Biological activities of a new crotamine-like peptide from Crotalus oreganus helleri on C2C12 and CHO cell lines, and ultrastructural changes on motor endplate and striated muscle

Background:: Indole and pyrazoles are one of the prime structural units in the field of medicinal chemistry and have been reported to exhibit a variety of biological activities specifically anti-cancer. In view of their medicinal significance, we synthesized a conjugate of the two moieties to get access to newer and potential anti-cancer agents. Methods: Indolyl pyrazoles [3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(1-methyl-1H-indole-3-carbon yl)acrylonitriles] (4a-l) were synthesized by adopting simple and greener protocol and all the synthesized derivatives were docked against Bcl-2 protein and the selected chemical moieties were screened for their cytotoxicity by using the MTT assay. Results: : All the synthesized compounds were docked against BCL-2 protein in order to understand their binding pattern. Among the 12 compounds docked, 4d, 4f, 4h, 4j, and 4l compounds exhibited better protein binding interactions and the same were screened for their anti-cancer activity against A549 (lung) cancer cell lines at a concentration of 100 μM using Doxorubicin as standard. Substitutions such as N-benzyl, N-ethyl groups and halogen groups such as Br, Cl on indole ring showed moderate activity against A-549 cell lines. Conclusion:: Among the 5 indolyl pyrazole derivatives screened, compounds 4h and 4j showed significantly better activity with an IC50 of 33.12 and 34.24 μM, respectively. Further, structural tweaking of the synthesized new chemical entities may lead to potential hit/lead-like molecules.

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1'-methylspiro[indoline-3,4'-piperidine] Derivatives: Design, Synthesis, Molecular Docking and Anti-tumor Activity Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201117150714 ◽

2020 ◽

Vol 17 ◽

Author(s):

Junjian Li ◽

Lianbao Ye ◽

Yuanyuan Wang ◽

Ying Liu ◽

Xiaobao Jin ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Active Sites ◽

Biological Activities ◽

Significant Inhibition ◽

Alkaline Condition ◽

Discovery Studio ◽

Hela Cell Lines ◽

Antiproliferative Activities

Background: Spirocyclic indoline compounds widely exist in numerous natural products with good biological activities and some drug molecules in many aspects. In recent years, it has attracted extensive attention as potent anti-tumor agents in the fields of pharmacology and chemistry. Objective: In this study, we focused on designing and synthesizing a set of novel 1'-H-spiro[indole-3,4'-piperidine] derivatives, which were evaluated by preliminary bioactivity experiment in vitro and molecular docking. Method: The key intermediate 1'-methylspiro[indoline-3,4'-piperidine] (B4) reacted with benzenesulfonyl chloride with different substituents under alkaline condition to obtain its sulfonyl derivatives (B5-B10). We evaluated their antiproliferative activities against A549, BEL-7402 and HeLa cells by MTT assay. We performed the CDOCKER module in Discovery Studio 2.5.5 software for molecular modeling of compound B5, and investigated the binding of compound B5 with the target proteins from PDB database. Results: The results indicated that compounds B4-B10 exhibited good antiproliferative activities against the above three types of cells, in which compound B5 with chloride atom as electron-withdrawing substituent on a phenyl ring showed the highest potency against BEL-7402 cells (IC50=30.03±0.43 μg/mL). By binging of the prominent bioactive compound B5 to CDK, c-Met, EGFR protein crystals, The binding energy of B5 with these three types receptors are -44.3583 kcal/mol, - 38.3292 kcal/mol, -33.3653 kcal/mol respectively. Conclusion: Six 1'-methylspiro[indoline-3,4'-piperidine] derivatives were synthesized and evaluated against BEL-7402, A- 549, HeLa cell lines. Compound B5 showed significant inhibition on BEL-7402 cell lines. Molecular docking revealed that B5 showed good affinity by the good fitting between B5 and these three targets with amino acid residues in active sites which encourage us to conduct further evaluation such as the kinase experiment.

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Synthesis and Cytotoxicity of New Mannich Bases of 6-[3-(3,4,5-Trimetoxyphenyl)-2- propenoyl]-2(3H)-Benzoxazolone

Letters in Drug Design & Discovery ◽

10.2174/1570180816666190730164952 ◽

2020 ◽

Vol 17 (4) ◽

pp. 512-517

Author(s):

Ognyan Ivanov Petrov ◽

Yordanka Borisova Ivanova ◽

Mariana Stefanova Gerova ◽

Georgi Tsvetanov Momekov

Keyword(s):

Tumor Cell ◽

Cell Lines ◽

Biological Activities ◽

Human Tumor ◽

Mannich Bases ◽

In Vitro Cytotoxicity ◽

Tumor Cell Lines ◽

Human Tumor Cell ◽

Human Tumor Cell Lines

Background: Chemotherapy is one of the mainstays of cancer treatment, despite the serious side effects of the clinically available anticancer drugs. In recent years increasing attention has been directed towards novel agents with improved efficacy and selectivity. Compounds with chalcone backbone have been reported to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic, antioxidant, etc. It was reported that aminomethylation of hydroxy chalcones to the corresponding Mannich bases increased their cytotoxicity. In this context, our interest has been focused on the design and synthesis of the so-called multi-target molecules, containing two or more pharmacophore fragments. Methods: A series of Mannich bases were synthesized by the reaction between 6-[3-(3,4,5- trimethoxyphenyl)-2-propenoyl]-2(3Н)-benzoxazolone, formaldehyde, and a secondary amine. The structures of the compounds were confirmed by elemental analysis, IR and NMR spectra. The new Mannich bases were evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines, including BV-173, SKW-3, K-562, HL-60, HD-MY-Z and MDA-MB-231. The effects of selected compounds on the cellular levels of glutathione (GSH) were determined. Results: The new compounds 4a-e exhibited concentration-dependent cytotoxic effects at micromolar concentrations in MTT-dye reduction assay against a panel of human tumor cell lines, similar to those of starting chalcone 3. The tested agents led to concentration - dependent depletion of cellular GSH levels, whereby the effects of the chalcone prototype 3 and its Mannich base-derivatives were comparable. Conclusion: The highest chemosensitivity to the tested compounds was observed in BV- 173followed by SKW-3 and HL-60 cell lines.

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Naphthoquinone-based hydrazone hybrids: synthesis and potent activity against cancer cell lines

Medicinal Chemistry ◽

10.2174/1573406416666200817164308 ◽

2020 ◽

Vol 16 ◽

Author(s):

Délis Galvão Guimarães ◽

Arlan de Assis Gonsalves ◽

Larissa Araújo Rolim ◽

Edigênia Cavalcante Araújo ◽

Victória Laysna dos Anjos Santos ◽

...

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Cancer Cell ◽

Biological Activities ◽

Supporting Electrolyte ◽

Cancer Cell Lines ◽

Molecular Structures ◽

Cytotoxic Activities ◽

Electrochemical Studies ◽

Ic50 Values

Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, then the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β-lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Method: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Result: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, being compounds 3 and 4 the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

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Influence of New Synthetic Xanthones on the Proliferation and Migration Potential of Cancer Cell Lines In Vitro

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190405113519 ◽

2020 ◽

Vol 19 (16) ◽

pp. 1949-1965 ◽

Cited By ~ 1

Author(s):

Natalia Szkaradek ◽

Daniel Sypniewski ◽

Dorota Żelaszczyk ◽

Sabina Gałka ◽

Paulina Borzdziłowska ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Higher Plants ◽

Biological Activities ◽

Human Tumor ◽

Plant Metabolites ◽

Xtt Assay ◽

Treatment Protocols

Background: Natural plant metabolites and their semisynthetic derivatives have been used for years in cancer therapy. Xanthones are oxygenated heterocyclic compounds produced as secondary metabolites by higher plants, fungi or lichens. Xanthone core may serve as a template in the synthesis of many derivatives that have broad biological activities. Objective: This study synthesized a series of 17 new xanthones, and their anticancer potential was also evaluated. Methods: The anticancer potential was evaluated in vitro using a highly invasive T24 cancer cell line. Direct cytotoxic effects of the xanthones were established by IC50 estimation based on XTT assay. Results: 5 compounds of the total 17 showed significant cytotoxicity toward the studied cancer cultures and were submitted to further detailed analysis, including studies examining their influence on gelatinase A and B expression, as well as on the cancer cells migration and adhesion to an extracellular matrix. These analyses were carried out on five human tumor cell lines: A2780 (ovarian cancer), A549 (lung cancer), HeLa (cervical cancer), Hep G2 (liver cancer), and T24 (urinary bladder cancer). All the compounds, especially 4, showed promising anticancer activity: they exhibited significant cytotoxicity towards all the evaluated cell lines, including MCF-7 breast cancer, and hindered migration-motility activity of cancer cells demonstrating more potent activity than α-mangostin which served as a reference xanthone. Conclusion: These results suggest that our xanthone derivatives may be further analyzed in order to include them in cancer treatment protocols.

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Synthesis and Biological Activities of Cyclodepsipeptides of Aurilide Family from Marine Origin

Marine Drugs ◽

10.3390/md19020055 ◽

2021 ◽

Vol 19 (2) ◽

pp. 55

Author(s):

Synthia Michon ◽

Florine Cavelier ◽

Xavier J. Salom-Roig

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Biological Activities ◽

Natural Compounds ◽

Cancer Cell Lines ◽

Hydroxy Ester ◽

Marine Cyanobacteria ◽

Synthetic Analogues ◽

Marine Origin ◽

Total Syntheses

Aurilides are a class of depsipeptides occurring mainly in marine cyanobacteria. Members of the aurilide family have shown to exhibit strong cytotoxicity against various cancer cell lines. These compounds bear a pentapeptide, a polyketide, and an α-hydroxy ester subunit in their structure. A large number of remarkable studies on aurilides have emerged since 1996. This comprehensive account summarizes the biological activities and total syntheses of natural compounds of the aurilide family as well as their synthetic analogues.

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Recombinant γY278H Fibrinogen Showed Normal Secretion from CHO Cells, but a Corresponding Heterozygous Patient Showed Hypofibrinogenemia

International Journal of Molecular Sciences ◽

10.3390/ijms22105218 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5218

Author(s):

Tomu Kamijo ◽

Takahiro Kaido ◽

Masahiro Yoda ◽

Shinpei Arai ◽

Kazuyoshi Yamauchi ◽

...

Keyword(s):

Cell Lines ◽

Cho Cells ◽

Fibrinogen Level ◽

Culture Media ◽

Chinese Hamster ◽

Plasma Fibrinogen ◽

Enzyme Linked Immunosorbent Assay ◽

Cho Cell ◽

Accelerated Degradation ◽

Heterozygous Patient

We identified a novel heterozygous hypofibrinogenemia, γY278H (Hiroshima). To demonstrate the cause of reduced plasma fibrinogen levels (functional level: 1.12 g/L and antigenic level: 1.16 g/L), we established γY278H fibrinogen-producing Chinese hamster ovary (CHO) cells. An enzyme-linked immunosorbent assay demonstrated that synthesis of γY278H fibrinogen inside CHO cells and secretion into the culture media were not reduced. Then, we established an additional five variant fibrinogen-producing CHO cell lines (γL276P, γT277P, γT277R, γA279D, and γY280C) and conducted further investigations. We have already established 33 γ-module variant fibrinogen-producing CHO cell lines, including 6 cell lines in this study, but only the γY278H and γT277R cell lines showed disagreement, namely, recombinant fibrinogen production was not reduced but the patients’ plasma fibrinogen level was reduced. Finally, we performed fibrinogen degradation assays and demonstrated that the γY278H and γT277R fibrinogens were easily cleaved by plasmin whereas their polymerization in the presence of Ca2+ and “D:D” interaction was normal. In conclusion, our investigation suggested that patient γY278H showed hypofibrinogenemia because γY278H fibrinogen was secreted normally from the patient’s hepatocytes but then underwent accelerated degradation by plasmin in the circulation.

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Mapping the molecular basis for growth related phenotypes in industrial producer CHO cell lines using differential proteomic analysis

BMC Biotechnology ◽

10.1186/s12896-021-00704-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Laura Bryan ◽

Michael Henry ◽

Ronan M. Kelly ◽

Christopher C. Frye ◽

Matthew D. Osborne ◽

...

Keyword(s):

Cell Culture ◽

Cell Density ◽

Cell Lines ◽

Viable Cell ◽

Viable Cell Density ◽

High Peak ◽

Proteomic Profiling ◽

Cho Cell ◽

Extended Culture ◽

Key Pathways

Abstract Background The ability to achieve high peak viable cell density earlier in CHO cell culture and maintain an extended cell viability throughout the production process is highly desirable to increase recombinant protein yields, reduce host cell impurities for downstream processing and reduce the cost of goods. In this study we implemented label-free LC-MS/MS proteomic profiling of IgG4 producing CHO cell lines throughout the duration of the cell culture to identify differentially expressed (DE) proteins and intracellular pathways associated with the high peak viable cell density (VCD) and extended culture VCD phenotypes. Results We identified key pathways in DNA replication, mitotic cell cycle and evasion of p53 mediated apoptosis in high peak VCD clonally derived cell lines (CDCLs). ER to Golgi vesicle mediated transport was found to be highly expressed in extended culture VCD CDCLs while networks involving endocytosis and oxidative stress response were significantly downregulated. Conclusion This investigation highlights key pathways for targeted engineering to generate desirable CHO cell phenotypes for biotherapeutic production.

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