66585-05-5Relevant articles and documents
Oxygenolysis of a series of copper(ii)-flavonolate adducts varying the electronic factors on supporting ligands as a mimic of quercetin 2,4-dioxygenase-like activity
Anoop, Anakuthil,Dey, Subhasis,Mandal, Sukanta,Podder, Nirmalya
supporting information, p. 4338 - 4353 (2022/04/07)
Four copper(ii)-flavonolate compounds of type [Cu(LR)(fla)] {where LR = 2-(p-R-benzyl(dipyridin-2-ylmethyl)amino)acetate; R = -OMe (1), -H (2), -Cl (3) and -NO2 (4)} have been developed as a structural and functional enzyme-substrate (ES) model of the Cu2+-containing quercetin 2,4-dioxygenase enzyme. The ES model complexes 1-4 are synthesized by reacting 3-hydroxyflavone in the presence of a base with the respective acetate-bound copper(ii) complexes, [Cu(LR)(OAc)]. In the presence of dioxygen the ES model complexes undergo enzyme-type oxygenolysis of flavonolate (dioxygenase type bond cleavage reaction) at 80 °C in DMF. The reactivity shows a substituent group dependent order as -OMe (1) > -H (2) > -Cl (3) > ?NO2 (4). Experimental and theoretical studies suggest a single-electron transfer (SET) from flavonolate to dioxygen, rather than valence tautomerism {[CuII(fla?)] ? [CuI(fla˙)]}, to generate the reactive flavonoxy radical (fla˙) that reacts further with the superoxide radical to bring about the oxygenative ring opening reaction. The SET pathway has been further verified by studying the dioxygenation reaction with a redox-inactive Zn2+ complex, [Zn(LOMe)(fla)] (5).
Exploring 3-Benzyloxyflavones as new lead cholinesterase inhibitors: synthesis, structure–activity relationship and molecular modelling simulations
Mughal, Ehsan Ullah,Sadiq, Amina,Ayub, Momna,Naeem, Nafeesa,Javid, Asif,Sumrra, Sajjad Hussain,Zafar, Muhammad Naveed,Khan, Bilal Ahmad,Malik, Fouzia Perveen,Ahmed, Ishtiaq
, p. 6154 - 6167 (2020/08/10)
In this protocol, a series of 3-benzyloxyflavone derivatives have been designed, synthesized, characterized and investigated in?vitro as cholinesterase inhibitors. The findings showed that all the synthesized target compounds (1–10) are potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes with varying IC50 values. In comparison, they are more active against AChE than BChE. Remarkably, amongst the series, the compound 2 was identified as the most active inhibitor of both AChE (IC50 = 0.05 ± 0.01 μM) and BChE (IC50 = 0.09 ± 0.02 μM) relative to the standard Donepezil (IC50 = 0.09 ± 0.01 for AChE and 0.13 ± 0.04 μM for BChE). Moreover, the derivatives 5 (IC50 = 0.07 ± 0.02 μM) and 10 (0.08 ± 0.02 μM) exhibited the highest selective inhibition against AChE as compared to the standard. Preliminary structure-activity relationship was established and thus found that cholinesterase inhibitory activities of these compounds are highly dependent on the nature and position of various substituents on Ring-B of the 3-Benzyloxyflavone scaffolds. In order to find out the nature of binding interactions of the compounds and active sites of the enzymes, molecular docking studies were carried out. (Figure presented.) HIGHLIGHTS 3-benzyloxyflavone analogues were designed, synthesized and characterized. The target molecules (1–10) were evaluated for their inhibitory potential against AChE and BChE inhibitory activities. Limited structure-activity relationship was developed based on the different substituent patterns on aryl part. Molecular docking studies were conducted to correlate the in?vitro results and to identify possible mode of interactions at the active pocket site of the enzyme. Communicated by Ramaswamy H. Sarma.
Synthesis, inverse docking-assisted identification and in vitro biological characterization of Flavonol-based analogs of fisetin as c-Kit, CDK2 and mTOR inhibitors against melanoma and non-melanoma skin cancers
Roy, Tithi,Boateng, Samuel T.,Banang-Mbeumi, Sergette,Singh, Pankaj K.,Basnet, Pratik,Chamcheu, Roxane-Cherille N.,Ladu, Federico,Chauvin, Isabel,Spiegelman, Vladimir S.,Hill, Ronald A.,Kousoulas, Konstantin G.,Nagalo, Bolni Marius,Walker, Anthony L.,Fotie, Jean,Murru, Siva,Sechi, Mario,Chamcheu, Jean Christopher
, (2021/01/14)
Due to hurdles, including resistance, adverse effects, and poor bioavailability, among others linked with existing therapies, there is an urgent unmet need to devise new, safe, and more effective treatment modalities for skin cancers. Herein, a series of flavonol-based derivatives of fisetin, a plant-based flavonoid identified as an anti-tumorigenic agent targeting the mammalian targets of rapamycin (mTOR)-regulated pathways, were synthesized and fully characterized. New potential inhibitors of receptor tyrosine kinases (c-KITs), cyclin-dependent kinase-2 (CDK2), and mTOR, representing attractive therapeutic targets for melanoma and non-melanoma skin cancers (NMSCs) treatment, were identified using inverse-docking, in vitro kinase activity and various cell-based anticancer screening assays. Eleven compounds exhibited significant inhibitory activities greater than the parent molecule against four human skin cancer cell lines, including melanoma (A375 and SK-Mel-28) and NMSCs (A431 and UWBCC1), with IC50 values ranging from 0.12 to 15 μM. Seven compounds were identified as potentially potent single, dual or multi-kinase c-KITs, CDK2, and mTOR kinase inhibitors after inverse-docking and screening against twelve known cancer targets, followed by kinase activity profiling. Moreover, the potent compound F20, and the multi-kinase F9 and F17 targeted compounds, markedly decreased scratch wound closure, colony formation, and heightened expression levels of key cancer-promoting pathway molecular targets c-Kit, CDK2, and mTOR. In addition, these compounds downregulated Bcl-2 levels and upregulated Bax and cleaved caspase-3/7/8 and PARP levels, thus inducing apoptosis of A375 and A431 cells in a dose-dependent manner. Overall, compounds F20, F9 and F17, were identified as promising c-Kit, CDK2 and mTOR inhibitors, worthy of further investigation as therapeutics, or as adjuvants to standard therapies for the control of melanoma and NMSCs.
