10 research outputs found
Chemistry of Sulfines, Part V: Chemo- and Stereoselective Synthesis and Hetero-DielsâAlder Reactions of Stable Sulfines
<div><p></p><p>The stereoselective synthesis of a variety of Z-sulfines by the oxidation of organic trithiocarbonates with m-chloroperbenzoic acid (m-CPBA) is described. Transient E-sulfines that are formed upon heating of Z-sulfines during cycloaddition reactions were trapped with 2,3-dimethyl-1,3-butadiene to yield only one of the possible diastereomers of the functionalized cyclic allylic sulfoxides. An X-ray analysis and ab initio calculations were performed to provide insight into the steric course of the oxidation and cycloaddition reactions.</p>
<p>[Supplementary materials are available for this article. Go to the publisher's online edition of <i>Phosphorus, Sulfur, and Silicon and the Related Elements</i> for the following free supplemental files: Additional tables and figures.]</p>
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Cytotoxic Potential of Novel Quinoline Derivative: 11-(1,4-Bisaminopropylpiperazinyl)5-methyl-5H-indolo[2,3-b]quinoline against Different Cancer Cell Lines via Activation and Deactivation of the Expression of Some Proteins
The current study evaluated the cytotoxic activity of 11-(1,4-bisaminopropylpiperazinyl)5-methyl-5H-indolo[2,3-b]quinoline (BAPPN), a novel derivative of 5-methyl-5H-indolo[2,3-b]quinoline, against hepatocellular carcinoma (HepG2), colon carcinoma (HCT-116), breast (MCF-7), and lung (A549) cancer cell lines and the possible molecular mechanism through which it exerts its cytotoxic activity. BAPPN was synthesized and characterized with FT-IR and NMR spectroscopy. The binding affinity scores of BAPPN for caspase-3 PDB: 7JL7 was â7.836, with an RMSD of 1.483° A. In silico screening of ADME properties indicated that BAPPN showed promising oral bioavailability records in addition to their high gastrointestinal absorption and bloodâbrain barrier penetrability. BAPPN induced cytotoxicity, with IC50 values of 3.3, 23, 3.1, and 9.96 ÎŒg/mL against cancer cells HepG2, HCT-116, MCF-7, and A549, respectively. In addition, it induced cell injury and morphological changes in ultracellular structure, including cellular delayed activity, vanishing of membrane blebbing, microvilli, cytoplasmic condensation, and shrunken nucleus with more condensed chromatin autophagosomes. Furthermore, BAPPN significantly increased the protein expression of caspase-3 and tumor suppressor protein (P53). However, it significantly reduced the secretion of vascular endothelial growth factor (VEGF) protein into the medium and decreased the protein expression of proliferation cellular nuclear antigen (PCNA) and Ki67 in HepG2, HCT-116, MCF-7, and A549 cells. This study indicates that BAPPN has cytotoxic action against liver, colon, breast, and lung cancer cell lines via the up-regulation of apoptotic proteins, caspase-3 and P53, and the downregulation of proliferative proteins, VEGF, PCNA, and Ki67
Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38 alpha Mitogen-Activated Protein Kinase to c-Jun N-Terminal Kinase 3
Discovery and Evaluation of Enantiopure 9H-pyrimido[4,5-b]indoles as Nanomolar GSK-3ÎČ Inhibitors with Improved Metabolic Stability
Glycogen synthase kinase-3 beta (GSK-3 beta) is a potential target in the field of Alzheimer's disease drug discovery. We recently reported a new class of 9H-pyrimido[4,5-b]indole-based GSK-3 beta inhibitors, of which 3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile (1) demonstrated promising inhibitory potency. However, this compound underwent rapid degradation by human liver microsomes. Starting from 1, we prepared a series of amide-based derivatives and studied their structure-activity relationships against GSK-3 beta supported by 1 mu s molecular dynamics simulations. The biological potency of this series was substantially enhanced by identifying the eutomer configuration at the stereocenter. Moreover, the introduction of an amide bond proved to be an effective strategy to eliminate the metabolic hotspot. The most potent compounds, (R)-3-(3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)-3-oxopropanenitrile ((R)-2) and (R)-1-(3-((7-bromo-9Hpyrimido[4,5-b]indol-4-yl)(methyl)amino)piperidin-1-yl)propan-1-one ((R)-28), exhibited IC50 values of 480 nM and 360 nM, respectively, and displayed improved metabolic stability. Their favorable biological profile is complemented by minimal cytotoxicity and neuroprotective properties
Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3ÎČ Inhibitors
In small molecule binding, water is not a passive bystander but rather takes an active role in the binding site, which may be decisive for the potency of the inhibitor. Here, by addressing a high-energy water, we improved the IC50 value of our co-crystallized glycogen synthase kinase-3 beta (GSK-3 beta) inhibitor by nearly two orders of magnitude. Surprisingly, our results demonstrate that this high-energy water was not displaced by our potent inhibitor (S)-3-(3-((7-ethynyl-9H-pyrimido[ 4,5-b]-indol-4-yl)(methyl)amino)piperidin-1-yl)propanenitrile ((S)-15, IC50 value of 6 nM). Instead, only a subtle shift in the location of this water molecule resulted in a dramatic decrease in the energy of this high-energy hydration site, as shown by the WaterMap analysis combined with microsecond timescale molecular dynamics simulations. (S)-15 demonstrated both a favorable kinome selectivity profile and target engagement in a cellular environment and reduced GSK-3 autophosphorylation in neuronal SH-SY5Y cells. Overall, our findings highlight that even a slight adjustment in the location of a high-energy water can be decisive for ligand binding
Chemistry of Sulfines, Part V: Chemo- and Stereoselective Synthesis and Hetero-DielsâAlder Reactions of Stable Sulfines
Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to câJun NâTerminal Kinase 3
Starting from known
p38α mitogen-activated protein kinase
(MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal
kinase (JNK) 3 was obtained. Altering the substitution pattern of
the pyridinylimidazole scaffold proved to be effective in shifting
the inhibitory activity from the original target p38α MAPK to
the closely related JNK3. In particular, a significant improvement
for JNK3 selectivity could be achieved by addressing the hydrophobic
region I with a small methyl group. Furthermore, additional structural
modifications permitted to explore structureâactivity relationships.
The most potent inhibitor 4-(4-methyl-2-(methylthio)-1<i>H</i>-imidazol-5-yl)-<i>N</i>-(4-morpholinophenyl)Âpyridin-2-amine
showed an IC<sub>50</sub> value for the JNK3 in the low triple digit
nanomolar range and its binding mode was confirmed by X-ray crystallography
Structural Optimization of a Pyridinylimidazole Scaffold: Shifting the Selectivity from p38α Mitogen-Activated Protein Kinase to câJun NâTerminal Kinase 3
Starting from known
p38α mitogen-activated protein kinase
(MAPK) inhibitors, a series of inhibitors of the c-Jun N-terminal
kinase (JNK) 3 was obtained. Altering the substitution pattern of
the pyridinylimidazole scaffold proved to be effective in shifting
the inhibitory activity from the original target p38α MAPK to
the closely related JNK3. In particular, a significant improvement
for JNK3 selectivity could be achieved by addressing the hydrophobic
region I with a small methyl group. Furthermore, additional structural
modifications permitted to explore structureâactivity relationships.
The most potent inhibitor 4-(4-methyl-2-(methylthio)-1<i>H</i>-imidazol-5-yl)-<i>N</i>-(4-morpholinophenyl)Âpyridin-2-amine
showed an IC<sub>50</sub> value for the JNK3 in the low triple digit
nanomolar range and its binding mode was confirmed by X-ray crystallography