Structure-based design, synthesis and preliminary anti-inflammatory activity of bolinaquinone analogues

Petronzi, Carmen; Filosa, Rosanna; Peduto, Antonella; Monti, Maria Chiara; Margarucci, Luigi; Massa, António; Ercolino, Simona Francesca; Bizzarro, Valentina; Parente, Luca; Riccio, Raffaele; Caprariis, P. De

doi:10.1016/j.ejmech.2010.11.028

Cited by 33 publications

(16 citation statements)

References 21 publications

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“…Bolinaquinone is a sesquiterpene hydroquinone/quinone belonging to one class of marine sponge metabolites, which have received considerable attention due to their varied biological activities . Aiming at the improvement in the bolinaquinone activity, we proposed structural changes in the basic molecule variations in the aromatic system and evaluated the inhibition of PGE 2 production in the LPS‐treated RAW 264.7 cells .…”

Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationship of Terpenes with Anti‐Inflammatory Profile – A Systematic Review

Souza

Almeida

Araújo

et al. 2014

Basic Clin Pharma Tox

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Inflammation is a complex biological response that in spite of having available treatments, their side effects limit their usefulness. Because of this, natural products have been the subject of incessant studies, among which the class of terpenes stands out. They have been the source of study for the development of anti-inflammatory drugs, once their chemical diversity is well suited to provide skeleton for future anti-inflammatory drugs. This systematic review reports the studies present in the literature that evaluate the anti-inflammatory activity of terpenes suffering any change in their structures, assessing whether these changes also brought changes in their effects. The search terms anti-inflammatory agents, terpenes, and structure-activity relationship were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between January 2002 and August 2013. Twenty-seven papers were found concerning the structural modification of terpenes with the evaluation of antiinflammatory activity. The data reviewed here suggest that modified terpenes are an interesting tool for the development of new anti-inflammatory drugs.

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Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationship of Terpenes with Anti‐Inflammatory Profile – A Systematic Review

Souza

Almeida

Araújo

et al. 2014

Basic Clin Pharma Tox

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“…However, in the presence of Na 2 CO 3 as base and a mixture of H 2 O/THF as solvent, was obtained the best results (Entry 7) [15]. …”

Section: Methodsmentioning

confidence: 99%

Cyclohexa-2,5-diene-1,4-dione-based antiproliferative agents: design, synthesis, and cytotoxic evaluation

Petronzi

Festa

Peduto

et al. 2013

J Exp Clin Cancer Res

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BackgroundTumors are diseases characterized by uncontrolled cell growth and, in spite of the progress of medicine over the years, continue to represent a major threat to the health, requiring new therapies. Several synthetic compounds, such as those derived from natural sources, have been identified as anticancer drugs; among these compounds quinone represent the second largest class of anticancer agents in use. Several studies have shown that these act on tumor cells through several mechanisms. An important objective of this work is to develop quinoidscompounds showing antitumor activity, but with fewer side effects. The parachinone cannabinol HU-331, is a small molecule that with its core 4-hydroxy-1,4-benzoquinone, exhibits a potent and selective cytotoxic activity on different tumor cell lines. A series of derivatives 3-hydroxy-1,4-benzochinoni were thus developed through HU-331 chemical modifications. The purpose of the work is to test the ability of the compounds to induce proliferative inhibition and study the mechanisms of cell death.MethodsThe antitumor activities were evaluated in vitro by examining their cytotoxic effects against different human cancer cell lines. All cell lines tested were plated in 96-multiwell and treated with HU-100-V at different concentrations and cell viability was evaluated byMTT assay. Subsequently via flow cytometry (FACS) it was possible to assess apoptosis by the system of double labeling with PI and Annexin-V, and the effect of the compounds on ROS formation by measuring the dichlorofluorescein fluorescence.ResultsThe substitution by n-hexyl chain considerably enhanced the bioactivity of the compounds. In details, 2-hexyl-5-hydroxycyclohexa-2,5-diene-1,4-dione (V), 2,5-Dimethoxy-3-hexyl-2,5-cyclohexadiene-1,4-dione (XII) and 2-hydroxy-5-methoxy-3-hexyl-cyclohexa-2,5-diene-1,4-dione (XIII) showed most prominent cytotoxicity against almost human tumour cell lines. Compound V was further subjected to downstream apoptotic analysis, demostrating a time-dependent pro-apoptotic activity on human melanoma M14 cell line mediated by caspases activation and poly-(ADP-ribose)-polymerase (PARP) protein cleavage.ConclusionsThese findings indicate that 2-hexyl-5-idrossicicloesa-2,5-diene-1,4-dione can be a promising compound for the design of a new class of antineoplastic derivatives.Carmen Petronzi, Michela Festa, Antonella Peduto and Maria Castellano: equally contributed equally to this work.

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“…We have recently discovered a series of 1,4‐benzoquinones, exemplified by 3‐((decahydronaphthalen‐6‐yl)methyl)‐2,5‐dihydroxycyclohexa‐2,5‐diene‐1,4‐dione (RF‐Id; Figure ), that act as potent inhibitors of 5‐LOX in human neutrophils (IC 50 = 0.58 μM; Filosa et al ., ). Compounds possessing a 1,4‐benzoquinone moiety exhibit multiple biological properties, including antioxidant, anti‐inflammatory and anti‐cancer activities (Dandawate et al ., ; Petronzi et al ., 2011; 2013; Schaible et al ., ). The anti‐inflammatory effects of 1,4‐benzoquinones have been found to be associated with suppression of LT formation (Werz, ), and the 1,4‐benzoquinone AA‐861 (Figure ) is a well‐recognized 5‐LOX inhibitor (Yoshimoto et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4‐benzoquinone that inhibits 5‐lipoxygenase

Schaible

Filosa

Temml

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSE1,4-Benzoquinones are well-known inhibitors of 5-lipoxygenase (5-LOX, the key enzyme in leukotriene biosynthesis), but the molecular mechanisms of 5-LOX inhibition are not completely understood. Here we investigated the molecular mode of action and the pharmacological profile of the novel 1,4-benzoquinone derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id) in vitro and its effectiveness in vivo. EXPERIMENTAL APPROACHMechanistic investigations in cell-free assays using 5-LOX and other enzymes associated with eicosanoid biosynthesis were conducted, along with cell-based studies in human leukocytes and whole blood. Molecular docking of RF-Id into the 5-LOX structure was performed to illustrate molecular interference with 5-LOX. The effectiveness of RF-Id in vivo was also evaluated in two murine models of inflammation. KEY RESULTSRF-Id consistently suppressed 5-LOX product synthesis in human leukocytes and human whole blood. RF-Id also blocked COX-2 activity but did not significantly inhibit COX-1, microsomal PGE2 synthase-1, cytosolic PLA2 or 12-and 15-LOX. Although RF-Id lacked radical scavenging activity, reducing conditions facilitated its inhibitory effect on 5-LOX whereas cell stress impaired its efficacy. The reduced hydroquinone form of RF-Id (RED-RF-Id) was a more potent inhibitor of 5-LOX as it had more bidirectional hydrogen bonds within the 5-LOX substrate binding site. Finally, RF-Id had marked anti-inflammatory effects in mice in vivo. CONCLUSIONS AND IMPLICATIONSRF-Id represents a novel anti-inflammatory 1,4-benzoquinone that potently suppresses LT biosynthesis by direct inhibition of 5-LOX with effectiveness in vivo. Mechanistically, RF-Id inhibits 5-LOX in a non-redox manner by forming discrete molecular interactions within the active site of 5-LOX.

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Structure-based design, synthesis and preliminary anti-inflammatory activity of bolinaquinone analogues

Cited by 33 publications

References 21 publications

Structure–Activity Relationship of Terpenes with Anti‐Inflammatory Profile – A Systematic Review

Structure–Activity Relationship of Terpenes with Anti‐Inflammatory Profile – A Systematic Review

Cyclohexa-2,5-diene-1,4-dione-based antiproliferative agents: design, synthesis, and cytotoxic evaluation

Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4‐benzoquinone that inhibits 5‐lipoxygenase

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