Mohammed A. Alamri, Zeynep Ates-Alagoz and Adeboye Adejare*
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.
sigma-2 receptor, anticancer, doxorubicin, drug delivery, bicycloheptylamine, cancer
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia