Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB2R affinity

Hassan, Ahmed H.E.; Cho, Min Chang; Kim, Hye In; Yang, Jae-Seung; Park, Kyung Tae; Hwang, Ji Young; Jang, Choon‐Gon; Park, Ki Duk; Lee, Yong Sup

doi:10.1016/j.bmc.2018.09.007

Cited by 6 publications

(2 citation statements)

References 31 publications

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“…Although lipids play crucial roles within cells, lipid-based therapeutics received relatively little attention in comparison with classical small molecules or peptide-based therapeutics which represent the principal focus of most of conducted drug discovery and development programs. In fact, lipids are not only major structural components of biological systems (e.g., glycerophospholipids in the cytoplasmic and cellular organelles’ membranes), but several lipids; such as endocannabinoids, eicosanoids, prostanoids, sphingomyelin, ceramides, are known as endogenous bioactive molecules triggering and/or modulating diverse biological functions and signalling pathways within cells 1–4 . Development of lipid analogs might offer new opportunities to modulate such lipid-mediated functions and signals 3–6 .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase

Hassan

Lee

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Phenethyl-based edelfosine-analogs with saturated, monounsaturated, or polyunsaturated alkoxy substituents on phenyl ring were designed as novel antitumor lipids modulating p38 MAPK. Evaluation of the synthesised compounds against nine panels of diverse cancer cells presented saturated and monounsaturated alkoxy-substituted derivatives as the most active than other derivatives. In addition, ortho -substituted compounds were more active than meta - or ortho -substituted compounds. They were potential anticancer agents against blood, lung, colon, CNS, ovary, renal, and prostate cancers but not against skin nor breast cancers. Compounds, 1b and 1a emerged as the most potential anticancer agents. Assessment of compound 1b impact on p38 MAPK and AKT confirmed it as an inhibitor of p38 MAPK but not AKT. In silico study suggested compounds 1b and 1a as possible binders to the lipid binding pocket of p38 MAPK. Overall, compounds 1b and 1a as novel broad spectrum antitumor lipids modulating activity of p38 MAPK for further development.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase

Hassan

Lee

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Many academic laboratories are focusing their efforts in identifying novel selective CB2R agonists, which show high affinity for this receptor and exhibit little or no affinity towards CB1R, with the aim of using these new compounds in the treatment of different chronic inflammatory pathologies avoiding the CB1R-related side effects [ 19 , 20 , 21 , 22 ]. However, it is known that selectivity, mechanism of action and pharmacokinetics of the most common CB2R ligands are still poorly characterized, which obviously hampers the translation of results from preclinical studies to clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Activity of a CB2 Selective Cannabinoid Receptor Agonist: Signaling and Cytokines Release in Blood Mononuclear Cells

et al. 2021

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The endocannabinoid system (ECS) exerts immunosuppressive effects, which are mostly mediated by cannabinoid receptor 2 (CBR2), whose expression on leukocytes is higher than CBR1, mainly localized in the brain. Targeted CBR2 activation could limit inflammation, avoiding CBR1-related psychoactive effects. Herein, we evaluated in vitro the biological activity of a novel, selective and high-affinity CBR2 agonist, called JT11, studying its potential CBR2-mediated anti-inflammatory effect. Trypan Blue and MTT assays were used to test the cytotoxic and anti-proliferative effect of JT11 in Jurkat cells. Its pro-apoptotic activity was investigated analyzing both cell cycle and poly PARP cleavage. Finally, we evaluated its impact on LPS-induced ERK1/2 and NF-kB-p65 activation, TNF-α, IL-1β, IL-6 and IL-8 release in peripheral blood mononuclear cells (PBMCs) from healthy donors. Selective CB2R antagonist SR144528 and CBR2 knockdown were used to further verify the selectivity of JT11. We confirmed selective CBR2 activation by JT11. JT11 regulated cell viability and proliferation through a CBR2-dependent mechanism in Jurkat cells, exhibiting a mild pro-apoptotic activity. Finally, it reduced LPS-induced ERK1/2 and NF-kB-p65 phosphorylation and pro-inflammatory cytokines release in human PBMCs, proving to possess in vitro anti-inflammatory properties. JT11 as CBR2 ligands could enhance ECS immunoregulatory activity and our results support the view that therapeutic strategies targeting CBR2 signaling could be promising for the treatment of chronic inflammatory diseases.

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Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study

Hassan

Park

Kim

et al. 2020

Bioorganic Chemistry

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Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB2R affinity

Cited by 6 publications

References 31 publications

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase

Anti-Inflammatory Activity of a CB2 Selective Cannabinoid Receptor Agonist: Signaling and Cytokines Release in Blood Mononuclear Cells

Fluorinated CRA13 analogues: Synthesis, in vitro evaluation, radiosynthesis, in silico and in vivo PET study

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