Synthesis of Antioxidants for Prevention of Age-Related Macular Degeneration

Joshi, Dharati; Field, James B.; Murphy, J. S.; Abdelrahim, Mohammed; Schönherr, Heike; Sparrow, Janet R.; Ellestad, George A.; Nakanishi, Koji; Zask, Arie

doi:10.1021/np300769c

Cited by 33 publications

(20 citation statements)

References 16 publications

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“…The derivatives of Q, shown in Scheme , were designed in order to increase the lipophilicity of Q (8MQPM) or its toxicity (6,8‐diBrQ). On the other hand, QD (see Scheme ) proved to be in a previous study, an effective antioxidant for prevention of age‐related macular degeneration and for this reason it was included in this study.…”

Section: Discussionsupporting

confidence: 93%

“…51 Several evidences also show that Q and its analogues inhibit enzymes such as xanthine oxidase, lipoxygenase, cyclooxygenase and NADPH oxidase attenuating therefore the oxidative stress. 52 On the other hand, QD (see Scheme 1) proved to be in a previous study, 32 an effective antioxidant for prevention of age-related macular degeneration and for this reason it was included in this study. These data confirm the results of previous studies done in different areas and model systems.…”

Section: Discussionmentioning

confidence: 99%

“…Quercetin dihydrate (HPLC) ≥98%, 6, 8‐diBrQ and QD were available from previous studies. The syntheses of 6, 8‐diBrQ and QD along with the NMR spectra are reported in references and respectively. The synthesis of 8MQPM and its carbon and proton NMR spectra are instead reported below.…”

Section: Methodsmentioning

confidence: 99%

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Anti‐angiogenic effect of quercetin and its 8‐methyl pentamethyl ether derivative in human microvascular endothelial cells

Lupo

Cambria

Olivieri

et al. 2019

J Cellular Molecular Medi

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Angiogenesis is involved in many pathological states such as progression of tumours, retinopathy of prematurity and diabetic retinopathy. The latter is a more complex diabetic complication in which neurodegeneration plays a significant role and a leading cause of blindness. The vascular endothelial growth factor (VEGF) is a powerful pro‐angiogenic factor that acts through three tyrosine kinase receptors (VEGFR‐1, VEGFR‐2 and VEGFR‐3). In this work we studied the anti‐angiogenic effect of quercetin (Q) and some of its derivates in human microvascular endothelial cells, as a blood retinal barrier model, after stimulation with VEGF‐A. We found that a permethylated form of Q, namely 8MQPM, more than the simple Q, is a potent inhibitor of angiogenesis both in vitro and ex vivo. Our results showed that these compounds inhibited cell viability and migration and disrupted the formation of microvessels in rabbit aortic ring. The addition of Q and more significantly 8MQPM caused recoveries or completely re‐establish the transendothelial electrical resistance (TEER) to the control values and suppressed the activation of VEGFR2 downstream signalling molecules such as AKT, extracellular signal‐regulated kinase, and c‐Jun N‐terminal kinase. Taken together, these data suggest that 8MQPM might have an important role in the contrast of angiogenesis‐related diseases.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Anti‐angiogenic effect of quercetin and its 8‐methyl pentamethyl ether derivative in human microvascular endothelial cells

Lupo

Cambria

Olivieri

et al. 2019

J Cellular Molecular Medi

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“…The inherent instability of anthocyanins inspired analog synthesis that led to novel, stable inhibitors of A2‐E oxidation reactions with improved physicochemical properties and the potential to treat AMD ( 46 , 47 ). 75, 76 …”

Section: Resultsmentioning

confidence: 99%

The enduring legacy of Koji Nakanishi's research on bioorganic chemistry and natural products. Part 1: Isolation, structure determination and mode of action

2020

Self Cite

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In this brief review on Koji Nakanishi's remarkable career in natural products chemistry, we have highlighted a number of his accomplishments that illustrate the broad diversity of his interests. These include the isolation, structure determination, and biological mechanism of action of many natural products including the triterpenoid pristimerin; the diterpenoid ginkgolides; insect and crustacean molting hormones; phytoalexins; the toxic red tide principle brevetoxin; the vanadium tunicate pigments; philanthotoxin from killer wasps; antisickling agents; mitomycin DNA adducts; insect antifeedants; a mitotic hormone, the small molecule fish attractants from the sea anemone; new isolation and purification technologies; molecular chemistry of vision; age‐related macular degeneration; and the development of the exciton circular dichroism (CD) chirality method for microscale determination of absolute configuration of natural products and chirality of other chiral molecules and supramolecular assembly.

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“…Therefore, improving the potency against cancer of ICA II is important for its further application. A literature survey shows that most of the important classes of drugs are nitrogen-containing, and the presence of an amine moiety in drugs may increase their biological potency due to the greater number of molecular sites for electrophilic attack by cellular constituents, as well as due to the cascade effect of preferential chemosensitization [ 26 ]. Amine moieties in drugs could also enhance their physicochemical properties (e.g., water solubility) and improve the bioavailability of bioactive molecules [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Alkyl Amine Substituted Icariside II Derivatives as Potential Anticancer Agents

Kang

et al. 2018

Molecules

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A series of novel alkyl amine-substituted icariside II (ICA II) derivatives were synthesized by Mannich reactions at the 6-C position (compounds 4a–d) and changing the carbon chain length at the 7-OH position (compounds 7a–h), and their in vitro antitumor activity towards human breast cancer lines (MCF-7 and MDA-MB-231) and human hepatoma cell lines (HepG2 and HCCLM3-LUC) were evaluated by the MTT assay. Compared with ICA II, most of the twelve derivatives showed good micromole level activity and a preliminary structure-activity relationship (SAR) for the anticancer activity was obtained. Compound 7g showed the most potent inhibitory activity for the four cancer cell lines (13.28 μM for HCCLM3-LUC, 3.96 μM for HepG2, 2.44 μM for MCF-7 and 4.21 μM for MDA-MB-231), which was 2.94, 5.54, 12.56 and 7.72-fold stronger than that of ICA II. The preliminary SAR showed that the introduction of a alkyl amine substituent at 6-C was not favorable for the anticancer activity, while most of the 7-O-alkylamino derivatives exhibited good antitumor activity and the anticancer activity 7-O-alkylamino derivatives were influenced by the alkyl chain length and the different terminal amine substituents. Furthermore, the effects of compound 7g on apoptosis and cell cycle of MCF-7 cells were further investigated, which showed that compound 7g triggered apoptosis and arrested the cell cycle at the G0/G1 phase in MCF-7 cells. Our findings indicate that compound 7g may be a promising anticancer drug candidate lead.

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Synthesis of Antioxidants for Prevention of Age-Related Macular Degeneration

Cited by 33 publications

References 16 publications

Anti‐angiogenic effect of quercetin and its 8‐methyl pentamethyl ether derivative in human microvascular endothelial cells

Anti‐angiogenic effect of quercetin and its 8‐methyl pentamethyl ether derivative in human microvascular endothelial cells

The enduring legacy of Koji Nakanishi's research on bioorganic chemistry and natural products. Part 1: Isolation, structure determination and mode of action

Synthesis and Biological Evaluation of Novel Alkyl Amine Substituted Icariside II Derivatives as Potential Anticancer Agents

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