Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis

Dodo, Kosuke; Kuboki, Erika; Shimizu, Tadashi; Imamura, Ryu; Magarisawa, Megumi; Takahashi, Masahiro; Tokuhiro, Takuto; Yotsumoto, Satoshi; Asano, Kenichi; Nakao, Shuhei; Terayama, Naoki; Suda, Takafumi; Tanaka, Masato; Sodeoka, Mikiko

doi:10.1021/acsmedchemlett.9b00142

Cited by 7 publications

(8 citation statements)

References 31 publications

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“…Given the potential for interaction between different forms of cell death (Fig. 5 ), pan-cell death inhibitors that act on two or three pathways may increase the likelihood of success 71 , 95 , 166 , 227 , 228 . However, safety concerns may be exacerbated by such an approach.…”

Section: Discussionmentioning

confidence: 99%

Regulated cell death pathways in kidney disease

et al. 2023

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Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death — including apoptosis and necrosis — have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.

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Section: Discussionmentioning

confidence: 99%

Regulated cell death pathways in kidney disease

et al. 2023

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“…The combined organic phases were dried on sodium sulphate, concentrated under reduced pressure, and purified by chromatography (silica gel, EtOAc:hexane 4 : 1) to yield 3-bromo-1-methyl-4-(3indolyl)maleimide as an orange coloured solid in 78 % yield. [7,8] Procedure for synthesis of 3-bromo-4-(1-methyl-1H-indol-3-yl)-1methyl-1H-pyrrole-2,5-dione (1). To a solution of 3-bromo-1-methyl-4-(3-indolyl)maleimide (4.63 mmol) in acetone (20 mL), K 2 CO 3 (1.5 equiv.)…”

Section: Discussionmentioning

confidence: 99%

“…Then the crude mixture was purified using column chromatography (silica gel, EtOAc:hexane 1.5 : 8.5) to obtain the methylated compound 1 with 72 % yield. [8] General procedure for the synthesis of 1 a-1 j'. A pressure tube was charged with 1 (0.3 mmol, 100 mg), substituted/unsubstituted anilines and 2-aminopyridines (0.45 mmol, 1.5 equiv.…”

Section: Discussionmentioning

confidence: 99%

“…Sodeoka et al synthesized 3-bromo-1-methyl-4-(1-methyl-3-indolyl)maleimide (1) and performed S N Ar reactions with a variety of aliphatic and cyclic amines (Scheme 1a). [8] Inaba et al performed synthesis of anilino-monoindolylmaleimides (5) by heating 3-hydroxymaleimide (4) with an excess amount of amine in AcOH (Scheme 1b). [9] Zhao et al treated 3-bromo-4-indolylmaleimide (6) with sodium azide to get 3-azideindolylmaleimide, which was reduced by PPh 3 to give 3-aminoindolylmaleimides (7).…”

Section: Introductionmentioning

confidence: 99%

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Efficient Pd‐catalysed Synthesis of 3‐Amino‐4‐indolylmaleimides and 3‐Amido‐4‐indolylmaleimides

Das,

Verma,

Indurthi

et al. 2024

ChemistrySelect

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The Buchwald–Hartwig cross‐coupling reaction of 3‐bromo‐4‐indolylmaleimide with various anilines, aminopyridines and amides is described. A wide variety of 3‐amino‐4‐indolylmaleimides and 3‐amido‐4‐indolylmaleimides was prepared in good to excellent yields. We envisage that our protocol to access 3‐(amino/amido)‐4‐indolylmaleimides will find use towards constituting new potentially biologically active compounds.

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“…Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal cellular levels [69]. GPX4 converts potentially toxic lipid hydroperoxides (L-OOH) to non-toxic lipid alcohols (L-OH).…”

Section: Discussionmentioning

confidence: 99%

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

Liu

Wang

et al. 2020

J Nanobiotechnol

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Primary intracerebral hemorrhage (ICH) is a leading cause of long-term disability and death worldwide. Drug delivery vehicles to treat ICH are less than satisfactory because of their short circulation lives, lack of specific targeting to the hemorrhagic site, and poor control of drug release. To exploit the fact that metal ions such as Fe 2+ are more abundant in peri-hematomal tissue than in healthy tissue because of red blood cell lysis, we developed a metal ion-responsive nanocarrier based on a phosphonated calix[4]arene derivative in order to deliver the neuroprotective agent dauricine (DRC) specifically to sites of primary and secondary brain injury. The potential of the dauricine-loaded nanocarriers for ICH therapy was systematically evaluated in vitro and in mouse models of autologous whole blood double infusion. The nanocarriers significantly reduced brain water content, restored blood-brain barrier integrity and attenuated neurological deficits by inhibiting the activation of glial cells, infiltration by neutrophils as well as production of proinflammatory factors (IL-1β, IL-6, TNF-α) and matrix-metalloprotease-9. These results suggest that our dauricine-loaded nanocarriers can improve neurological outcomes in an animal model of ICH by reducing inflammatory injury and inhibiting apoptosis and ferroptosis.

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Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis

Cited by 7 publications

References 31 publications

Regulated cell death pathways in kidney disease

Regulated cell death pathways in kidney disease

Efficient Pd‐catalysed Synthesis of 3‐Amino‐4‐indolylmaleimides and 3‐Amido‐4‐indolylmaleimides

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage

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