Indole Inhibitors of Human Nonpancreatic Secretory Phospholipase A<sub>2</sub>. 1. Indole-3-acetamides

Dillard, Robert D.; Bach, Nicholas J.; Draheim, Susan E.; Berry, Dennis R.; Carlson, Donald G.; Chirgadze, Nickolay Y.; Clawson, David K.; Hartley, Lawrence W.; Johnson, Lea M.; Jones, Noel D.; McKinney, Emma R.; Mihelich, Edward D.; Olkowski, Jennifer L.; Schevitz, Richard W.; Smith, Alex; Snyder, David W.; Sommers, Cynthia D.; Wery, Jean-Pierre

doi:10.1021/jm960485v

Cited by 79 publications

(52 citation statements)

References 33 publications

(41 reference statements)

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“…This mixture was washed with saturated NaHCO 3 (75 mL), and then brine (50 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo to produce an oil which was purified by chromatography (0% to 20% EtOAc/hexanes) to yield a white solid (2.80 g, 81%): mp 79–80 °C (76–80 °C [39]). TLC R f 0.55 (20% EtOAc/hexanes).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

Trabbic

George

Alexander

et al. 2016

European Journal of Medicinal Chemistry

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Certain indolyl-pyridinyl-propenone analogues kill glioblastoma cells that have become resistant to conventional therapeutic drugs. Some of these analogues induce a novel form of non-apoptotic cell death called methuosis, while others primarily cause microtubule disruption. Ready access to 5-indole substitution has allowed characterization of this position to be important for both types of mechanisms when a simple methoxy group is present. We now report the syntheses and biological effects of isomeric methoxy substitutions on the indole ring. Additionally, analogues containing a trimethoxyphenyl group in place of the pyridinyl moiety were evaluated for anticancer activity. The results demonstrate that the location of the methoxy group can alter both the potency and the mechanism of cell death. Remarkably, changing the methoxy from the 5-position to the 6-position switched the biological activity from induction of methuosis to disruption of microtubules. The latter may therefore represent a prototype for a new class of mitotic inhibitors with potential therapeutic utility.

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Section: Methodsmentioning

confidence: 99%

Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

Trabbic

George

Alexander

et al. 2016

European Journal of Medicinal Chemistry

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“…It should be noticed that Phe-5 is precisely the residue demonstrated by X-ray diffraction studies 40,41 to explain the preferred binding of indoxam derivatives to groups IB and IIA sPLA2s ( Figure 4C), by edge to face aromatic interactions with the indole ring of the synthetic inhibitors. [42][43][44] The exact value of the in silico screen is unknown since it would require assaying both all predicted active and inactive targets, which is unfortunately not feasible and is the basic justification of a computer-guided target prioritization. We cannot exclude having selected sPLA2 for wrong reasons.…”

Section: Discussionmentioning

confidence: 99%

In Silico-Guided Target Identification of a Scaffold-Focused Library: 1,3,5-Triazepan-2,6-diones as Novel Phospholipase A2 Inhibitors

et al. 2006

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A collection of 2150 druggable active sites from the Protein Data Bank was screened by high-throughput docking to identify putative targets for five representative molecules of a combinatorial library sharing a 1,3,5-triazepan-2,6-dione scaffold. Five targets were prioritized for experimental evaluation by computing enrichment in individual protein entries among the top 2% scoring targets. Out of the five proposed proteins, secreted phospholipase A2 (sPLA2) was shown to be a true target for a panel of 1,3,5-triazepan-2,6-diones which exhibited micromolar affinities toward two human sPLA2 members.

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“…Indole derivatives have been found to inhibit the catalytic function of PLA 2 -II [37][38][41][42][43][44][45][46]. As illustrated in Fig.…”

Section: Indoles As Inhibitors Of Plamentioning

confidence: 99%

Structural Elements of Ligand Recognition Site in Secretory Phospholipase A2 and Structure-Based Design of Specific Inhibitors

Singh

Somvanshi²,

Sharma³

et al. 2007

CTMC

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Phospholipases A2 (phosphotide 2-acylhydrolases, PLA2s, EC 3.1.1.4) are widely distributed enzymes in the animal world. They catalyze the hydrolysis of the sn-2 acyl ester linkage of phospholipids, producing fatty acids and lysophospholipids. The mammalian type II secreted phospholipase A2 (PLA2-II) is one of the most extensively studied member of low molecular weight (13-18 kDa) PLA2s. PLA2-II contains 120-125 amino acid residues and seven disulphide bridges. The important features of overall structure of PLA2-II contain an N-terminal helix, H1 (residues: 2-12), an external loop (residues: 14-23), a calcium binding loop (Ca2+-loop, residues: 25-35), a second alpha-helix, H2 (residues: 40-55), a short two stranded anti-parallel beta-sheet referred to as beta-wing (residues: 75-84), a third alpha-helix, H3 (residues: 90-108) which is antiparallel to H2 and two single helical turns, SH4 (residues: 114-117) and SH5 (residues: 121-125). The three-dimensional structure of PLA2-II has defined a conserved active site within a hydrophobic channel lined by invariant hydrophobic residues. The active site residues His48, Asp49, Tyr52 and Asp99 are directly connected to the channel. An important water molecule that bridges His48 and Asp49 through hydrogen bonds is a part of catalytic network. Based on the structures of various complexes of group II PLA2, the ligand-recognition site has been divided into six subsites consisting of residues 2-10 (subsite 1), residues 17-23 (subsite 2), residues 28-32 (subsite 3), residues 48-52 (subsite 4), residues 68-70 (subsite 5) and residues 98-106 (subsite 6). It is observed that most of the currently available ligands saturate only part of the ligand-recognition site leaving a wide scope to improve the ligand complementarity. Naturally, the ligands that interact with the largest number of subsites would also correspond to the maximum affinity. Therefore, for the design of potent inhibitors of PLA2, the stereochemical knowledge of the binding site as well as their potential to interact with ligands must be known so as to make the structure-based ligand design successful.

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Indole Inhibitors of Human Nonpancreatic Secretory Phospholipase A₂. 1. Indole-3-acetamides

Cited by 79 publications

References 33 publications

Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

In Silico-Guided Target Identification of a Scaffold-Focused Library: 1,3,5-Triazepan-2,6-diones as Novel Phospholipase A2 Inhibitors

Structural Elements of Ligand Recognition Site in Secretory Phospholipase A2 and Structure-Based Design of Specific Inhibitors

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Indole Inhibitors of Human Nonpancreatic Secretory Phospholipase A2. 1. Indole-3-acetamides

Cited by 79 publications

References 33 publications

Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

Synthesis and biological evaluation of isomeric methoxy substitutions on anti-cancer indolyl-pyridinyl-propenones: Effects on potency and mode of activity

In Silico-Guided Target Identification of a Scaffold-Focused Library: 1,3,5-Triazepan-2,6-diones as Novel Phospholipase A2 Inhibitors

Structural Elements of Ligand Recognition Site in Secretory Phospholipase A2 and Structure-Based Design of Specific Inhibitors

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Indole Inhibitors of Human Nonpancreatic Secretory Phospholipase A₂. 1. Indole-3-acetamides