Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching

Furet, Pascal; Bold, Guido; Hofmann, Francesco; Manley, Paul W.; Meyer, Thomas; Altmann, Karl‐Heinz

doi:10.1016/s0960-894x(03)00626-7

Cited by 62 publications

(31 citation statements)

References 18 publications

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“…In these cases, the intramolecular hydrogen bond is crucial and removal of either hydrogen bond acceptor or donor results in a drastic loss of binding affinity. Rational design of internal hydrogen bonds for conformational preorganization was pursued in scaffold replacements for a diverse set of targets [225,226,227,228,229]. In addition to its effects on receptor binding, an improved property profile has been associated with molecules containing intramolecular hydrogen bonds.…”

Section: Intramolecular Hydrogen Bondsmentioning

confidence: 99%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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The effect of weak intermolecular interactions on the binding affinity between ligand-protein complexes plays an important role in stabilizing a ligand at the interface of a protein structure. In this review article, we will explore the different ways of taking into account these interactions, mainly intramolecular hydrogen bonds, in docking calculations. Their possible limitations and their suitable application domains are highlighted. Inspection of the outliers of this study probed very stimulating, as it provides opportunities and inspiration to medicinal chemists, being a reminder of the impact that minimal chemical modifications can have on biological activities.

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Section: Intramolecular Hydrogen Bondsmentioning

confidence: 99%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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“…VRI, a pyridinyl-anthranilamide compound that displays antiangiogenic properties, has been shown to potently inhibit the kinase activities of both VEGF receptors 1 and 2 (Furet et al, 2003). The pretreatment of zebrafish embryos 24 hours after fertilization with 1 mM VRI for 2 hours followed by 24 hours of incubation in embryo medium (0.1% DMSO) at 28.5°C allowed development of blood vessel loss in regions of intersegmental vessels (ISVs) and dorsal longitudinal anastomotic vessels (DLAVs) as well as the formation of impaired subintestinal vessels (SIVs) (Fig.…”

Section: Ms/ms Analysis Of M/z 283 Yielded a Predominant Fragment Ionmentioning

confidence: 99%

The Presystemic Interplay between Gut Microbiota and Orally Administered Calycosin-7-O-β-d-Glucoside

Ruan

et al. 2015

Drug Metab Dispos

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Presystemic interactions with gut microbiota might play important roles in the holistic action of herbal medicines in their traditional oral applications. However, research interests usually focus on biologic activities of the in vivo available herb-derived components and their exposure in circulation. In this study, we illustrated the importance of studying the presystemic interplay with gut microbiota for understanding the holistic actions of medicinal herbs by using calycosin-7-O-b-D-glucoside (C7G), the most abundant flavonoid and chemical marker in Astragali Radix, as a model compound. When C7G was orally administrated to rats, calycosin-39-O-glucuronide (G2) was the major circulating component in the blood together with a minor calycosin but not C7G. Rat gut microbiota hydrolyzed C7G in vitro rapidly and produced its aglycone calycosin. Calycosin exhibited higher permeability than C7G and further underwent extensive glucuronidation to yield 3ʹ-glucuronide as the dominant metabolite. Bioactivity assays revealed that G2 exhibited similar or more potent proangiogenic effects than calycosin in human umbilical vein endothelial cells in vitro and in the vascular endothelial growth factor receptor tyrosine kinase inhibitor II-induced blood vessel loss model in zebrafish. More interestingly, the incubation of C7G with gut microbiota from both normal and colitic rats showed a probiotics-like effect through stimulating the growth of the beneficial bacteria Lactobacillus and Bifidobacterium. In conclusion, C7G interacts reciprocally with gut microbiota after oral dosing, which makes it not only an angiogenic prodrug but also a modulator of gut microbiota.

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“…Melting points (Mp) were determined using a Büchi capillary melting point apparatus and were uncorrected. The proton nuclear magnetic resonance ( 1 H-NMR) spectra were recorded on a Bruker Avance DRX600 instrument using tetramethylsilane (TMS) as an internal standard in DMSO-d 6 solutions. The chemical shifts (δ) are reported in parts per million (ppm) downfield from TMS and the coupling constants (J) are expressed in Hertz (Hz).…”

Section: Chemistry: General Proceduresmentioning

confidence: 99%

“…P. Furet et al reasoned that an anthranilamide moiety ( Figure 1) presenting a strong intramolecular hydrogen bond between the amine and keto functionalities to form a pseudo six membered ring could mimic the phthalazine ring of PTK787 (6). Thus, a series of anthranilamide derivatives with promising in vivo anti-tumor effects were investigated.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel anthranilamide derivatives as anticancer agents

Liu¹

2013

Drug Discov Ther

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Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching

Cited by 62 publications

References 18 publications

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

The Presystemic Interplay between Gut Microbiota and Orally Administered Calycosin-7-O-β-d-Glucoside

Synthesis and biological evaluation of novel anthranilamide derivatives as anticancer agents

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