An Efficient and Practical Method for the Preparation of a Branched Oligoglycerol with Acetonide Protection Groups

Nemoto, Hisao; Kamiya, M.; Nakamoto, Aki; Katagiri, Ayato; Yoshitomi, Kohsuke; Kawamura, Tomoyuki; Hattori, Hatsuhiko

doi:10.1246/cl.2010.856

Cited by 9 publications

(5 citation statements)

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“…BGL003 (1,3-bis[(2,2-dimethyl-1,3-dioxan-5-yl)oxy]-2-propanol) and fenofibrate-BGL003 conjugate (FF-BGL) (Fig. 1C) were synthesized as described elsewhere Nemoto et al, 2007bNemoto et al, , 2010Nemoto et al, , 2012c.…”

Section: Materials and Reagentsmentioning

confidence: 99%

“…Therefore, we have designed symmetrically branched oligoglycerols (BGL) such as the trimer (BGL003) (Fig. 1A), of which molecular weight is as small as 240.25, as alternative highly hydrophilic modular molecules and have shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds were much improved by conjugation to BGL (BGLation) (Ishihara et al, 2010Nemoto et al, 1999Nemoto et al, , 2007aNemoto et al, , 2007bNemoto et al, , 2010Nemoto et al, , 2011Nemoto et al, , 2012aNemoto et al, and 2012bYamaguchi et al, 2008). Albeit these beneficial effects of BGLation, little was known whether BGL could be used in safety.…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

et al. 2012

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-An appropriate balance between lipophilicity and hydrophilicity is necessary for pharmaceuticals to achieve fine Absorption, Distribution, Metabolism and Excretion (ADME) properties including absorption and distribution, in particular. We have designed and proposed symmetrically branched oligoglycerols (BGL) as an alternative approach to improve the lipophilic-hydrophilic balance. We have previously shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds are much improved by conjugation to BGL. Albeit these successful applications of BGL, little was known whether BGL could be used in safety. Thus we conducted evaluation of the cytotoxicity of a representative BGL, symmetrically branched glycerol trimer (BGL003) in the cultured cells to clarify its biological safeness. Here we demonstrate that water-solubility of an extremely hydrophobic agent, fenofibrate was more than 2,000-fold improved just by conjugated with BGL003. BGL003 did not exhibit any significant cytotoxicity in human hepatocarcinoma HepG2 cells. Thus BGL003 should be safe and suitable strategy to endow hydrophobic molecules with much hydrophilicity.

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Section: Materials and Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

et al. 2012

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“…1B). We have successfully improved stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds by conjugation to BGL to date (Ishihara et al, 2010(Ishihara et al, , 2012Nemoto et al, 1999Nemoto et al, , 2007aNemoto et al, , 2007bNemoto et al, , 2010Nemoto et al, , 2011Nemoto et al, , 2012aNemoto et al, and 2012bYamaguchi et al, 2008). In the accompanying paper, we demonstrated that hydrophilicity and water-solubility of fenofibrate, a quite hydrophobic anti-hyperlipidemic drug (Fig.…”

Section: Introductionmentioning

confidence: 99%

Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice

et al. 2012

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-Lipophilic-hydrophilic balance is a quite important determinant of pharmacokinetic properties of pharmaceuticals. Thus it is a key step to successfully manage lipophilic-hydrophilic balance in drug design. We have designed unique modular molecules, symmetrically branched oligoglycerols (BGL) as an alternative means to endow hydrophobic molecules with much hydrophilicity. We have succeeded in improving the water-solubility of several hydrophobic medicinal small molecules and thermal stability of artificial protein by covalent conjugation to BGL. We have also demonstrated that a representative BGL, symmetrically branched glycerol trimer (BGL003) does not exhibit significant cytotoxicity against human hepatocarcinoma HepG2 cells. However, there have been no reports suggesting whether BGL could be used in safety in vivo. Therefore, evaluation of acute oral toxicity of BGL003 in healthy mice was conducted. Here we demonstrate that an oral administration of BGL003 did not exhibit acute lethal toxicity up to 3,000 mg/kg. Body weight, food intake, blood glucose levels and weights of tissues were not affected by a short-term repetitive administration of increasing doses of BGL003. Biochemical indications related to hepatic disorders and tissue damage were unchanged, either. A single administration study revealed that 50% lethal dose of BGL003 should be more than 2,000 mg/kg. BGL003 will be safe and suitable approach to improve hydrophilicity of hydrophobic compounds.

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“…Therefore, we have designed symmetrically branched oligoglycerols (BGL) such as the trimer (BGL003) (Figure A) as alternative small uniform highly hydrophilic modular molecules. We have successfully improved stability in circulation and water solubility of such molecules as proteins, liposomes, and hydrophobic compounds by conjugation to BGL to date. − In addition, we have demonstrated biological safety of BGL003, the simplest BGL in cultured cells and rodents, suggesting BGL is innoxiously applicable to a prodrug. , However, it remained unclear whether the molecular modification by conjugation to BGL actually improves ADME properties of pharmaceuticals in terms of pharmacological effects.…”

Section: Introductionmentioning

confidence: 99%

A Novel Prodrug Strategy for Extremely Hydrophobic Agents: Conjugation to Symmetrically Branched Glycerol Trimer Improves Pharmacological and Pharmacokinetic Properties of Fenofibrate

et al. 2013

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Management of a lipophilic-hydrophilic balance is a key element in drug design to achieve desirable pharmacokinetic characters. Therefore we have created unique modular molecules, symmetrically branched oligoglycerols (BGL), as an alternative way to endow hydrophobic molecules with sufficient hydrophilicity. We have successfully demonstrated amelioration of the water solubility and thermal stability of several hydrophobic agents by covalent conjugation to BGL so far. However, it has not been clarified whether the molecular modification by BGL also improves the pharmacological and/or pharmacokinetic properties indeed. Recently, we synthesized a novel BGL-prodrug derivative of fenofibrate, which is an antihyperlipidemic agent and one of the most hydrophobic medicinal compounds currently used clinically, by conjugating fenofibric acid to symmetrically branched glycerol trimer (BGL003), the simplest BGL. We have previously demonstrated that the hydrophilicity and water solubility of fenofibrate are improved more than 2000 times just by conjugation to the BGL003. To verify our hypothesis that the prodrug strategy with BGL should improve pharmacological efficacy and pharmacokinetic properties of extremely hydrophobic agents such as fenofibrate by the rise in hydrophilicity, we evaluated the BGL003-prodrug derivative of fenofibrate (FF-BGL) using rodent models. Here we demonstrate that the lipid-lowering effects of fenofibrate are much potentiated by chemical conjugation to BGL003 without exhibiting significant toxicity. Plasma concentration of fenofibric acid, an active metabolite of fenofibrate, after single oral administration of FF-BGL was more than 3 times higher than that of fenofibrate, in accordance. In fasting rats, plasma concentration of fenofibric acid after fenofibrate administration was curtailed into less than half of that in ad libitum-fed rats, while FF-BGL showed about the same plasma level even in the starving rats. This is the first report showing that BGL-prodrug improves pharmacological and pharmacokinetic properties as well as hydrophilicity of highly hydrophobic compounds. Furthermore, prodrug strategy using BGL suggests the possibility of diminishing the food-drug interaction effects, which should be advantageous for promoting drug compliance. BGL will be a suitable prodrug strategy to ameliorate physical, pharmacological, and pharmacokinetic characteristics of extremely hydrophobic compounds.

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An Efficient and Practical Method for the Preparation of a Branched Oligoglycerol with Acetonide Protection Groups

Abstract: A novel method for the preparation of 1,3-bis(2,2-dimethyl-1,3-dioxan-5-yloxy)propan-2-ol, a branched oligoglycerols (BGL), was developed from 1,3-diallylated glycerol in excellent yield.

Cited by 9 publications

References 14 publications

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice

A Novel Prodrug Strategy for Extremely Hydrophobic Agents: Conjugation to Symmetrically Branched Glycerol Trimer Improves Pharmacological and Pharmacokinetic Properties of Fenofibrate

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