Synthesis, X-ray structure,<i>in vitro</i>HIV and kinesin Eg5 inhibition activities of new arene ruthenium complexes of pyrimidine analogs

Al-Masoudi, Wasfi A.; Al‐Masoudi, Najim A.; Weibert, Bernhard; Winter, Rainer F.

doi:10.1080/00958972.2017.1334259

Cited by 10 publications

(12 citation statements)

References 41 publications

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“…monastrol: Yield: 65%; pale yellow powder; melting point (MP): 185-187 °C (lit. 185-186 °C ( 24 )); C14H16N2O3S; IR Vmax cm -1 : 3308 (broad band; O-H and N-H str. ), 3184 (C-H str.…”

Section: Resultsmentioning

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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“…monastrol: Yield: 65%; pale yellow powder; melting point (MP): 185-187 °C (lit. 185-186 °C ( 24 )); C14H16N2O3S; IR Vmax cm -1 : 3308 (broad band; O-H and N-H str. ), 3184 (C-H str.…”

Section: Resultsmentioning

confidence: 99%

Monastrol derivatives: in silico and in vitro cytotoxicity assessments

et al. 2020

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“…In contrast, the Ru and Os ( R )- 2 -type complexes were found to be significantly stronger KSP inhibitors than analogous ( S )- 2 complexes, with the former leading to a maximal inhibition of approximately 40% at 100 nM concentration. These results are especially interesting in view of the fact that ruthenium complexes of another KSP inhibitor, monastrol, were shown to exhibit lower KSP inhibitory activity than the parent compound. , …”

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

“…These results are especially interesting in view of the fact that ruthenium complexes of another KSP inhibitor, monastrol, were shown to exhibit lower KSP inhibitory activity than the parent compound. 58,59 Docking Study. In order to elucidate contrasting structural features of relevance to protein interaction for the organometallic compounds, molecular modeling was used to investigate the possible binding mode for the ligands (R)and (S)-2 and their half-sandwich complexes 3a−6b as well as the respective diastereomers 3a′, 3b′, 5a′, and 5b′ to KSP.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands

et al. 2020

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Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich complexes of Ru, Os, Rh, and Ir bearing the ispinesib-derived N , N -bidentate ligands ( R )- and ( S )-2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one and studies on their chemical and biological properties. Using the enantiomerically pure ( R )- and ( S )-forms of the ligand, depending on the organometallic moiety, either the S M , R or R M , S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η 6 - p -cymene) compounds, whereas the R M , R or S M , S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η 5 -pentamethylcyclopentadienyl) derivatives. However, density functional theory (DFT) calculations suggest that the energy difference between the diastereomers is very small, and therefore a mixture of both will be present in solution. The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the ( R )-enantiomer of the ligand being more potent than the ( S )-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active.

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“…Chemistry of half-sandwich arene–ruthenium(II) complexes has been intensively investigated in the recent years, due to their applications in different areas such as catalysis and pharmacology. Such complexes demonstrated high antiviral, − antibiotic, − and antitumor − activity.…”

Section: Introductionmentioning

confidence: 99%

Arene–Ruthenium(II) Complexes Containing 11H-Indeno[1,2-b]quinoxalin-11-one Derivatives and Tryptanthrin-6-oxime: Synthesis, Characterization, Cytotoxicity, and Catalytic Transfer Hydrogenation of Aryl Ketones

et al. 2020

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A series of novel mono- and binuclear arene–ruthenium(II) complexes [(p-cym)Ru(L)Cl] containing 11H-indeno[1,2-b]quinoxalin-11-one derivatives or tryptanthrin-6-oxime were synthesized and characterized by X-ray crystallography, IR, NMR spectroscopy, cyclic voltammetry, and elemental analysis. Theoretical calculations invoking singlet state geometry optimization, solvation effects, and noncovalent interactions were done using density functional theory (DFT). DFT calculations were also applied to evaluate the electronic properties, and time-dependent DFT was applied to clarify experimental UV–vis results. Cytotoxicity for cancerous and noncancerous human cell lines was evaluated with cell viability MTT assay. Complexes demonstrated a moderate cytotoxic effect toward cancerous human cell line PANC-1. The catalytic activity of the complexes was evaluated in transfer hydrogenation of aryl ketones. All complexes exhibited good catalytic activity and functional group tolerance.

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Synthesis, X-ray structure,in vitroHIV and kinesin Eg5 inhibition activities of new arene ruthenium complexes of pyrimidine analogs

Cited by 10 publications

References 41 publications

Monastrol derivatives: in silico and in vitro cytotoxicity assessments

Monastrol derivatives: in silico and in vitro cytotoxicity assessments

Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands

Arene–Ruthenium(II) Complexes Containing 11H-Indeno[1,2-b]quinoxalin-11-one Derivatives and Tryptanthrin-6-oxime: Synthesis, Characterization, Cytotoxicity, and Catalytic Transfer Hydrogenation of Aryl Ketones

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