Bicycloheptylamine-Doxorubicin Conjugate: Synthesis and Anticancer Activities in σ2 Receptor-Expressing Cell Lines

Author(s): Mohammed A. Alamri, Zeynep Ates-Alagoz, Adeboye Adejare*

Journal Name: Medicinal Chemistry

Volume 16 , Issue 2 , 2020

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Graphical Abstract:


Background: Novel bicycloheptylamines were designed and synthesized. These compounds were found to be selective for sigma-2 receptors. These receptors have been found to be up to 10 fold over-expressed in certain cancer cell lines, leading to investigation of possible uses as a biomarker in diagnosis and/or treatment especially in cancers with poor prognosis.

Objectives: The aim was to conjugate a novel sigma-2 receptor ligand to doxorubicin to examine anticancer activities, with and without conjugation, and therefore possibilities in drug delivery.

Methods: Conjugation was conducted using N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide HCl as a coupling agent. Affinity towards the sigma-2 receptor was tested using ligand-receptor binding studies. Anticancer activities against cancer cell lines were carried out using cell viability assays. Caspase dependency was tested using Z-VAD-FMK, a pan-caspase inhibitor, to begin to investigate mechanisms of action.

Results: The target compound retained affinity towards the sigma-2 receptor and exhibited potent anticancer activities on cancer cell lines expressing the sigma-2 receptor. The potencies exceeded those of doxorubicin, the lead sigma-2 receptor ligand, as well as non-covalent combination of both drugs. The activity was also found to be caspase-dependent.

Conclusion: The conjugation of target bicycloheptylamines with cytotoxic moieties may yield potent and selective molecules for detection and/or treatment of certain cancers.

Keywords: Sigma-2 receptor, anticancer, doxorubicin, drug delivery, bicycloheptylamine, cancer.

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Year: 2020
Page: [192 - 201]
Pages: 10
DOI: 10.2174/1573406415666190301145203
Price: $65

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