Chemistry of Sulfines, Part V: Chemo- and Stereoselective Synthesis and Hetero-Diels–Alder 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> </div

Synthesis and antimalarial activity of some neocryptolepine analogues carrying a multifunctional linear and branched carbon-side chains

The synthesis and in vitro antimalarial activity of several neocryptolepine analogues carrying either a linear or branched dibasic side chain at C11 are described. Many of these neocryptolepine analogues have low nanomolar antimalarial activity against the chloroquine-sensitive P. falciparum strain (NF54). The data also dernonstrated that a branched structural motif is not superior for antimalarial activity over a linear side chain, but their thioureido derivatives showed lower cytotoxicity than the linear one. Ureido and thioureido derivatives also showed stronger beta-haematin inhibition than the corresponding free amine

Synthesis and in vitro testing of antimalarial activity of non-natural-type neocryptolepines : structure-activity relationship study of 2,11- and 9,11-disubstituted 6-methylindolo[2,3-b]quinolines

This report describes the synthesis and in vitro anti-malarial evaluations of certain C2 or C8 and C11-disubstituted 6-methyl-5H-indolo[2,3-b]quinoline (neocryptolepine congener) derivatives. To attain higher activities, the structure-activity relationship (SAR) studies were conducted by varying the kind of alkylamino or ?-aminoalkylamino stubstituents at C11 and with Cl at the C2 position, or CO2Me at the C9 position. The anti-malarial activities of the tested compounds were significantly increased compared to the 11-non(alkylamino) derivatives. The 3-aminopropylamino group at C11 was further modified to urea and thiourea, which improved the cytotoxicity against normal cells. The best results were achieved with compounds 8 and 9d against the NF54 strain with the IC50/SI values as of 86 nM/20 and 317 nM/370, respectively. Furthermore, the compounds were tested for ?-haematin inhibition. Twelve were found to have IC50 values below 100 µM and a linear correlation between the ?-haematin inhibition and cell growth inhibition in the NF54 strain was found for those derivatives with basic amino side chains. A second correlation was identified between the NF54 activity and physico-chemical factors related to solvation and polarity

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 −7.836, 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 blood–brain barrier penetrability. BAPPN induced cytotoxicity, with IC50 values of 3.3, 23, 3.1, and 9.96 μg/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

Discovery and evaluation of enantiopure 9H-pyrimido[4,5\u2010b]indoles as nanomolar GSK\u20103\u3b2 inhibitors with improved metabolic stability

Glycogen synthase kinase\u20103\u3b2 (GSK\u20103\u3b2) is a potential target in the field of Alzheimer\u2019s disease drug discovery. We recently reported a new class of 9H\u2010pyrimido[4,5\u2010b]indole\u2010based GSK\u2010 3\u3b2 inhibitors, of which 3\u2010(3\u2010((7\u2010chloro\u20109H\u2010pyrimido[4,5\u2010b]indol\u20104\u2010yl)(methyl)amino)piperidin\u20101\u2010yl)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\u2010based derivatives and studied their structure\u2013activity relationships against GSK\u20103\u3b2 supported by 1 \u3bcs 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)\u20103\u2010(3\u2010((7\u2010chloro\u20109H\u2010pyrimido[4,5\u2010b]indol\u20104\u2010 yl)(methyl)amino)piperidin\u20101\u2010yl)\u20103\u2010oxopropanenitrile ((R)\u20102) and (R)\u20101\u2010(3\u2010((7\u2010bromo\u2010 9Hpyrimido[4,5\u2010b]indol\u20104\u2010yl)(methyl)amino)piperidin\u20101\u2010yl)propan\u20101\u2010one ((R)\u201028), 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

Discovery and Evaluation of Enantiopure 9H-pyrimido[4,5-b]indoles as Nanomolar GSK-3β 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-3β 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