Affiliation:
1. Department of Chemistry, National Central University, Taoyuan City 32001, Taiwan
2. Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
Abstract
Background:
To block the metastatic and angiogenic pathways during the tumor progression arouses
considerable pharmacological interests in the development of anticancer drugs.
Objective:
To develop alternative antiangiogenic and antimetastic agents, we designed and prepared a series of
nature inspired isomalyngamide A analogs containing ribose conjugate with 1,2-diaminoethane or 1,3-
diaminopropane linkers (1-8).
Methods:
The target glycosylated isomalyngamide A analogs 1-8 were constructed through condensation of the
malonic acids 16-19 and the corresponding aminoethoxyl ribosides 20 and 21, using HBTU/DIPEA as the coupling
agent. The cell growth inhibition assay, cell migration assay, transwell invasion assay, adhesion assay,
tube formation assay and western blot analysis were used to validate the biological actions of compounds.
Results:
The most effective compound, isomalyngamide A riboside 1 (CY01), possessing a D-ribose core structure
and a 1,3-diaminopropane linker, showed significant suppression of MDA-MB-231 cell migration and
inhibited tube formation of Human Umbilical Vascular Endothelial Cells (HUVECs) in a dose-dependent manner.
Effect of the latter is comparable to that of sorafenib, an orally active multikinase inhibitor and an inhibitor
of angiogenesis. CY01 also showed slight inhibition on collagen type IV- and laminin-mediated cell adhesion.
These actions may be regulated through the blockade of the VEGF/VEGFR2 signaling pathway by inhibiting
the VEGF induced phosphorylation of p-VEGFR2 and p-AKT.
Conclusion:
In this effort, we have discovered synthetic and glycosylated marine metabolites which may serve
as an alternative antiangiogenic and antimetastic agent during multitherapy.
Funder
Academia Sinica
Ministry of Science and Technology
Publisher
Bentham Science Publishers Ltd.
Subject
Cancer Research,Pharmacology,Molecular Medicine
Cited by
2 articles.
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