Synthesis of novel 5-substituted indirubins as protein kinases inhibitors (original) (raw)
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An Evaluation of Indirubin Analogues as Phosphorylase Kinase Inhibitors
Journal of Molecular Graphics and Modelling, 2015
Phosphorylase kinase (PhK) has been linked with a number of conditions such as glycogen storage diseases, psoriasis, type 2 diabetes and more recently, cancer (Camus S. et al., Oncogene 2012, 31, 4333). However, with few reported structural studies on PhK inhibitors, this hinders a structure based drug design approach. In this study, the inhibitory potential of 38 indirubin analogues have been investigated. 11 of these ligands had IC50 values in the range 0.170-0.360 µM, with indirubin-3'-acetoxime (1c) the most potent. 7-bromoindirubin-3'-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas J. et al., Oncogene, 2006, 25, 6304) is revealed as a specific inhibitor of PhK (IC50 = 1.8 µM). Binding assay experiments performed using both PhK-holo and PhK-γtrnc confirmed the inhibitory effects to arise from binding at the kinase domain (γ subunit). High level computations using QM/MM-PBSA binding free energy calculations were in good agreement with experimental binding data, as determined using statistical analysis, and support binding at the ATP-binding site. The value of a QM description for the binding of halogenated ligands exhibiting σ-hole effects is highlighted. A new statistical metric, the 'sum of the modified logarithm of ranks' (SMLR), has been defined which measures performance of a model for both the "early recognition" (ranking earlier/higher) of active compounds and their relative ordering by potency. Through a detailed structure activity relationship analysis considering other kinases (CDK2, CDK5 and GSK-3α/β), 6'(Z) and 7(L) indirubin substitutions have been identified to achieve selective PhK inhibition. The key PhK binding site residues involved can also be targeted using other ligand scaffolds in future work.
Synthesis of new indirubin derivatives and their in vitro anticancer activity
Chemical Papers, 2018
The opening of epoxy rings from (2′Z)-N-1-(oxiran-2-ylmethyl)indirubin (2) and (2′Z-3′E)-indirubin-3ʹ-[O-oxiran-2-ylmethyl) oxime] (6) with thiols gave 17 new derivatives of indirubin in good yields. Their structures were elucidated by 1D-, 2D-NMR and HRMS spectra. Screening for anticancer activity was performed with four human cancer cell lines: SW480, LU-1, HepG2 and HL-60 in comparison with indirubin, indirubin-3′-oxime and 6-mercaptopurine. The results showed that cytotoxic and anti-proliferative activities of five derivatives were found in the range of 1.35-19.24 µM. Among synthesized derivatives, 4f showed the strongest activity against all four tested cancer cell lines with IC 50 values of 1.65, 2.21, 1.90 and 1.35 µM, respectively.
Inhibitory Effects of Indirubin Derivatives on the Growth of HL-60 Leukemia Cells
Natural Product Communications, 2010
Six indirubin derivatives have been synthesized and their inhibitory effects on the growth of HL-60 human promyelocytic leukemia cells investigated. Cell viability was determined using the trypan blue exclusion method. Indirubin-3′-oxime (I-1) inhibited the growth of HL-60 cells with a GI50 value of 36.6 μM, whereas I-0, I-2, I-3, I-4 and I-6 showed only weak cytotoxic activities against HL-60 cancer cells with GI50 values in the range of 97.3 to over 100 μM. These results indicate that indirubin derivatives might be useful candidate agents for exploring potential antileukemic drugs.
Novel Inverse Binding Mode of Indirubin Derivatives Yields Improved Selectivity for DYRK Kinases
ACS Medicinal Chemistry Letters, 2013
DYRK kinases are involved in alternative pre-mRNA splicing as well as in neuropathological states such as Alzheimer's disease and Down syndrome. In this study, we present the design, synthesis, and biological evaluation of indirubins as DYRK inhibitors with enhanced selectivity. Modifications of the bis-indole included polar or acidic functionalities at positions 5′ and 6′ and a bromine or a trifluoromethyl group at position 7, affording analogues that possess high activity and pronounced specificity. Compound 6i carrying a 5′-carboxylate moiety demonstrated the best inhibitory profile. A novel inverse binding mode, which forms the basis for the improved selectivity, was suggested by molecular modeling and confirmed by determining the crystal structure of DYRK2 in complex with 6i. Structure−activity relationships were further established, including a thermodynamic analysis of binding site water molecules, offering a structural explanation for the selective DYRK inhibition.
Scientific Reports, 2020
The addition of chalcone and amine components into indirubin-3′-oxime resulted in 15 new derivatives with high yields. Structures of new derivatives were also elucidated through 1D, 2D-NMR and HR-MS(ESI) spectra and X-ray crystallography. All designed compounds were screened for cytotoxic activity against four human cancer cell lines (HepG2, LU-1, SW480 and HL-60) and one human normal kidney cell line (HEK-293). Compound 6f exhibited the most marked cytotoxicity meanwhile cytotoxicity of compounds 6e, 6h and 6l was more profound toward cancer cell lines than toward normal cell. These new derivatives were further analyzed via molecular docking studies on GSK-3β enzyme. Docking analysis shows that most of the derivatives exhibited potential inhibition activity against GSK-3β with characteristic interacting residues in the binding site. The fast pulling of ligand scheme was then employed to refine the binding affinity and mechanism between ligands and GSK-3β enzyme. The computational r...
Journal of Medicinal Chemistry, 2008
Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective as GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues of 6-bromo-indirubin-3′-oxime with increased hydrophilicity based on the GSK-3/indirubins cocrystal structures. The new derivatives with an extended amino side chain attached at position 3′ showed potent GSK-3 inhibitory activity, enhanced selectivity, and dramatically increased water solubility. Furthermore, some of them displayed little or no cytotoxicity. The new indirubins inhibit GSK-3 in a cellular reporter model. They alter the circadian period measured in rhythmically expressing cell cultures, suggesting that they might constitute tools to investigate circadian rhythm regulation. targets. 27,28,32-36 The second is the bromine substitution at position 6, which is the selectivity determinant of 6BIO toward A detailed analysis of the crystal structure of GSK-3 in complex with 6BIO 27,28 provided critical information suggesting that the 3′ position might be ideal for carrying out chemical modifications on the indirubin scaffold. We thus designed and synthesized a series of 6-bromo-indirubins with various substitutions on position 3′. Some of these molecules displayed high potency toward GSK-3, enhanced selectivity, and much increased water solubility. These molecules were evaluated for their GSK-3 inhibitory actions in several cellular systems.