmented Cell Signaling by Betanin insights Cancer Cell Remodeling: A Molecular Docking and Experimental Approach

2021 ◽  
Vol 12 (3) ◽  
pp. 3161-3172
Keyword(s):  
Cell Cycle ◽  
Molecular Docking ◽  
Cancer Cell ◽  
In Silico ◽  
Topoisomerase I ◽  
Caspase 3 ◽  
Dependent Manner ◽  
Dna Topoisomerase ◽  
Docking Analysis

Molecular docking analysis has shown to be an important tool for systematically harnessing natural pigment betanin's structural diversity. Natural betanin pigment was used to investigate its anticancer efficacy by in vitro cytotoxicity and cell cycle analysis in A549 lung cancer cell line. Furthermore, docking analysis was used to determine the promising molecular targets for the betanin using different receptor proteins and enzymes responsible for DNA replication (DNA topoisomerases I and II), cell cycle (CDK-6), and in silico apoptotic markers (Bcl-2 and caspase-3) using Glide Schrodinger. In vitro analysis revealed that betanin exerts cytotoxic effects in a cancer cell by inducing apoptosis in a dose-dependent manner with an IC50 value of 17 µM. Furthermore, the cell cycle arrest in response to betanin treatment was strongly observed in flow cytometry analysis. The in silico docking results revealed that betanin exhibited splendid interaction with high affinity against the CDK-6, Bcl-2, and caspase-3 with superior docking scores. Betanin was best docked with DNA topoisomerase II than DNA topoisomerase I. Overall, our report provides scientific evidence that betanin is a novel drug moiety with anticancer property attributes that might be developed and formulated as drug candidate/lead compounds for cancer chemotherapy.

scholarly journals Computational and in vitro Investigation of miRNA-Gene Regulations in Retinoblastoma Pathogenesis: miRNA Mimics Strategy

2015 ◽  
Vol 9 ◽  
pp. BBI.S21742 ◽  
Author(s):  
Nalini Venkatesan ◽  
Perinkulam Ravi Deepa ◽  
Vikas Khetan ◽  
Subramanian Krishnakumar
Keyword(s):  
Cell Cycle ◽  
In Silico ◽  
Apoptotic Cell ◽  
Minimum Energy ◽  
Mirna Gene ◽  
Stem Cell Markers ◽  
Qrt Pcr ◽  
Mirna Mimic ◽  
In Vitro Investigation

Purpose Retinoblastoma (RB), a primary pediatric intraocular tumor, arises from primitive retinal layers. Several novel molecular strategies are being developed for the clinical management of RB. miRNAs are known to regulate cancer-relevant biological processes. Here, the role of selected miRNAs, namely, miR-532-5p and miR-486-3p, has been analyzed for potential therapeutic targeting in RB. Methods A comprehensive bioinformatic analysis was performed to predict the posttranscriptional regulators (miRNAs) of the select panel of genes [Group 1: oncogenes (HMGA2, MYCN, SYK, FASN); Group 2: cancer stem cell markers (TACSTD, ABCG2, CD133, CD44, CD24) and Group 3: cell cycle regulatory proteins (p53, MDM2)] using Microcosm, DIANALAB, miRBase v 18, and REFSEQ database, and RNA hybrid. The expressions of five miRNAs, namely, miR-146b-5p, miR-532-5p, miR-142-5p, miR-328, and miR-486-3p, were analyzed by qRT-PCR on primary RB tumor samples (n = 30; including 17 invasive RB tumors and 13 noninvasive RB tumors). Detailed complementary alignment between 5’ seed sequence of differentially expressed miRNAs and the sequence of target genes was determined. Based on minimum energy level and piCTAR scores, the gene targets were selected. Functional roles of these miRNA clusters were studied by using mimics in cultured RB (Y79, Weri Rb-1) cells in vitro. The gene targets (SYK and FASN) of the studied miRNAs were confirmed by qRT-PCR and western blot analysis. Cell proliferation and apoptotic studies were performed. Results Nearly 1948 miRNAs were identified in the in silico analysis, From this list, only 9 upregulated miRNAs (miR-146b-5p, miR-305, miR-663b, miR-299, miR-532-5p, miR-892b, miR-501, miR-142-5p, and miR-513b) and 10 downregulated miRNAs (miR-1254, miR-328, miR-133a, miR-1287, miR-1299, miR-375, miR-486-3p, miR-720, miR-98, and miR-122*) were found to be common with the RB serum miRNA profile. Downregulation of five miRNAs (miR-146b-5p, miR-532-5p, miR-142-5p, miR-328, and miR-486-3p) was confirmed experimentally. Predicted common oncogene targets (SYK and FASN) of miR-486-3p and miR-532-5p were evaluated for their mRNA and protein expression in these miRNA mimic-treated RB cells. Experimental overexpression of these miRNAs mediated apoptotic cell death without significantly altering the cell cycle in RB cells. Conclusion Key miRNAs in RB pathogenesis were identified by an in silico approach. Downregulation of miR-486-3p and miR-532-5p in primary retinoblastoma tissues implicates their role in tumorigenesis. Prognostic and therapeutic potential of these miRNA was established by the miRNA mimic strategy.

scholarly journals Synthesis and Evaluation of Biological Activities of Bis(spiropyrazolone)cyclopropanes: A Potential Application against Leishmaniasis

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4960
Author(s):  
Olalla Barreiro-Costa ◽  
Gabriela Morales-Noboa ◽  
Patricio Rojas-Silva ◽  
Eliana Lara-Barba ◽  
Javier Santamaría-Aguirre ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
In Silico ◽  
Potential Application ◽  
Mammalian Cells ◽  
Biological Activities ◽  
Antioxidant Properties ◽  
Therapeutic Use ◽  
Derivatives Of

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models—S. cerevisiae, five cancer cell lines, and the parasite L. mexicana—were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells.

scholarly journals In Silico Identification of Small Molecules as New Cdc25 Inhibitors through the Correlation between Chemosensitivity and Protein Expression Pattern

2021 ◽  
Vol 22 (7) ◽  
pp. 3714
Author(s):  
Antonino Lauria ◽  
Annamaria Martorana ◽  
Gabriele La Monica ◽  
Salvatore Mannino ◽  
Giuseppe Mannino ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Small Molecules ◽  
Expression Pattern ◽  
In Silico ◽  
Molecular Structures ◽  
Phase Cell ◽  
Protein Expression Pattern ◽  
Active Inhibitor

The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach and taking advantage of the correlation between the chemosensitivity of selected structures and the protein expression pattern of the proposed target. In the first step of the in silico protocol, a set of molecules acting as Cdc25 inhibitors were identified through a new ligand-based protocol and the evaluation of a large database of molecular structures. Subsequently, induced-fit docking (IFD) studies allowed us to further reduce the number of compounds biologically screened. In vitro antiproliferative and enzymatic inhibition assays on the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins. Among them, J3955, the most active inhibitor, showed concentration-dependent antiproliferative activity against HepG2 cells, with GI50 in the low micromolar range. When J3955 was tested in cell-cycle perturbation experiments, it caused mitotic failure by G2/M-phase cell-cycle arrest. Finally, Western blotting analysis showed an increment of phosphorylated Cdk1 levels in cells exposed to J3955, indicating its specific influence in cellular pathways involving Cdc25 proteins.

scholarly journals Antioxidant Activity and Toxic Effects of Phosphorus-Containing Derivatives of 2,6-Di-tert-Butylphenol in silico and in vitro, in vivo

2019 ◽  
Vol 75 (1) ◽  
Author(s):  
Maria Aleksandrovna Polovinkina ◽  
Victoria Pavlovna Osipova ◽  
Margarita Nikolaevna Kolyada ◽  
Anastasia Dmitrievna Osipova ◽  
Nadezhda Titovna Berberova ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
In Silico ◽  
Toxic Effects ◽  
Phosphorus Containing ◽  
Derivatives Of

scholarly journals In Vitro and In Silico Evaluation of New 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone as Promising Cyclooxygenase Inhibitors

2021 ◽  
Vol 22 (17) ◽  
pp. 9130
Author(s):  
Krzysztof Peregrym ◽  
Łukasz Szczukowski ◽  
Benita Wiatrak ◽  
Katarzyna Potyrak ◽  
Żaneta Czyżnikowska ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Binding Mode ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Cyclooxygenase Inhibitors ◽  
Molecular Docking Studies ◽  
Cox 2 ◽  
Derivatives Of

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX‑2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions.

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