Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

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

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

Volume 16, Issue 2, 2020

Page: [192 - 201] Pages: 10

DOI: 10.2174/1573406415666190301145203

Price: $65

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.

Graphical Abstract
[1]
Martin, W.R.; Eades, C.E.; Thompson, J.A.; Huppler, R.E. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther., 1976, 197, 517-532.
[2]
Quirion, R.; Chicheportiche, R.; Contreras, P.C.; Johnson, K.M.; Lodge, D.; Tam, S.W.; Woods, J.H.; Zukin, S.R. Classification and nomenclature of phencyclidine and sigma receptor sites. Trends Neurosci., 1987, 10, 444-446.
[3]
Mangan, J.; Patterson, S.J.; Tavani, A.; Kosterlits, H.W. The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties. Naunyn Schmiedebergs Arch. Pharmacol., 1982, 319, 197-205.
[4]
Zukini, S.R. Differing stereospecifities distinguish opiate receptor subtypes. Life Sci., 1982, 31, 1307-1310.
[5]
Zukini, S.R.; Tempel, A.; Gardner, E. Interaction of [3H](-)-SKF 10047 with brain sigma receptors: characterization and autoradiographic visualization. J. Neurosci., 1986, 46, 1032-1041.
[6]
Su, P.T. Evidence for sigma opioid receptor binding of [3H]SKF 10047 to etorphine-inaccessible sites in guinea-pig brain. J. Pharmacol. Exp. Ther., 1982, 223, 284-290.
[7]
Tam, S.W. Naloxone-inaccessible sigma receptor in rat central nervous system. Proc. Natl. Acad. Sci. USA, 1983, 80, 6703-6707.
[8]
McLean, S.; Weber, E. Autoradiographic visualization of haloperidol-sensitive sigma receptors in guinea-pig brain. Neuroscience, 1988, 25, 259-289.
[9]
Walker, J.M.; Matsumoto, R.R.; Bowen, W.D.; Gans, D.L.; Jones, K.D.; Walker, F.O. Evidence for a role of haloperidol-sensitive sigma-‘opiate’ receptors in the motor effects of antipsychotic drugs. Neurology, 1988, 38, 961-965.
[10]
Hellwell, S.B.; Bowen, W.D. Photolabeling of sigma receptors in guenia pig brain, rat brain, and PC-12 cells using [3H]azido-di-tolyguanidine: evidence for receptor heterogeneity. Soc. Neurosci. Abstracts, 1988, 14, 703.
[11]
Hellwell, S.B.; Bowen, W.D. A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res., 1990, 527, 244-253.
[12]
Hellwell, S.B.; Burck, A.E.; Bowen, W.D. Characterization of “sigma-like” binding sites in rat liver membranes: further evidence for sigma-1 and sigma-2 sites. Proceedings of the International Narcotics Research Conference, 1990, 914, pp. 270-271.
[13]
Schmidt, H.R.; Zheng, S.; Gurpinar, E.; Koehl, A.; Manglik, A.; Kruse, A.C. Crystal structure of the human σ1 receptor. Nature, 2016, 532, 527-530.
[14]
Abate, C.; Elenweski, J.; Niso, M.; Berardi, F.; Colabufo, N.A.; Azzariti, A.; Perrone, R. Interaction of the σ 2 receptor ligand PB28 with the human nucleosome: computational and experimental probes of interaction with the H2A/H2B dimer. ChemMedChem, 2010, 5, 268-273.
[15]
Colabufo, N.A.; Berardi, F.; Abate, C.; Contino, M.; Niso, M.; Perrone, R. Is the σ 2 receptor a histone binding protein? J. Med. Chem., 2006, 49, 4153-4158.
[16]
Vilner, B.J.; John, C.S.; Bowen, W.D. Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res., 1995, 55, 408-413.
[17]
Bem, W.T.; Thomas, G.E.; Mamone, J.Y.; Homan, S.M.; Levy, B.K.; Johnson, F.E.; Coscia, C.J. Overexpression of sigma receptors in nonneural human tumors. Cancer Res., 1991, 51, 558-6562.
[18]
Makvandi, M.; Tilahun, E.D.; Lieberman, B.P.; Anderson, R.; Zeng, C.; Xu, K.; Hou, C.; McDonald, E.S.; Pryma, D.A.; Mach, R.H. The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer. Biochem. Biophys. Res. Commun., 2015, 467, 1070-1075.
[19]
Kashiwagi, H.; McDunn, J.E.; Simon, Jr, P.O.; Goedegebuure, P.S.; Xu, J.; Jones, L.; Chang, K.; Johnston, F.; Trinkaus, K.; Hotchkiss, R.S.; Mach, R.H.; Hawkins, W.G. Selective sigma-2 ligands preferentially bind to pancreatic adenocarcinomas: applications in diagnostic imaging and therapy. Mol. Cancer, 2007, 6, 48.
[20]
Zeng, C.; Vangveravong, S.; Xu, J.; Chang, K.C.; Hotchkiss, R.S.; Wheeler, K.T.; Shen, D.; Zhuang, Z.; Kung, H.F.; Mach, R.H. Subcellular localization of sigma-2 receptors in breast cancer cells using two-photon and confocal microscopy. Cancer Res., 2007, 67, 6708-6716.
[21]
Safrany, S.T.; Abbas, H.; Ferry, D.R.; Brimson, J.M. In: Sigma receptor content in a range of cancer cell lines; British Pharmacological Society, Pharmacology conference, 2014.
[22]
Xu, J.; Zeng, C.; Chu, W.; Pan, F.; Rothfuss, J.M.; Zhang, F.; Tu, Z.; Zhou, D.; Zeng, D.; Vangveravong, S.; Johnston, F.; Spitzer, D.; Chang, K.C.; Hotchkiss, R.S.; Hawkins, W.G.; Wheeler, K.T.; Mach, R.H. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat. Commun., 2011, 2, 380.
[23]
Peluso, J.J.; Liu, X.; Saunders, M.M.; Claffey, K.P.; Phoenix, K. Regulation of ovarian cancer cell viability and sensitivity to cisplatin by progesterone receptor membrane component-1. J. Clin. Endocrinol. Metab., 2008, 93, 1592-1599.
[24]
Lee, I.; Lieberman, B.P.; Li, S.; Hou, C.; Makvandi, M.; Mach, R.H. Comparative evaluation of 4 and 6-carbon spacer conformationally flexible tetrahydroisoquinolinyl benzamide analogues for imaging the sigma-2 receptor status of solid tumors. Nucl. Med. Biol., 2016, 43, 721-731.
[25]
Makvandi, M.; Lieberman, B.P.; LeGeyt, B.; Hou, C.; Mankoff, D.A.; Mach, R.H.; Pryma, D.A. The pre-clinical characterization of an alpha-emitting sigma-2 receptor targeted radiotherapeutic. Nucl. Med. Biol., 2016, 43, 35-41.
[26]
Shogi, K.I.; Xu, J.; Su, Y.; He, J.; Rowland, D.; Yan, Y.; Garbow, J.R.; Tu, Z.; Jones, L.A.; Higashikubo, R.; Wheeler, K.T.; Lubet, R.A.; Mach, R.H.; You, M. Quantitative receptor-based imaging of tumor proliferation with the sigma-2 ligand [18F]ISO-1. PLoS One, 2013, 8e74188
[27]
Hornick, J.R.; Vangveravong, S.; Spitzer, D.; Abate, C.; Berardi, F.; Goedegebuur, P.; Mach, R.H.; Hawkins, W.G. Lysosomal membrane permeabilization is an early event in sigma-2 receptor ligand mediated cell death in pancreatic cancer. J. Exp. Clin. Cancer Res., 2012, 31, 41.
[28]
Jonhede, S.; Petersen, A.; Zetterberg, M.; Karlsson, J. Acute effects of the sigma-2 receptor agonist siramesine on lysosomal and extra-lysosomal proteolytic systems in lens epithelialcells. Mol. Vis., 2010, 16, 819-827.
[29]
Korpis, K.; Weber, F.; Brune, S.; Wunsch, B.; Bednarski, P.J. Involvement of apoptosis and autophagy in the death of RPMI 8226 multiple myeloma cells by two enantiomeric sigma receptor ligands. Bioorg. Med. Chem., 2014, 22, 221-233.
[30]
Zeng, C.; Rothfuss, J.; Zhang, J.; Chu, W.; Vangveravong, S.; Tu, Z.; Pan, F.; Chang, K.C.; Hotchkiss, R.; Mach, R.H. Sigma-2 ligands induce tumour cell death by multiple signalling pathways. Br. J. Cancer, 2012, 106, 693-701.
[31]
Crawford, K.W.; Bowen, W.D. Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. Cancer Res., 2002, 62, 313-322.
[32]
Ostenfeld, M.S.; Fehrenbacher, N.; Høyer-Hansen, M.; Thomsen, C.; Farkas, T.; Jaattela, M. Effective tumor cell death by σ-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res., 2005, 65, 8975-8983.
[33]
Ohman, K.A.; Hashim, Y.M.; Vangveravong, S.; Nywening, T.M.; Cullinan, D.R.; Goedegebuure, S.P.; Liu, J.; Van Tine, B.A.; Tiriac, H.; Tuveson, D.A.; DeNardo, D.G.; Spitzer, D. Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm- Erastin into a potent pancreatic cancer therapeutic. Oncotarget, 2016, 7, 23.
[34]
Kashiwagi, H.; McDunn, J.E.; Simon, Jr, P.O.; Goedegebuure, P.S.; Vangveravong, S.; Chang, K.; Hotchkiss, R.S.; Mach, R.H.; Hawkins, W.G. Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma. J. Transl. Med., 2009, 7, 24.
[35]
Hornick, J.R.; Xu, J.; Vangveravong, S.; Tu, Z.; Mitchem, B.J.; Spitzer, D.; Goedegebuure, P.; Mach, R.H.; Hawkins, W.G. The novel sigma-2 receptor ligand SW43 stabilizes pancreas cancer progression in combination with gemcitabine. Mol. Cancer, 2010, 9, 298.
[36]
Zhang, Y.; Huang, Y.; Zhang, P.; Gao, X.; Gibbs, R.B.; Li, S. Incorporation of a selective sigma-2 receptor ligand enhances uptake of liposomes by multiple cancer cells. Int. J. Nanomedicine, 2012, 7, 4473-4485.
[37]
Wang, Y.; Xu, J.; Xia, X.; Yang, M.; Vangveravong, S.; Chen, J.; Mach, R.H.; Xia, Y. SV119-gold nanocage conjugates: a new platform for targeting cancer cells via sigma-2 receptors. Nanoscale, 2012, 20, 421-424.
[38]
Puri, R.; Bhatia, R.K.; Pandey, R.S.; Jain, U.K.; Katare, O.P.; Madan, J. Sigma-2 receptor ligand anchored telmisartan loaded nanostructured lipid particles augmented drug delivery, cytotoxicity, apoptosis and cellular uptake in prostate cancer cells. Drug Dev. Ind. Pharm., 2016, 1, 1-11.
[39]
Garg, G.; Vangveravong, S.; Zeng, C.; Collins, L.; Hornick, M.; Hashim, Y.; Piwnica-Worms, D.; Powell, M.A.; Mutch, D.G.; Mach, R.H.; Hawkins, W.G.; Spitzer, D. Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer. Mol. Cancer, 2014, 13, 50.
[40]
Spitzer, D.; Simon, Jr, P.O.; Kashiwagi, H.; Xu, J.; Zeng, C.; Vangveravong, S.; Zhou, D.; Chang, K.; McDunn, J.E.; Hornick, J.R.; Goedegebuure, P.; Hotchkiss, R.S.; Mach, R.H.; Hawkins, W.G. Use of multifunctional sigma-2 receptor ligand conjugates to trigger cancer-selective cell death signaling. Cancer Res., 2011, 72, 201-209.
[41]
Ates-Alagoz, Z.; Sun, S.; Wallach, J.; Adejare, A. Syntheses and pharmacological evaluations of novel N-substituted bicyclo- heptan-2-amines at NMDA receptors. Chem. Biol. Drug Des., 2011, 78, 25-32.
[42]
Besnard, J.; Ruda, G.F.; Setola, V.; Abecassis, K.; Rodriguiz, R.M.; Huang, X.P.; Norval, S.; Sassano, M.S.; Shin, A.I.; Webster, L.A.; Simeons, F.R.; Stojanovski, L.; Prat, A.; Seidah, N.G.; Constam, D.B.; Bickerton, G.R.; Read, K.D.; Wetsel, W.C.; Gilbert, I.H.; Roth, B.L.; Hopkins, A.L. Automated design of ligands to polypharmacological profiles. Nature, 2012, 492, 215-220.
[43]
Psychoactive Drug Screening Program. Available at. https://pdspdb.unc.edu/pdspWeb/content/PDSP%20Protocols%20II %202013-03-28.pdf
[44]
NCI-60 Human Tumor Cell Lines Screen. Available at. https://dtp.cancer.gov/discovery_development/nci- 60/methodology.htm
[45]
Yousefpour, P.; Atyabi, F.; Vasheghani-Farahani, E.; Movahedi, M.A.; Dinarvand, R. Targeted delivery of doxorubicin-utilizing chitosan nanoparticles surface-functionalized with anti-her2 trastuzumab. Int. J. Nanomedicine, 2011, 6, 1977-1990.
[46]
Chatterjee, K.; Zhang, J.; Honbo, N.; Karliner, J.S. Doxorubicin cardiomyopathy. Cardiology, 2010, 115, 155-162.
[47]
Christy, S.; Vilner, B.J.; Geyer, B.C.; Moody, T.; Bowen, W.D. Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors. Cancer Res., 1999, 59, 4578-4583.
[48]
Naidu, M.; Mason, J.; Pica, R.; Fung, H.; Pena, L. Radiation resistance in glioma cells determined by DNA damage repair activity of Ape1/Ref-1. J. Radiat. Res., 2010, 51, 393-404.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy