Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents

Fu, Rong-Geng; You, Qidong; Yang, Lei; Wu-tong, WU; Jiang, Cheng; Xu, Xiu

doi:10.1016/j.bmc.2010.09.020

Cited by 39 publications

(8 citation statements)

References 18 publications

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“…In order to better rationalize SAR of the proposed monastrol’s analogs and gain insights into the binding mode of molecules within the motor domain of Eg5, molecular docking studies were conducted. Among available X- ray structures of the Eg5-monastrol complex, the structure (PDB ID: 1Q0B) with a high resolution (1.9 Å) was chosen ( 6 27 28 29 ). The accuracy of the docking protocol was validated by removing the co-crystallized monastrol from the binding site of Eg5 and redocking into the active site.…”

Section: Discussionmentioning

confidence: 99%

Monastrol derivatives: in silico and in vitro cytotoxicity assessments

et al. 2020

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Background and purpose: Cancer is the leading cause of death in today’s world, therefore the efforts to achieve anticancer drugs with higher potency and fewer side effects have always been conducted by researchers in the field of pharmaceutical chemistry. Monastrol, a cytotoxic small molecule, from dihydropyrimidinone scaffold, is an inhibitor of the kinesin-5 protein. So, efforts to identify more derivatives of this molecule have been of interest. Experimental approach: Some of monastrol’s analogs as Eg5 inhibitors with different substitution patterns were analyzed, synthesized, and their cytotoxic effects were evaluated on MCF-7 and HeLa cancerous cells in vitro using the MTT assay. The structure-activity relationship (SAR) was studied in silico by molecular docking. Findings / Results: Among all proposed structures, in ducking study, those with hydrophobic moieties on the C2-N3 region, those with a hydroxyl group on the phenyl on C4 position, and those with a carboxylic group on C5 were the best candidates. In vitro studies, on the other side, emphasized that monastrol still was the most potent derivative. Another finding was the more moderate activity of synthesized compounds on the HeLa cell compared to the MCF-7 cell line. During different challenges for substitution at 5-position, some earlier reports around the dihydropyrimidinone reactions were questioned. It seems that the change at the position 5 is not merely accessible, as earlier reports claimed. Also, we could not achieve any better cell cytotoxicity by the larger group in the thiourea region or position 5; nonetheless, it seems that the introduction of a methylene group at this position could be beneficial. Conclusion and implications: The initial results of this study were valuable in terms of design and synthesis and will be useful for future investigations.

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Section: Discussionmentioning

confidence: 99%

Monastrol derivatives: in silico and in vitro cytotoxicity assessments

et al. 2020

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“…For details of hydrogen-bond motifs, see: Bernstein et al (1995). For background to and bioactivity of pyrazole derivatives, see: Ali (2009); Bharate et al (2008); Fu et al (2010); Thumar & Patel (2011). For a related structure, see: Fun et al (2011).…”

Section: Related Literaturementioning

confidence: 99%

“…Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2009). properties such as anti-cancer (Fu et al, 2010), anti-inflammatory (Bharate et al, 2008) and antimicrobial activities (Ali, 2009;Thumar & Patel, 2011). Pyrazolopyridine, a fused heterocycle, is of interest as a component of potential bioactive molecules.…”

Section: Crystal Datamentioning

confidence: 99%

5,6-Dimethyl-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

et al. 2012

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In the title molecule, C12H12N4S, the thiophene ring is disordered over two orientations with a refined site-occupancy ratio of 0.777 (4):0.223 (4). The pyrazolopyridine ring system is essentially planar with an r.m.s. deviation of 0.0069 (3) Å and makes dihedral angles of 82.8 (2) and 72.6 (5)°, respectively, with the major and minor components of the thiophene ring. In the crystal, molecules are linked into a chain along the a axis by a pair of N—H⋯N(pyrazole) hydrogen bonds and a pair of N—H⋯N(pyridine) hydrogen bonds, both having a centrosymmetric R 2 2(8) graph-set motif. A C—H⋯π interaction is also present.

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“…For example, Fu et al . have reported the Lewis acid FeCl 3 catalysed synthesis of dihydropyrazolo[3,4‐ b ]pyridines in a one‐pot manner from aldehydes, acetoacetanilides and 3‐amino‐pyrazoles under an ethanol medium [21] . Similar heterocyclization involving 1,3‐cyclohexanedione instead of acetoacetanilide led to the formation of pyrazolo[3,4‐ b ]quinoline analogues in PEG medium at 110 °C [22] .…”

Section: Introductionmentioning

confidence: 99%

Polyethylene glycol (PEG‐400) Mediated One‐pot Green Synthesis of 4,7‐Dihydro‐2H‐pyrazolo[3,4‐b]pyridines Under Catalyst‐free Conditions

et al. 2020

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Polyethylene glycol (PEG‐400) was proved a highly efficient and green solvent reaction medium for the synthesis of series of novel 3,6‐dimethyl‐4,7‐dihydro‐2H‐pyrazolo[3,4‐b]pyridine derivatives with excellent yields by a three‐component reaction of 1H‐pyrazol‐3‐amino‐5‐methyl, various aromatic or heteroaromatic aldehydes and chosen CH‐active compounds under catalyst‐free conditions via one‐pot strategy. This transformation is compatible with a broad diversity of functional group tolerance. Rapid synthesis, mild reaction conditions, high yields, no catalyst or column chromatography, cost‐effectiveness and green solvent are the benefits of this protocol.

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Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents

Cited by 39 publications

References 18 publications

Monastrol derivatives: in silico and in vitro cytotoxicity assessments

Monastrol derivatives: in silico and in vitro cytotoxicity assessments

5,6-Dimethyl-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine

Polyethylene glycol (PEG‐400) Mediated One‐pot Green Synthesis of 4,7‐Dihydro‐2H‐pyrazolo[3,4‐b]pyridines Under Catalyst‐free Conditions

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