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Total synthesis and absolute configuration of laurenditerpenol: a hypoxia inducible factor-1 activation inhibitor.

ABSTRACT: The absolute stereo structure of the natural product laurenditerpenol (1S, 6R, 7S, 10R, 11R, 14S, 15R) has been accomplished from eight plausible stereoisomers by its first asymmetric total synthesis in a highly convergent and flexible synthetic pathway. Six stereoisomers of laurenditerpenol were synthesized and evaluated for their biological activity.

SUBMITTER: Chittiboyina AG

PROVIDER: S-EPMC2911032 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Total synthesis and absolute configuration of laurenditerpenol: a hypoxia inducible factor-1 activation inhibitor.

Chittiboyina Amar G AG Kumar Gundluru Mahesh GM Carvalho Paulo B PB Liu Yang Y Zhou Yu-Dong YD Nagle Dale G DG Avery Mitchell A MA

Journal of medicinal chemistry 20071116 25

The absolute stereo structure of the natural product laurenditerpenol (1S, 6R, 7S, 10R, 11R, 14S, 15R) has been accomplished from eight plausible stereoisomers by its first asymmetric total synthesis in a highly convergent and flexible synthetic pathway. Six stereoisomers of laurenditerpenol were synthesized and evaluated for their biological activity. ...[more]

PMID: 18004798

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Project description:Background and aimsHypoxia inducible factor 1α (HIF1α) plays a critical role in atherosclerosis as demonstrated in endothelial-targeted HIF1α -deficient mice. However, it has not been shown if specific pharmacological inhibitors of HIF1α can be used as potential drugs for atherosclerosis. PX-478 is a selective inhibitor of HIF1α, which was used to reduce cancer and obesity in animal models. Here, we tested whether PX-478 can be used to inhibit atherosclerosis.MethodsWe first tested PX-478 in human aortic endothelial cells (HAEC) and found that it significantly inhibited expression of HIF1α and its targets, including Collagen I. Next, two independent atherosclerosis models, C57BL/6 mice treated with AAV-PCSK9 and ApoE-/- mice, were used to test the efficacy of PX-478. Both mouse models were fed a Western diet for 3 months with bi-weekly treatment with PX-478 (40 mg/kg) or saline.ResultsPX-478 treatment reduced atherosclerotic plaque burden in the aortic trees in both mouse models, while plaque burden in the aortic sinus was reduced in the AAV-PCSK9 mouse model, but not in the ApoE-/- mice. Russell-Movat's Pentachrome and Picrosirius Red staining showed a significant reduction in extracellular matrix remodeling and collagen maturation, respectively, in the PX-478-treated mice. As expected, PX-478 treatment reduced diet-induced weight-gain and abdominal adipocyte hypertrophy. Interestingly, PX-478 reduced plasma LDL cholesterol by 69% and 30% in AAV-PCSK9 and ApoE-/- mice, respectively. To explore the cholesterol-lowering mechanisms, we carried out an RNA sequencing study using the liver tissues from the ApoE-/- mouse study. We found 450 genes upregulated and 381 genes downregulated by PX-478 treatment in the liver. Further, gene ontology analysis showed that PX-478 treatment upregulated fatty acid and lipid catabolic pathways, while downregulating lipid biosynthesis and plasma lipoprotein particle remodeling processes. Of interest, Cfd, Elovl3, and Insig2 were some of the most downregulated genes by PX-478, and have been implicated in fat storage, fatty acid elongation, and cholesterol metabolism. The downregulation of Cfd, Elovl3, and Insig2 was further validated by qPCR in the liver tissues of ApoE-/- mice treated with PX-478.ConclusionsThese results suggest that PX-478 is a potential anti-atherogenic drug, which targets vascular endothelium and hepatic cholesterol pathways.

Dataset Information

Total synthesis and absolute configuration of laurenditerpenol: a hypoxia inducible factor-1 activation inhibitor.

Publications

Total synthesis and absolute configuration of laurenditerpenol: a hypoxia inducible factor-1 activation inhibitor.

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