Dataset Information

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

ABSTRACT: Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack ? character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

SUBMITTER: Xing H

PROVIDER: S-EPMC6436534 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Xing Hui H Houston Sevan D SD Chen Xuejie X Ghassabian Sussan S Fahrenhorst-Jones Tyler T Kuo Andy A Murray Cody-Ellen P CP Conn Kyna-Anne KA Jaeschke Kara N KN Jin Da-Yun DY Pasay Cielo C Bernhardt Paul V PV Burns Jed M JM Tsanaktsidis John J Savage G Paul GP Boyle Glen M GM De Voss James J JJ McCarthy James J Walter Gimme H GH Burne Thomas H J THJ Smith Maree T MT Tie Jian-Ke JK Williams Craig M CM

Chemistry (Weinheim an der Bergstrasse, Germany) 20190125 11

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the tw ...[more]

PMID: 30681236

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Project description:PurposeWe determined bioactivity of lysophospholipids generated by degradation of the low-density (LDL), very low-density (VLDL), and high-density (HDL) lipoproteins with hepatic lipase (HL), cholesterol esterase (CE), and lipoprotein-associated phospholipase A2 (Lp-PLA2).MethodsThe LDL, VLDL, and HDL were treated with HL, CE, and Lp-PLA2 after immobilization on plates, and complement activation studies were performed with diluted human serum. Complement component 3 (C3) fixation, a marker for complement activation, was determined with a monoclonal anti-human C3d antibody. Enzymatic properties of HL and CE were assayed with triglyceride and phosphatidylcholine substrates for triglyceride hydrolase and phospholipase A activities. The ARPE-19 cells were used for viability studies.ResultsThe HL degradation of human lipoproteins LDL, VLDL, or HDL results in the formation of modified lipoproteins that can activate the complement pathway. Complement activation is dose- and time-dependent upon HL and occurs via the classical pathway. Enzymatic studies suggest that the phospholipase A1 activity of HL generates complement-activating lysophospholipids. C-reactive protein (CRP), known to simultaneously interact with complement C1 and complement factor H (CFH), further enhances HL-induced complement activation. The lysophospholipids, 1-Palmitoyl-sn-glycero-3-phosphocholine and 1-Oleoyl-sn-glycero-3-phosphocholine, can be directly cytotoxic to ARPE-19 cells.ConclusionsThe HL degradation of lipoproteins, known to accumulate in the outer retina and in drusen, can lead to the formation of bioactive lysophospholipids that can trigger complement activation and induce RPE cellular dysfunction. Given the known risk associations for age-related macular degeneration (AMD) with HL, CRP, and CFH, this study elucidates a possible damage pathway for age-related macular degeneration (AMD) in genetically predisposed individuals, that HL activity may lead to accumulation of lysophospholipids to initiate complement activation, with CFH dysregulation exacerbating the effects of this process.

Dataset Information

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Publications

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Similar Datasets

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