Design, synthesis and evaluation of 3-quinoline carboxylic acids as new inhibitors of protein kinase CK2

Aim.To search for new CK2 inhibitors by virtual screening. Methods. Virtual screening of a small organic compounds library was performed by molecular docking using the Autodock 4.2.6 package and pharmacophore screening with the "PharmDeveloper" program. The compound activity was determined by in vitro biochemical tests using γ-P32 ATP. Results. 298 compounds were selected for biochemical testing according to the results of virtual screening. In vitro experiments showed that 18 compounds have inhibitory activity against CK2 with IC 50 in the range of 1.4 to 20 μM. The active compounds belonged to 15 chemical classes. Conclusions. A number of effective CK2 inhibitors were found using molecular modeling and biochemical testing methods. LE values of these compounds were higher than 0.3 that makes these compounds excellent candidates for further drug development. K e y w o r d s:CK2 protein kinase, molecular docking, pharmacophore modeling, virtual screening, in vitro testing.is the most pleiotropic kinase among the protein kinase superfamily [2]. One of the explanations of such a pleiotropy may be that CK2 is present in all compartments of the cell from the nuclear to the plasma membrane, where it can interact with a large number of substrates [3, 4]. Taking into account all these facts, it is not surprisingly that CK2 is involved

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“…The receptor was prepared using MGL Tools and AutoGrid [24]. We have used docking parameters reported earlier [26]. They are shown in table 1.…”

Section: Molecular Dockingmentioning

confidence: 99%

Hit identification of CK2 inhibitors by virtual screening

et al. 2017

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“…As we all know, carboxylic acids (RCOOH) can often be used to synthetize all kinds of products, such as polymers, pharmaceuticals [ 1 ] (Scheme 1), solvent, and food additives. Along with the development of science and technology, many kinds of carboxylic acids have been produced industrially on a large scale.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Csp²–H functionalization of aldehydes with triplet O₂ catalyzed by NHPI: A density functional theory investigation

Deng

Zhou

2020

J of Physical Organic Chem

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The mechanisms of Csp2–H activation of aldehydes to yield carboxylic acids catalyzed by NHPI have been investigated with M06‐2X‐D3/ma‐def2‐TZVP method and basis set in the Universal Solvation Model Based on Solute Electron Density (SMD). The computational results suggest that the activation of NHPI, rather than aldehydes, would be finished by triplet O2 with lower energy barrier. The obtained radicals PINO and HOO˙ could help to achieve this Csp2–H activation of aldehydes, then triplet O2 would continue to react with generated intermediate to obtain Criegee intermediate radical; the following H‐shift reactions happened to produce Criegee intermediate; finally, SN2 reaction would help to yield the final product carboxylic acid. Meanwhile, the obtained carboxylic acid radical captures one proton to yield carboxylic acid. The localized orbital locator (LOL) isosurfaces of pi orbitals, and electron spin density isosurface graphs could reveal the single electron transfer process. The results would provide valuable insights into these types of interactions and related ones.

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Novel quinoline derivatives carrying nitrones and oxime as nitric oxide donors were prepared and characterized using different spectroscopic techniques. Several mechanisms can explain the anticancer effect of quinoline derivatives including: topoisomerase inhibition, [21][22][23] DNA intercalation, [24] protein kinases inhibition, [25][26][27] tubulin polymerase inhibition, [28][29][30][31] and induction of apoptosis. Antiproliferative screening results showed that the 2-benzylthioquinoline nitrones 6e and 6f and the 2-methylthio analogues 6g and 6h exhibited promising antiproliferative activity especially against leukemia and colon cancer cell lines.

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mentioning

confidence: 99%

Novel quinoline derivatives carrying nitrones/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase-3 activation activities

Abdelbaset

Abdel‐Aziz

Abuo‐Rahma

et al. 2018

Arch. Pharm. Chem. Life Sci.

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Novel quinoline derivatives carrying nitrones and oxime as nitric oxide donors were prepared and characterized using different spectroscopic techniques. Nitrones can release nitric oxide in larger amounts compared to corresponding oximes. Antiproliferative screening results showed that the 2-benzylthioquinoline nitrones 6e and 6f and the 2-methylthio analogues 6g and 6h exhibited promising antiproliferative activity especially against leukemia and colon cancer cell lines. Compounds 6c, 6e, and 6f exhibited higher potency as anticancer agents compared to doxorubicin, with IC 50 ranging from 0.45 to 0.91 μM. A remarkable overexpression of caspase-3 protein levels was observed in cells treated with the tested compounds. Compound 6e exhibited more pre-G1 apoptosis and cell cycle arrest at the G2/M phase than in other phases.These results revealed that the tested compounds can cause programmed cell death through overexpression of caspase 3, which may be attributed to the release of nitric oxide. K E Y W O R D S antiproliferative, apoptosis, caspase 3, nitric oxide, nitrones, oximes 1 | INTRODUCTION Quinoline is a significant nucleus which has attracted the attention of medicinal chemists due to its variable pharmacological activities. Easy functionalization of various ring positions of quinoline makes it an attractive synthetic building block for design and synthesis of new drugs. Additionally, quinolines are considered as an interesting group of compounds, many of which have widespread pharmacologicalactions such as anti-microbial, [1][2][3][4] anti-inflammatory, [5][6][7][8] antitubercular, [9][10][11][12] anti-convulsant, [13] antihypertensive, [14,15] antioxidant, [16][17][18][19] and anticancer [20] activities. Several mechanisms can explain the anticancer effect of quinoline derivatives including: topoisomerase inhibition, [21][22][23] DNA intercalation, [24] protein kinases inhibition, [25][26][27] tubulin polymerase inhibition, [28][29][30][31] and induction of apoptosis. [32,33] Quinoline derivative I exhibited potent anticancer activity against brain cancer cell line U87 with IC 50 of 1.5 nM. [31] Compound II exhibits remarkable anticancer activity against HL60 cancer cell line with IC 50 of 0.68 μM (Figure 1). [33] Incorporation of biologically active moieties into quinoline such as nitrones [34] and oximes [35] may produce biologically active anticancer agents.Compound III showed significant anticancer activity with IC 50 of 31.42 μM against Hep-G 2 cancer cell line (Figure 1). [34] Nitrones are a Arch Pharm Chem Life Sci. 2019;352:e1800270.wileyonlinelibrary.com/journal/ardp

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Design, synthesis and evaluation of 3-quinoline carboxylic acids as new inhibitors of protein kinase CK2

Cited by 25 publications

References 27 publications

Hit identification of CK2 inhibitors by virtual screening

Hit identification of CK2 inhibitors by virtual screening

Mechanisms of Csp²–H functionalization of aldehydes with triplet O₂ catalyzed by NHPI: A density functional theory investigation

Novel quinoline derivatives carrying nitrones/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase-3 activation activities

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Design, synthesis and evaluation of 3-quinoline carboxylic acids as new inhibitors of protein kinase CK2

Cited by 25 publications

References 27 publications

Hit identification of CK2 inhibitors by virtual screening

Hit identification of CK2 inhibitors by virtual screening

Mechanisms of Csp2–H functionalization of aldehydes with triplet O2 catalyzed by NHPI: A density functional theory investigation

Novel quinoline derivatives carrying nitrones/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase-3 activation activities

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Mechanisms of Csp²–H functionalization of aldehydes with triplet O₂ catalyzed by NHPI: A density functional theory investigation