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Synthesis and structure-activity relationship studies of water-soluble ?-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents.

ABSTRACT: Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble ?-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of ?-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached ?-CD moiety, all these conjugates showed lower hydrophobicity (AlogP) compared with their parent compound GA. With the exception of per-O-methylated ?-CD-GA conjugate (35), all other conjugates showed no significant cytotoxicity to MDCK cells, and these conjugates were then screened against A/WSN/33 (H1N1) virus using the cytopathic effect assay. The preliminary results indicated that six conjugates showed promising antiviral activity, and the C-3 and C-30 of GA could tolerate some modifications. Our findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents.

SUBMITTER: Liang S

PROVIDER: S-EPMC7115653 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Synthesis and structure-activity relationship studies of water-soluble β-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents.

Liang Shuobin S Li Man M Yu Xiaojuan X Jin Hongwei H Zhang Yongmin Y Zhang Lihe L Zhou Demin D Xiao Sulong S

European journal of medicinal chemistry 20190130

Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble β-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of β-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached β-CD moiety, all these conjugates ...[more]

PMID: 30731401

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Project description:Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50=0.11-40nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50=0.62-1.5?M). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10-90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13-16, 42-45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0?M) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2h post treatment (80mg/kg), with similar results observed upon treatment (15mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.

Dataset Information

Synthesis and structure-activity relationship studies of water-soluble ?-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents.

Publications

Synthesis and structure-activity relationship studies of water-soluble β-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents.

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