scholarly journals Synthesis and Cytotoxic Activity of Novel Metal Complexes Derived from Methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as Potential CDK8 Kinase Inhibitors

ACS Omega ◽  
2021 ◽  
Vol 6 (8) ◽  
pp. 5244-5254
Author(s):  
Ahmed Aboelmagd ◽  
Samir M. El Rayes ◽  
Mohamed S. Gomaa ◽  
Walid Fathalla ◽  
Ibrahim A. I. Ali ◽  
...  
Keyword(s):  
Metal Complexes ◽  
Cytotoxic Activity ◽  
Kinase Inhibitors

BTK Inhibitors, Irrespective of ITK Inhibition, Increase Efficacy of a CD19/CD3 Bispecific Antibody in CLL

Blood ◽  
2021 ◽  
Author(s):  
Maissa Mhibik ◽  
Erika M. Gaglione ◽  
David Eik ◽  
Ellen K Kendall ◽  
Amy Blackburn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Kinase Inhibitors ◽  
Bispecific Antibody ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Lymphocytic Leukemia ◽  
Peripheral Blood Mononuclear

Bruton Tyrosine Kinase inhibitors (BTKis) are a preferred treatment for patients with chronic lymphocytic leukemia (CLL). Indefinite therapy with BTKis, while effective, presents clinical challenges. Combination therapy can deepen responses, shorten treatment duration, and possibly prevent or overcome drug resistance. We previously reported on a CD19/CD3 bispecific antibody (bsAb) that recruits autologous T cell cytotoxicity against CLL cells in vitro. Compared to observations with samples from treatment-naïve patients, T cells from patients being treated with ibrutinib expanded more rapidly and exerted superior cytotoxic activity in response to the bsAb. In addition to BTK, ibrutinib also inhibits IL2 inducible T cell Kinase (ITK). In contrast, acalabrutinib, does not inhibit ITK. Whether ITK inhibition contributes to the observed immune effects is unknown. To better understand how BTKis modulate T-cell function and cytotoxic activity, we cultured peripheral blood mononuclear cells (PBMCs) from BTKi-naive, and ibrutinib- or acalabrutinib-treated CLL patients with CD19/CD3 bsAb in vitro. T-cell expansion, activation, differentiation, and cytotoxicity were increased in PBMCs from patients on treatment with either BTKi compared to that observed for BKTi-naïve patients. BTKi therapy transcriptionally downregulated immunosuppressive effectors expressed by CLL cells, including CTLA-4 and CD200. CTLA-4 blockade with ipilimumab in vitro increased the cytotoxic activity of the bsAb in BTKi-naïve but not BTKi-treated PBMCS. Taken together, BTKis enhance bsAb induced cytotoxicity by relieving T cells of immunosuppressive restraints imposed by CLL cells. The benefit of combining bsAb immunotherapy with BTKis needs to be confirmed in clinical trials.

scholarly journals Effect of tyrosine kinase inhibitors on the cytotoxic activity against HIV-1 infection

2017 ◽  
Vol 3 ◽  
pp. 51-52
Author(s):  
S. Rodríguez-Mora ◽  
G. Bautista ◽  
E. Mateos ◽  
V. García ◽  
J.L. Steegmann ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cytotoxic Activity ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Hiv 1

scholarly journals Synthesis, characterization and cytotoxic activity of naturally isolated naringin-metal complexes

2019 ◽  
Vol 27 (4) ◽  
pp. 584-592
Author(s):  
Emad M. Atta ◽  
Khaled H. Hegab ◽  
Ahmed A.M. Abdelgawad ◽  
Abdelghany A. Youssef
Keyword(s):  
Metal Complexes ◽  
Cytotoxic Activity

DNA/protein interaction and cytotoxic activity of imidazole terpyridine derived Cu(ii)/Zn(ii) metal complexes

2014 ◽  
Vol 43 (34) ◽  
pp. 13018 ◽  
Author(s):  
V. M. Manikandamathavan ◽  
T. Weyhermüller ◽  
R. P. Parameswari ◽  
M. Sathishkumar ◽  
V. Subramanian ◽  
...  
Keyword(s):  
Metal Complexes ◽  
Cytotoxic Activity ◽  
Protein Interaction ◽  
Dna Protein Interaction

scholarly journals Synthesis, characterization, antimicrobial screening and cytotoxic properties of Cu(II) and Zn(II) complexes with bidentate hydroxylated 1,3-diaryl-2-propene-1-ones ligand

2020 ◽  
pp. 68-68
Author(s):  
Pravinkumar Patil ◽  
Sainath Zangade
Keyword(s):  
Antimicrobial Activity ◽  
Metal Complexes ◽  
Cytotoxic Activity ◽  
Anticancer Agents ◽  
Cancer Cell Line ◽  
Artemia Salina ◽  
Carbonyl Oxygen ◽  
Planar Geometry ◽  
Ft Ir

A series of binary metal complexes [halo, hydroxyl and methoxy sub-stituted bis (2-(E) acryloyl)naphthalen-1-yl)oxy)Cu(II) and Zn(II) (C1-C10)] of Cu2+ and Zn2+ ions derived from bi-coordinated hydroxylated 1,3-diaryl-2- -propene-1-ones were synthesized. The newly synthesized metal complexes were structurally determined by FT-IR, 1H NMR, 13CNMR, ESR spectral, XRD and TGA analysis. The FT-IR and ESR studies demonstrated that interactions between metal ions with ligands occur through carbonyl oxygen and deprotonated hydroxyl oxygen and corresponds to square-planar geometry for all complexes. In-vitro the metal complexes were screened and evaluated for their antimicrobial and cytotoxic activity. The complexes C1 and C4 showed the significant antimicrobial activity while the remaining complexes were showed the moderately antimicrobial activity against the tested pathogens. The complexes were evaluated for cytotoxic activity against the organism Artemia salina. The complexes C2, C3, C4 and C5 were showed the LC50 values as 630.45, 969.99, 921.94 and 918.41 ?M mL-1 respectively. Further complexes were evaluated for anticancer activity against liver cancer cell line (Hep G2) in comparison with 5-fluorouracil standard. The complex C5 showed the significant IC50 value 58.94 ?g mL-1. Therefore the present study is useful to develop the new class of antimicrobial and anticancer agents.

scholarly journals Full Structural Characterization of Homoleptic Complexes of Diacetylcurcumin with Mg, Zn, Cu, and Mn: Cisplatin-level Cytotoxicity in Vitro with Minimal Acute Toxicity in Vivo

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1598 ◽  
Author(s):  
William Meza-Morales ◽  
M. Mirian Estévez-Carmona ◽  
Yair Alvarez-Ricardo ◽  
Marco A. Obregón-Mendoza ◽  
Julia Cassani ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Metal Complexes ◽  
Single Crystal ◽  
Cytotoxic Activity ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

At the present time, scientists place a great deal of effort worldwide trying to improve the therapeutic potential of metal complexes of curcumin and curcuminoids. Herein, the synthesis of four homoleptic metal complexes with diacetylcurcumin (DAC), using a ligand designed to prevent the interaction of phenolic groups, rendering metal complexes through the β-diketone functionality, is reported. Due to their physiological relevance, we used bivalent magnesium, zinc, copper, and manganese for complexation with DAC. The resulting products were characterized by ultraviolet-visible (UV-Vis), fluorescence spectroscopy, infrared spectroscopy (IR), liquid and solid-state nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), magnetic moment, mass spectrometry (MS), single crystal, and powder X-ray diffraction (SCXRD and PXRD). Crystallization was achieved in dimethylsulfoxide (DMSO) or N,N-dimethylformamide (DMF) as triclinic systems with space group P-1, showing the metal bound to the β-diketone function, while the 1H-NMR confirmed the preference of the enolic form of the ligand. Single crystal data demonstrated a 1:2 metal:ligand ratio. The inhibition of lipid peroxidation was evaluated using the thiobarbituric acid reactive substance assay (TBARS). All four metal complexes (Mg, Zn, Cu, and Mn) exhibited good antioxidant effect (IC50 = 2.03 ± 0.27, 1.58 ± 0.07, 1.58 ± 0.15 and 1.24 ± 0.10 μM respectively) compared with butylated hydroxytoluene (BHT) and α-tocopherol. The cytotoxic activity in human cancer cell lines against colon adenocarcinoma (HCT-15), mammary adenocarcinoma (MCF-7), and lung adenocarcinoma (SKLU-1) was found comparable ((DAC)2Mg), or ca. 2-fold higher ((DAC)2Zn) than cisplatin. The acute toxicity assays indicate class 5 toxicity, according to the Organization for Economic Co-operation and Development (OECD) guidelines at doses of 3 g/kg for all complexes. No mortality or changes in the behavior of animals in any of the treated groups was observed. A therapeutic potential can be envisaged from the relevant cytotoxic activity upon human cancer cell lines in vitro and the undetected in vivo acute toxicity of these compounds.

Design, Synthesis, Cytotoxic Activity and Apoptosis-inducing Action of Novel Cinnoline Derivatives as Anticancer Agents

2018 ◽  
Vol 18 (8) ◽  
pp. 1208-1217 ◽  
Author(s):  
Manal M. Kandeel ◽  
Aliaa M. Kamal ◽  
Bassem H. Naguib ◽  
Marwa S.A. Hassan
Keyword(s):  
Tyrosine Kinase ◽  
Cytotoxic Activity ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Topoisomerase I ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Normal Breast ◽  
Biologically Active

Aims: Tyrosine kinases and topoisomerase I are common target enzymes for the majority of the anticancer agents. In contrast to quinazolines and quinolines, kinase inhibitors and topoisomerase inhibitors incorporating cinnoline scaffold are relatively infrequent. Thus the aim of this work was to replace the former scaffolds with the latter one. Eighteen novel cinnoline derivatives were designed, synthesized and characterized using both microanalytical and spectral data. Methods: The cytotoxic activity of the new compounds was screened in vitro against both human breast cancer cells and normal breast cells. Results: The enzymatic inhibition activity of promising candidates against both epidermal growth factor receptor tyrosine kinase and topoisomerase I was accomplished. Conclusions: Cell cycle profiles were observed at IC50 doses of representative biologically active compounds. Compound 7 represented a new scaffold incorporating triazepinocinnoline ring system and showed outstanding cytotoxic activity against MCF-7 (0.049 µM), tyrosine kinase inhibition (0.22 µM), apoptosis percentage and the highest selectivity index.

Cytotoxic Effect of Bendamustine Combined with Kinase Inhibitors in Hematologic Cell Lines

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4912-4912
Author(s):  
Kazumi Hagiwara ◽  
Yuki Kojima ◽  
Yasuhiko Miyata ◽  
Hirokazu Nagai
Keyword(s):  
Cell Viability ◽  
B Cell ◽  
Cytotoxic Activity ◽  
Cell Line ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
Kinase Inhibitors ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dependent Manner

Abstract Abstract 4912 Bendamustine, a kind of alkylating agent, has demonstrated a favorable anti-tumor activity both alone and in combination with rituximab in low grade B cell lymphoma. Because the kinase cascades, including B-cell receptor signaling, are necessary for the proliferation and survival of the lymphoma cells, the kinase inhibitors have been developed as molecular target agents of malignant lymphomas. We investigated the cytotoxic effect of bendamustine, both as a single agent and in combination with these new kinase inhibitors in human lymphoid cell lines. We used three B-cell lines, BALL-1 (acute lymphoblastic leukemia), SKLY16 (B-cell lymphoma) and DHL4 (diffuse large B cell lymphoma), and T-cell line THP-6 in this study. These cells were treated with bendamustine alone or combined with enzastaurin (a PKC-β inhibitor), CAL-101 (a p110δ PI3K inhibitor), PCI-32765 (a Btk inhibitor) or R406 (a Syk inhibitor) for 48 hours. Drug-induced cytotoxicity was evaluated using the MTT assay. Cell viability in each experiment was normalized using untreated controls. The treatment with bendamustine alone decreased cell viability in a dose-dependent manner on these three B-cell lines. In contrast, T-cell line THP-6 showed the resistance to bendamusitine. For the combination study, cells were exposed to bendamustine (10μM) and one of these kinase inhibitors at various concentrations simultaneously for 48 hours. CAL-101 and PCI-32765 did not enhance the cytotoxic effect on all of B-cell lines. In BALL-1 and SKLY16 cells, the combination with enzastaurin or R406 resulted in a higher cytotoxic activity than that induced by bendamustine alone. In DHL4 cells, the treatment combined with R406 inhibited cell growth effectively, but not with enzastaurin. To evaluate whether these drug combinations are synergistic, a combination index (CI) was calculated and normalized isobolograms were constructed from non-constant ratio drug combinations using Calcusyn software. The CI values were less than 0. 7 in SKLY16 cells treated with bendamustine and enzastaurin, indicating that these produced synergistic cytotoxic effects in cell line-dependent manner. Our results show that enzastaurin might potentiate the cytotoxic activity of bendamustine in vitro and be a good candidate for the combination with bendamustine. Disclosures: No relevant conflicts of interest to declare.

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