Design of Fluorine-Containing 3,4-Diarylfuran-2(5<i>H</i>)-ones as Selective COX-1 Inhibitors

Uddin, Md. Jashim; Elleman, Anna V.; Ghebreselasie, Kebreab; Daniel, Cristina; Crews, Brenda C.; Nance, Kellie D.; Huda, Tamanna; Marnett, Lawrence J.

doi:10.1021/ml500344j

Cited by 32 publications

(17 citation statements)

References 30 publications

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“…Novel COX-1 selective compounds are now in preclinical development [ 60 – 62 ]. To test emerging COX-1 compounds for therapeutic and diagnostic purposes, we will pursue future studies using our OVCAR-3 and SKOV-3 isogenic cell lines as xenografts.…”

Section: Discussionmentioning

confidence: 99%

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Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

et al. 2015

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Cyclooxygenase-1 (COX-1) is implicated in ovarian cancer. However, patterns of COX expression and function have been unclear and controversial. In this report, patterns of COX-1 and COX-2 gene expression were obtained from RNA-seq data through The Cancer Genome Atlas. Our analysis revealed markedly higher COX-1 mRNA expression than COX-2 in high-grade serous ovarian cancers (HGSOC) and higher COX-1 expression in HGSOC tumors than 10 other tumor types. High expression of COX-1 in HGSOC tumors was confirmed in an independent tissue microarray. In contrast, lower or similar expression of COX-1 compared to COX-2 was observed in endometrioid, mucinous and clear cell tumors. Stable COX-1 knockdown in HGSOC-representative OVCAR-3 ovarian cancer cells reduced gene expression in multiple pro-tumorigenic pathways. Functional cell viability, clonogenicity, and migration/invasion assays were consistent with transcriptomic changes. These effects were reversed by stable over-expression of COX-1 in SKOV-3 cells. Our results demonstrate a distinct pattern of COX-1 over-expression in HGSOC tumors and strong association of COX-1 with multiple pro-tumorigenic pathways in ovarian cancer cells. These findings provide additional insight into the role of COX-1 in human ovarian cancer and support further development of methods to selectively target COX-1 in the management of HGSOC tumors.

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Section: Discussionmentioning

confidence: 99%

“…We acknowledge that COX-1 is expressed in a broad spectrum of tissues and has important physiologic functions and toxicities will need to be addressed in the development of systemic COX-1 inhibitors. However, as suggested by recent preclinical mouse models, COX-1 selective compounds have been well-tolerated [ 60 – 62 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

et al. 2015

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“…Over the last two decades, limited effort has been devoted to developing selective COX-1 inhibitors [7–9], possibly due to the scarce knowledge of COX-1 biology and its involvement in human diseases [10]. In contrast, many COX-2 inhibitors (COXIBs) have been identified and characterized at the molecular level, and found in most cases to contain a diarylheterocycle bearing either a sulfonamide or a methylsulfamoyl group.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cingolani

Panella

Perrone

et al. 2017

European Journal of Medicinal Chemistry

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The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.

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“…In addition, VU0487836 (Fig. ) identification provided the basis to further develop radiotracers to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX‐1 …”

Section: Cox‐1 Exploitation In Selected Diseasesmentioning

confidence: 99%

COX‐1 Inhibitors: Beyond Structure Toward Therapy

Vitale

Panella

Scilimati

et al. 2016

Medicinal Research Reviews

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Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.

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Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors

Cited by 32 publications

References 30 publications

Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

COX‐1 Inhibitors: Beyond Structure Toward Therapy

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