scholarly journals Design, Synthesis and in vitro Evaluation of 2-(Quinoline-8-sulfonamido)pentanedioic Acid Analogues as Antiangiogenic and Antitumor Agents on Multiple Myeloma

2021 ◽  
Vol 33 (8) ◽  
pp. 1764-1770
Author(s):  
Avijit Ghosh ◽  
Abhijit Saha ◽  
Koushik Sarker ◽  
Suvasish Mishra ◽  
Subrata Sen
Keyword(s):  
Multiple Myeloma ◽  
Anticancer Agents ◽  
Antitumor Agents ◽  
In Vitro Study ◽  
Binding Mode ◽  
Amino Acid Residues ◽  
Design Synthesis ◽  
Human Multiple Myeloma ◽  
Pentanedioic Acid

Thalidomide is presently approved as antiangiogenic and anticancer drug in multiple myeloma. The authors present a number of analogue-based designs of N-(o-carboxybenzoyl)-DL-glutamic acid, a major thalidomide metabolite. The compounds were synthesized and biologically tested in multiple myeloma as anticancer agents. Three compounds inhibited HUVEC proliferation at low micromolar concentrations, indicating that they are antiangiogenic and cytotoxic to human multiple myeloma RPMI8226. The active compounds were tested for antiproliferative activity on HUVECs using the dye exclusion method with trypan blue. Dimethyl-2-(quinoline-8-sulfonamido)pentanedioate (2c), in particular, inhibits VEGFR-2 phosphorylation at the Tyr-1175 residue, as determined by SDS PAGE. The binding mode of (2c) was predicted in silico in order to better understand how it interacts with essential amino acid residues in the VEGFR-2 active site. The binding energy was calculated as -161.41kcal/mol. in vitro Study of the compounds on the Vero cell line shows less toxicity towards the normal endothelial cells than the cancer cells.

scholarly journals Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 4053-4062 ◽  
Author(s):  
Teru Hideshima ◽  
Laurence Catley ◽  
Hiroshi Yasui ◽  
Kenji Ishitsuka ◽  
Noopur Raje ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mononuclear Cells ◽  
Antitumor Agents ◽  
Mek Inhibitor ◽  
Peripheral Blood Mononuclear ◽  
Akt Phosphorylation ◽  
Human Multiple Myeloma ◽  
Induced Apoptosis

Perifosine is a synthetic novel alkylphospholipid, a new class of antitumor agents which targets cell membranes and inhibits Akt activation. Here we show that baseline phosphorylation of Akt in multiple myeloma (MM) cells is completely inhibited by perifosine [octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate] in a time- and dose-dependent fashion, without inhibiting phosphoinositide-dependent protein kinase 1 phosphorylation. Perifosine induces significant cytotoxicity in both MM cell lines and patient MM cells resistant to conventional therapeutic agents. Perifosine does not induce cytotoxicity in peripheral blood mononuclear cells. Neither exogenous interleukin-6 (IL-6) nor insulinlike growth factor 1 (IGF-1) overcomes Perifosine-induced cytotoxicity. Importantly, Perifosine induces apoptosis even of MM cells adherent to bone marrow stromal cells. Perifosine triggers c-Jun N-terminal kinase (JNK) activation, followed by caspase-8/9 and poly (ADP)-ribose polymerase cleavage. Inhibition of JNK abrogates perifosine-induced cytotoxicity, suggesting that JNK plays an essential role in perifosine-induced apoptosis. Interestingly, phosphorylation of extracellular signal–related kinase (ERK) is increased by perifosine; conversely, MEK inhibitor synergistically enhances Perifosine-induced cytotoxicity in MM cells. Furthermore, perifosine augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced MM cell cytotoxicity. Finally, perifosine demonstrates significant antitumor activity in a human plasmacytoma mouse model, associated with down-regulation of Akt phosphorylation in tumor cells. Taken together, our data provide the rationale for clinical trials of perifosine to improve patient outcome in MM.

The design, synthesis, in vitro biological evaluation and molecular modeling of novel benzenesulfonate derivatives bearing chalcone moieties as potent anti-microtubulin polymerization agents

RSC Advances ◽  
2015 ◽  
Vol 5 (30) ◽  
pp. 23767-23777 ◽  
Author(s):  
Yu-Ning Shen ◽  
Lin Lin ◽  
Han-Yue Qiu ◽  
Wen-Yan Zou ◽  
Yong Qian ◽  
...  
Keyword(s):  
Amino Acid ◽  
Molecular Modeling ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Amino Acid Residues ◽  
Design Synthesis

Binding mode of compound 6b with microtubule (PDB code: 1SA0). (a) 2D diagram of the interaction between compound 6b and amino acid residues of colchicine site nearby. (b) 3D diagram of compound 6b inserted in microtubulin colchicine site.

RATIONAL DESIGN, SYNTHESIS AND IN VITRO EVALUATION OF N-(4-ETHOXYPHENYLSULFONYL)-L-GLUTAMIC ACID ANALOGUES AS ANTIANGIOGENIC AND ANTICANCER AGENTS ON MULTIPLE MYELOMA

INDIAN DRUGS ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 26-35
Author(s):  
Abhijit Saha ◽  
Koushik Sarker ◽  
Avijit Ghosh ◽  
Suvasish Mishra ◽  
Subrata Sen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Glutamic Acid ◽  
Anticancer Agents ◽  
Rational Design ◽  
Umbilical Vein ◽  
Cytotoxic Action ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
African Green Monkey Kidney

We report the rational design, synthesis and evaluation of the anticancer and antiangiogenic activity of the N-(4-ethoxyphenylsulfonyl)-L-glutamic acid analogs on multiple myeloma. From the series, compound 2c, 2f, and 2h exhibit cytotoxic action on human multiple myeloma cell line RPMI8226 with IC50 (μM) value 2.72, 2.24, and 1.81, respectively. These compounds possess the antiangiogenic property and are selectively cytotoxic to cancer cells, as observed from the in vitro study of Human Umbilical Vein Endothelial Cell (HUVEC) and African green monkey kidney epithelial cell (VERO), respectively. The compounds also have an antiproliferative effect on HUVECs, which was carried out using the dye exclusion method with trypan blue. Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Tyr-1175 phosphorylation inhibition assay showed compound 2f, and 2h to be the active inhibitors of roangiogenic responses mediated by VEGFR-2. A molecular docking study of 2f with VEGFR-2 showed possible interaction with a binding energy of -74.19 kcal/mol.

scholarly journals Design, Synthesis, Molecular Docking and in vitro Evaluation of N-(4-Ethoxyphenylsulfonyl)pyrrolidine-2-carboxylic Acid Analogues as Antiangiogenic and Anticancer Agents on Multiple Myeloma

2021 ◽  
Vol 33 (4) ◽  
pp. 727-733
Author(s):  
A. GHOSH ◽  
A. SAHA ◽  
K. SARKER ◽  
S. MISHRA ◽  
S. SEN
Keyword(s):  
Multiple Myeloma ◽  
Molecular Docking ◽  
Carboxylic Acid ◽  
Anticancer Agents ◽  
Umbilical Vein ◽  
Growth Factor Receptor ◽  
In Vitro Study ◽  
Cytotoxic Action ◽  
Molecular Docking Study

In present work, N-(4-ethoxyphenylsulfonyl)pyrrolidine-2-carboxylic acid analogs were designed, synthesized and biologically evaluated as an antiangiogenic and anticancer agent on multiple myeloma. Compounds 3i, 3k and 3m exhibited the cytotoxic action on human multiple myeloma cell line RPMI8226 with IC50 (μM) value 3.72, 3.89 2.28, respectively. These compounds possessed the antiangiogenic property and are selectively cytotoxic to cancer cells, as observed from the in vitro study of human umbilical vein endothelial cell (HUVEC) and African green monkey epithelial cell (VERO), respectively. Antiproliferative assay of the compounds on HUVECs was carried out using the dye exclusion method with trypan blue. Molecular docking study of compound 3m with vascular endothelial growth factor receptor-2 (VEGFR-2) showed possible interaction with a binding energy -62.27 kcal/mol.

Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

2019 ◽  
Vol 16 (10) ◽  
pp. 837-845
Author(s):  
Sandhya Jonnala ◽  
Bhaskar Nameta ◽  
Murthy Chavali ◽  
Rajashaker Bantu ◽  
Pallavi Choudante ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Mouse Skin ◽  
Coupling Reaction ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

Design, Synthesis, In vitro and In silico Evaluation of New Hydrazonebased Antitumor Agents as Potent Akt Inhibitors

2020 ◽  
Vol 17 (11) ◽  
pp. 1380-1392
Author(s):  
Emine Merve Güngör ◽  
Mehlika Dilek Altıntop ◽  
Belgin Sever ◽  
Gülşen Akalın Çiftçi
Keyword(s):  
Cell Line ◽  
Anticancer Agents ◽  
In Silico ◽  
Antitumor Agents ◽  
Colorimetric Assay ◽  
Fibroblast Cell ◽  
Lipinski’S Rule ◽  
In Silico Docking ◽  
Embryonic Fibroblast

Background: Akt is overexpressed or activated in a variety of human cancers, including gliomas, lung, breast, ovarian, gastric and pancreatic carcinomas. Akt inhibition leads to the induction of apoptosis and inhibition of tumor growth and therefore extensive efforts have been devoted to the discovery of potent antitumor drugs targeting Akt. Objectives: The objective of this work was to identify potent anticancer agents targeting Akt. Methods: New hydrazone derivatives were synthesized and investigated for their cytotoxic effects on 5RP7 H-ras oncogene transformed rat embryonic fibroblast and L929 mouse embryonic fibroblast cell lines. Besides, the apoptotic effects of the most active compounds on 5RP7 cell line were evaluated using flow cytometry. Their Akt inhibitory effects were also investigated using a colorimetric assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package. Results and Discussion: Compounds 3a, 3d, 3g and 3j were found to be effective on 5RP7 cells (with IC50 values of <0.97, <0.97, 1.13±0.06 and <0.97 μg/mL, respectively) when compared with cisplatin (IC50= 1.87±0.15 μg/mL). It was determined that these four compounds significantly induced apoptosis in 5RP7 cell line. Among them, N'-benzylidene-2-[(4-(4-methoxyphenyl)pyrimidin- 2-yl)thio]acetohydrazide (3g) significantly inhibited Akt (IC50= 0.5±0.08 μg/mL) when compared with GSK690693 (IC50= 0.6±0.05 μg/mL). Docking studies suggested that compound 3g showed good affinity to the active site of Akt (PDB code: 2JDO). According to in silico ADME studies, the compound also complies with Lipinski's rule of five and Jorgensen's rule of three. Conclusion: Compound 3g stands out as a potential orally bioavailable cytotoxic agent and apoptosis inducer targeting Akt.

Design, Synthesis, In Vitro and In Silico Studies of Some Novel Triazoles as Anticancer Agents for Breast Cancer

2021 ◽  
pp. 131198
Author(s):  
Derya Osmaniye ◽  
Begum Nurpelin Saglik ◽  
Serkan Levent ◽  
Sinem Ilgın ◽  
Yusuf Ozkay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
In Silico ◽  
Design Synthesis ◽  
In Silico Studies

scholarly journals Pterostilbene Inhibits Human Multiple Myeloma Cells via ERK1/2 and JNK Pathway In Vitro and In Vivo

2016 ◽  
Vol 17 (11) ◽  
pp. 1927 ◽  
Author(s):  
Bingqian Xie ◽  
Zhijian Xu ◽  
Liangning Hu ◽  
Gege Chen ◽  
Rong Wei ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Jnk Pathway ◽  
Myeloma Cells ◽  
Human Multiple Myeloma
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