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Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer.

ABSTRACT: Dysregulated receptor tyrosine kinase c-Met and its ligand HGF is valid and attractive molecular target for therapeutic blockade in cancer. Inspired by the chemical structure of the naturally occurring olive secoiridoid (-)-oleocanthal (1) and its documented anticancer activity against c-Met-dependent malignancies, a previous study reported tyrosol sinapate (4) as a c-Met inhibitor hit. This study reports additional semisynthetic optimization and SAR of 4 to improve its selective activity against c-Met-dependent breast cancer by increasing its capacity to inhibit c-Met phosphorylation. Forty-three compounds (5-47) were synthesized, among which the novel analog homovanillyl sinapate (HVS-16) was distinguished for its remarkable activity. HVS-16 substantially impaired c-Met-mediated proliferation, migration, and invasion across human breast cancer cell lines in two- and three-dimensional culture systems, while similar treatment doses were found to have effect neither on the non-tumorigenic human mammary epithelial cell growth nor on the c-Met independent breast cancer cell viability. HVS-16 showed a dose-dependent inhibition of ligand-mediated c-Met activation in human breast cancer cells. Docking studies revealed that HVS-16 fits very well inside c-Met crystal structures, satisfying critical interactions at the ATP binding site. This study identified important structural pharmacophoric features in HVS-16 and correlated its postulated binding pose with c-Met kinase assay data that would guide future olive secoiridoid bioisostere lead design. Results presented herein suggest HVS-16 as a promising c-Met inhibitor validated hit with potential to control invasive breast malignancies with aberrant c-Met activity.

SUBMITTER: Mohyeldin MM

PROVIDER: S-EPMC5073051 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer.

Mohyeldin Mohamed M MM Busnena Belnaser A BA Akl Mohamed R MR Dragoi Ana Maria AM Cardelli James A JA El Sayed Khalid A KA

European journal of medicinal chemistry 20160808

Dysregulated receptor tyrosine kinase c-Met and its ligand HGF is valid and attractive molecular target for therapeutic blockade in cancer. Inspired by the chemical structure of the naturally occurring olive secoiridoid (-)-oleocanthal (1) and its documented anticancer activity against c-Met-dependent malignancies, a previous study reported tyrosol sinapate (4) as a c-Met inhibitor hit. This study reports additional semisynthetic optimization and SAR of 4 to improve its selective activity agains ...[more]

PMID: 27258622

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Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer.

Publications

Novel c-Met inhibitory olive secoiridoid semisynthetic analogs for the control of invasive breast cancer.

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