Novel synthesised flavone derivatives provide significant insight into the structural features required for enhanced anti-proliferative activity

Ravishankar, Divyashree; Watson, Kimberly A.; Greco, Francesca; Osborn, Helen M. I.

doi:10.1039/c6ra11041j

Cited by 30 publications

(43 citation statements)

References 63 publications

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“…Exhaustive O -methylation of quercetin to the 3,3′,4′,5,7- O -pentamethyl derivative ( 20 , Figure 4 ) followed by thionation gave access to compound 54 , which was eventually deprotected yielding 53 [ 55 , 56 ]. It has been shown that both compounds possess in vitro antiangiogenic and antiproliferative properties [ 55 ].…”

Section: Synthesis and Anticancer-related Activities Of Quercetin mentioning

confidence: 99%

“…Overall, derivative 20 was found to be the top of the line as it optimally balanced the high antiangiogenic activity with minimal toxicity. Further antiproliferative studies using breast cancer cell line MDA-MB-231 evidenced that the 4-thio compounds, and in particular 53 , had greater effects than 20 and the parent quercetin [ 56 ]. However, 53 did not reach the IC 50 at 10 μM.…”

Section: Synthesis and Anticancer-related Activities Of Quercetin mentioning

confidence: 99%

“…The co-occurrence of a C-4 selenocarbonyl residue and methoxy substituents at 3,3′,4′,7 positions led to a dramatic increase of cytotoxicity [ 54 ]. Also, the unprotected thionated analog proved to possess greater antiproliferative effects than the mother flavone [ 56 ]. These results indicated that the chalcogenated carbonyl function rather than the flavonoid framework seemed to determine biological activity.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

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Research Progress in the Modification of Quercetin Leading to Anticancer Agents

et al. 2017

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The flavonoid quercetin (3,3′,4′,5,7-pentahydroxyflavone) is widely distributed in plants, foods, and beverages. This polyphenol compound exhibits varied biological actions such as antioxidant, radical-scavenging, anti-inflammatory, antibacterial, antiviral, gastroprotective, immune-modulator, and finds also application in the treatment of obesity, cardiovascular diseases and diabetes. Besides, quercetin can prevent neurological disorders and exerts protection against mitochondrial damages. Various in vitro studies have assessed the anticancer effects of quercetin, although there are no conclusive data regarding its mode of action. However, low bioavailability, poor aqueous solubility as well as rapid body clearance, fast metabolism and enzymatic degradation hamper the use of quercetin as therapeutic agent, so intense research efforts have been focused on the modification of the quercetin scaffold to obtain analogs with potentially improved properties for clinical applications. This review gives an overview of the developments in the synthesis and anticancer-related activities of quercetin derivatives reported from 2012 to 2016.

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Section: Synthesis and Anticancer-related Activities Of Quercetin mentioning

confidence: 99%

Section: Synthesis and Anticancer-related Activities Of Quercetin mentioning

confidence: 99%

Section: Structure-activity Relationshipmentioning

confidence: 99%

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Research Progress in the Modification of Quercetin Leading to Anticancer Agents

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“…The synthetic flavones used in this study are grouped into four main classes namely; hydroxy flavones with free –OH and 4-C=O, hydroxy 4-thioflavones with free –OH and 4-C=S, methoxy flavones with –OMe and 4-C=O and methoxy 4-thioflavones with–OMe and 4-C=S 35 . The hydroxy flavones include 7,8-dihydroxy-2-phenyl-4 H -chromen-4-one (F-1), 7,8-dihydroxy-2(thiophen-2-yl)-4 H -chromen-4-one (F-2), 2-(furan-2-yl)-7-8,dihydroxy-4 H -chromen-4-one (F-3) and 7,8-dihydroxy-2(pyridine-3yl)-4 H -chromen-4-one (F-4).…”

Section: Methodsmentioning

confidence: 99%

Impact of specific functional groups in flavonoids on the modulation of platelet activation

Ravishankar

Salamah

Akimbaev

et al. 2018

Sci Rep

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Flavonoids exert innumerable beneficial effects on cardiovascular health including the reduction of platelet activation, and thereby, thrombosis. Hence, flavonoids are deemed to be a molecular template for the design of novel therapeutic agents for various diseases including thrombotic conditions. However, the structure-activity relationships of flavonoids with platelets is not fully understood. Therefore, this study aims to advance the current knowledge on structure-activity relationships of flavonoids through a systematic analysis of structurally-related flavones. Here, we investigated a panel of 16 synthetic flavones containing hydroxy or methoxy groups at C-7,8 positions on the A-ring, with a phenyl group or its bioisosteres as the B-ring, along with their thio analogues possessing a sulfur molecule at the 4th carbon position of the C-ring. The antiplatelet efficacies of these compounds were analysed using human isolated platelets upon activation with cross-linked collagen-related peptide by optical aggregometry. The results demonstrate that the hydroxyl groups in flavonoids are important for optimum platelet inhibitory activities. In addition, the 4-C=O and B ring phenyl groups are less critical for the antiplatelet activity of these flavonoids. This structure-activity relationship of flavonoids with the modulation of platelet function may guide the design, optimisation and development of flavonoid scaffolds as antiplatelet agents.

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“…Further, studies focusing on the blood-brain barrier (BBB) permeability of flavonoids have highlighted that the lipophilic flavonoids possess greater BBB permeability than the polar flavonoids 22,23 ; the permeability potency of the compounds also correlated with their lipophilicity (log P) [24][25][26] . With our interest in developing novel flavone derivatives as therapeutic agents, we had previously synthesised and characterised a library of 76 hydroxy flavones, methoxy flavones and their 4-thio derivatives 27 (Figure- (Figure-1). The purities of all compounds were established prior to evaluation, by reverse phase HPLC, and were found to be >95%.…”

Section: A R T I C L E I N F O Abstract 1 Introductionmentioning

confidence: 99%

Thioflavones as novel neuroprotective agents

Ravishankar

Corona

Hogan

et al. 2016

Bioorganic & Medicinal Chemistry

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Oxidative stress is associated with the pathology of neurodegenerative diseases. Identification of small molecules capable of protecting against oxidative stress is therefore of significant importance. In this context, a library of 76 hydroxy flavones, methoxy flavones and their 4-thio analogues has been evaluated for neuroprotection against HO-induced oxidative stress. This revealed the synthetic 7,8-dihydroxy 4-thioflavones as neuroprotective compounds, with 14d and 18d showing highest neuroprotective effects at lower concentrations (0.3μM). Neuroprotection was found to be mediated via activation of the anti-apoptotic cell survival proteins of the ERK1/2 and PI3K/Akt pathways. Structure-activity relationship analysis revealed the B-ring phenyl group as essential for greater neuroprotection. Replacing the 4-CO moiety with a 4-CS moiety also generally enhanced neuroprotection.

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Novel synthesised flavone derivatives provide significant insight into the structural features required for enhanced anti-proliferative activity

Abstract: Synthesis and antiproliferative evaluation of a library of 76 methoxy and hydroxy flavones, and their 4-thio analogues showed that the novel thioflavones 15f and 16f exhibit 7–46 fold greater anti-proliferative potency than the natural flavone chrysin (2d).

Cited by 30 publications

References 63 publications

Research Progress in the Modification of Quercetin Leading to Anticancer Agents

Research Progress in the Modification of Quercetin Leading to Anticancer Agents

Impact of specific functional groups in flavonoids on the modulation of platelet activation

Thioflavones as novel neuroprotective agents

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