Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis of a Novel Gold(I) Complex and Evaluation of Its Anticancer Properties in Breast Cancer Cells

Author(s): Haseeb Ahmad Khan*, Anvarhusein Abdulkadir Isab, Abdullah Saleh Alhomida, Mansour Khalil Gatasheh, Ali Rashid Alhoshani, Bashayr Ahmed Aldhafeeri and N Rajendra Prasad

Volume 24, Issue 5, 2024

Published on: 04 January, 2024

Page: [379 - 388] Pages: 10

DOI: 10.2174/0118715206281182231127113608

Price: $65

Abstract

Background: Platinum complexes are commonly used for cancer chemotherapy; however, they are not only highly-priced but also have various side effects. It is, therefore, important to design affordable anticancer drugs with minimal side effects.

Methods: We synthesized a new gold(I) complex, PF6{(BDPEA)(TPPMS) digold(I)} (abbreviated as PBTDG) and tested its cytotoxicity in MCF-7 breast cancer cells. We also evaluated the effects of PBTDG on mitochondrial membrane potential, generation of reactive oxygen species (ROS) and apoptosis in breast cancer cells.

Results: The IC50 values for PBTDG and sorafenib were found to be 1.48 μM and 4.45 μM, respectively. Exposure to PBTDG caused significant and concentration-dependent depletion of ATP and disruption of mitochondrial membrane potential. PBTDG induced 2.6, 3.6, and 5.7-fold apoptosis for 1 μM, 3 μM, and 10 μM concentrations, respectively. The induction of apoptosis by the same concentrations of sorafenib was 1.2, 1.3, and 1.6-fold, respectively. The low concentration of PBTDG (1 μM) induced the generation of ROS by 99.83%, which was significantly higher than the ROS generation caused by the same concentration of sorafenib (73.76%). The ROS induction caused by higher concentrations (5 μM) of PBTDG and sorafenib were 104.95% and 122.11%, respectively.

Conclusion: The lower concentration of PBTDG produced similar cytotoxicity and apoptotic effects that were caused by a comparatively higher concentration of known anticancer drug (sorafenib). The anticancer effects of PBTDG are attributed to its tendency to disrupt mitochondrial membrane potential, induction of apoptosis and generation of ROS. Further studies are warranted to test the anticancer effects of PBTDG in animal models of cancer.

« Previous Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Ferlay, J.; Colombet, M.; Bray, F.; Mery, L.; Piñeros, M.; Znaor, A.; Zanetti, R. 2021. Available from: http://ci5.iarc.fr
[3]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[4]
Key, T.J.; Verkasalo, P.K.; Banks, E. Epidemiology of breast cancer. Lancet Oncol., 2001, 2(3), 133-140.
[http://dx.doi.org/10.1016/S1470-2045(00)00254-0] [PMID: 11902563]
[5]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[6]
Tacar, O.; Sriamornsak, P.; Dass, C.R. Doxorubicin: An update on anticancer molecular action, toxicity and novel drug delivery systems. J. Pharm. Pharmacol., 2012, 65(2), 157-170.
[http://dx.doi.org/10.1111/j.2042-7158.2012.01567.x] [PMID: 23278683]
[7]
Emadi, A.; Jones, R.J.; Brodsky, R.A. Cyclophosphamide and cancer: Golden anniversary. Nat. Rev. Clin. Oncol., 2009, 6(11), 638-647.
[http://dx.doi.org/10.1038/nrclinonc.2009.146] [PMID: 19786984]
[8]
Rowinsky, E.K.; Cazenave, L.A.; Donehower, R.C. Taxol: A novel investigational antimicrotubule agent. J. Natl. Cancer Inst., 1990, 82(15), 1247-1259.
[http://dx.doi.org/10.1093/jnci/82.15.1247] [PMID: 1973737]
[9]
Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat. Rev. Cancer, 2003, 3(5), 330-338.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[10]
Dasari, S.; Bernard Tchounwou, P. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur. J. Pharmacol., 2014, 740, 364-378.
[http://dx.doi.org/10.1016/j.ejphar.2014.07.025] [PMID: 25058905]
[11]
Wang, D.; Lippard, S.J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov., 2005, 4(4), 307-320.
[http://dx.doi.org/10.1038/nrd1691] [PMID: 15789122]
[12]
Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer, 2007, 7(8), 573-584.
[http://dx.doi.org/10.1038/nrc2167] [PMID: 17625587]
[13]
Siddik, Z.H. Cisplatin: Mode of cytotoxic action and molecular basis of resistance. Oncogene, 2003, 22(47), 7265-7279.
[http://dx.doi.org/10.1038/sj.onc.1206933] [PMID: 14576837]
[14]
Pabla, N.; Dong, Z. Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney Int., 2008, 73(9), 994-1007.
[http://dx.doi.org/10.1038/sj.ki.5002786] [PMID: 18272962]
[15]
Rybak, L.P.; Mukherjea, D.; Jajoo, S.; Ramkumar, V. Cisplatin ototoxicity and protection: Clinical and experimental studies. Tohoku J. Exp. Med., 2009, 219(3), 177-186.
[http://dx.doi.org/10.1620/tjem.219.177] [PMID: 19851045]
[16]
Cavaletti, G.; Marmiroli, P. Chemotherapy-induced peripheral neurotoxicity. Nat. Rev. Neurol., 2010, 6(12), 657-666.
[http://dx.doi.org/10.1038/nrneurol.2010.160] [PMID: 21060341]
[17]
Huaizhi, Z.; Yuantao, N. China’s ancient gold drugs. Gold Bull., 2001, 34(1), 24-29.
[http://dx.doi.org/10.1007/BF03214805]
[18]
Benedek, T.G. The history of gold therapy for tuberculosis. J. Hist. Med. Allied Sci., 2004, 59(1), 50-89.
[http://dx.doi.org/10.1093/jhmas/jrg042] [PMID: 15011812]
[19]
Sutton, B.M.; McGusty, E.; Walz, D.T.; DiMartino, M.J. Oral gold. Antiarthritic properties of alkylphosphinegold coordination complexes. J. Med. Chem., 1972, 15(11), 1095-1098.
[http://dx.doi.org/10.1021/jm00281a001] [PMID: 4654656]
[20]
Mirabelli, C.K.; Johnson, R.K.; Sung, C.M.; Faucette, L.; Muirhead, K.; Crooke, S.T. Evaluation of the in vivo antitumor activity and in vitro cytotoxic properties of auranofin, a coordinated gold compound, in murine tumor models. Cancer Res., 1985, 45(1), 32-39.
[PMID: 3917372]
[21]
Tian, S.; Siu, F.M.; Kui, S.C.F.; Lok, C.N.; Che, C.M. Anticancer gold(i)–phosphine complexes as potent autophagy-inducing agents. Chem. Commun., 2011, 47(33), 9318-9320.
[http://dx.doi.org/10.1039/c1cc11820j] [PMID: 21584293]
[22]
Zou, T.; Lum, C.T.; Lok, C.N.; To, W.P.; Low, K.H.; Che, C.M. A binuclear gold(I) complex with mixed bridging diphosphine and bis(N-heterocyclic carbene) ligands shows favorable thiol reactivity and inhibits tumor growth and angiogenesis in vivo. Angew. Chem. Int. Ed., 2014, 53(23), 5810-5814.
[http://dx.doi.org/10.1002/anie.201400142] [PMID: 24729298]
[23]
Marzano, C.; Pellei, M.; Colavito, D.; Papini, G.; Lobbia, G.G.; Gandin, V. Anticancer potency of new gold(I) phosphine complexes containing the 5,7-dichloro-2-methyl-8-quinolinolato ligand. J. Med. Chem., 2007, 50, 4315-4321.
[24]
Ott, I.; Gust, R.; Herscheid, J.D.M. Antitumor gold(I) NHC complexes derived from selenourea by oxidative addition of AuI(tht). Eur. J. Inorg. Chem., 2010, 2010, 5076-5080.
[25]
Bertrand, B.; Casini, A.; Nolan, S.P. Gold (I)-mediated inhibition of VEGF(165)-induced angiogenesis: A molecular modeling approach. Chem. Commun., 2011, 47, 11146-11148.
[26]
Navarro-Ranninger, C.; Vicente, C.; Pérez, J.M. Gold(I)-phosphine-thiolate complexes as protein kinase inhibitors. Dalton Trans., 2008, 33, 4400-4408.
[27]
Rubbiani, R.; Kitanovic, I.; Alborzinia, H.; Can, S.; Kitanovic, A.; Onambele, L.A.; Stefanopoulou, M.; Geldmacher, Y.; Sheldrick, W.S.; Wolber, G.; Prokop, A.; Wölfl, S.; Ott, I. Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties. J. Med. Chem., 2010, 53(24), 8608-8618.
[http://dx.doi.org/10.1021/jm100801e] [PMID: 21082862]
[28]
Ott, I.; Gust, R. Non platinum metal complexes as anti-cancer drugs. Arch. Pharm., 2007, 340(3), 117-126.
[http://dx.doi.org/10.1002/ardp.200600151] [PMID: 17315259]
[29]
Casini, A.; Messori, L.; Marcon, G. Molecular mechanisms and proposed targets for selected anticancer gold compounds. Curr. Top. Med. Chem., 2008, 8, 421-433.
[PMID: 22039866]
[30]
Marzo, T.; Massai, L.; Pratesi, A. Gold (I) NHC-based homodimers: The key role of a robust intramolecular sigma-hole interaction. New J. Chem., 2017, 41, 9443-9945.
[31]
Kim, J.H.; Reeder, E.; Parkin, S.; Awuah, S.G. Gold(I/III)-phosphine complexes as potent antiproliferative agents. Sci. Rep., 2019, 9(1), 12335.
[http://dx.doi.org/10.1038/s41598-019-48584-5] [PMID: 31451718]
[32]
Rubbiani, R.; Salassa, L.; de Almeida, A.; Casini, A.; Ott, I. Cytotoxic gold(I) N-heterocyclic carbene complexes with phosphane ligands as potent enzyme inhibitors. ChemMedChem, 2014, 9(6), 1205-1210.
[http://dx.doi.org/10.1002/cmdc.201400056] [PMID: 24677779]
[33]
Nobili, S.; Landini, I.; Giglioni, B.; Mini, E. Pharmacological strategies for overcoming multidrug resistance. Curr. Drug Targets, 2009, 10, 227-239.
[PMID: 16842217]
[34]
Jakupec, M.A.; Galanski, M.S.; Keppler, B.K. Tumour-inhibiting platinum complexes—state of the art and future perspectives. Rev. Physiol. Biochem. Pharmacol., 2003, 146, 1-53.
[http://dx.doi.org/10.1007/s10254-002-0001-x] [PMID: 12605304]
[35]
Frezza, M.; Hindo, S.; Chen, D.; Davenport, A.; Schmitt, S.; Tomco, D.; Ping, Dou Q. Novel metals and metal complexes as platforms for cancer therapy. Curr. Pharm. Des., 2010, 16(16), 1813-1825.
[http://dx.doi.org/10.2174/138161210791209009] [PMID: 20337575]
[36]
Khan, H.A.; Al-Hoshani, A.; Isab, A.A.; Alhomida, A.S. A gold(III) complex with potential anticancer properties. ChemistrySelect, 2022, 7(45), e202202956.
[http://dx.doi.org/10.1002/slct.202202956]
[37]
Yang, Y.; Hall, M.D. Metal-based anticancer chemotherapeutics: Mechanisms of action and future perspectives. Chem. Asian J., 2015, 10, 1814-1834.
[38]
Praveen, C.; Dupeux, A.; Michelet, V. Catalytic gold chemistry: From simple salts to complexes for regioselective C-H bond functionalization. Chemistry, 2021, 27(41), 10495-10532.
[http://dx.doi.org/10.1002/chem.202100785] [PMID: 33904614]
[39]
Jeyaveeran, J.C.; Praveen, C.; Arun, Y.; Prince, A A M.; Perumal, P.T. Flexible synthesis of isomeric pyranoindolones and evaluation of cytotoxicity towards HeLa cells. J. Chem. Sci., 2016, 128(5), 787-802.
[http://dx.doi.org/10.1007/s12039-016-1070-8]
[40]
Parthasarathy, K.; Praveen, C.; Jeyaveeran, J.C.; Prince, A.A.M. Gold catalyzed double condensation reaction: Synthesis, antimicrobial and cytotoxicity of spirooxindole derivatives. Bioorg. Med. Chem. Lett., 2016, 26(17), 4310-4317.
[http://dx.doi.org/10.1016/j.bmcl.2016.07.036] [PMID: 27476145]
[41]
Praveen, C.; Ananth, D.B. Design, synthesis and cytotoxicity of pyrano[4,3-b]indol-1(5H)-ones: A hybrid pharmacophore approach via gold catalyzed cyclization. Bioorg. Med. Chem. Lett., 2016, 26(10), 2507-2512.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.087] [PMID: 27040658]
[42]
Khan, H.A.; Alghamdi, A.A.; Prasad, N.R.; Alrokayan, S.H.; Almansour, B.S.; Hatamilah, A.A.K. The role of mitochondrial dysfunction in cytotoxic effects of Solanum nigrum water extract on MCF-7 and MDA-MB-231 breast cancer cells. Frontiers in Bioscience-Landmark, 2023, 28(8), 180.
[http://dx.doi.org/10.31083/j.fbl2808180] [PMID: 37664945]
[43]
Nobili, S.; Mini, E.; Landini, I.; Gabbiani, C.; Casini, A.; Messori, L. Gold compounds as anticancer agents: Chemistry, cellular pharmacology, and preclinical studies. Med. Res. Rev., 2010, 30(3), 550-580.
[http://dx.doi.org/10.1002/med.20168] [PMID: 19634148]
[44]
Gorin, D.J.; Toste, F.D.; Toste, F.D. Relativistic effects in homogeneous gold catalysis. Nature, 2007, 446(7134), 395-403.
[http://dx.doi.org/10.1038/nature05592] [PMID: 17377576]
[45]
Lu, Y.; Ma, X.; Chang, X.; Liang, Z.; Lv, L.; Shan, M.; Lu, Q.; Wen, Z.; Gust, R.; Liu, W. Recent development of gold(I) and gold(III) complexes as therapeutic agents for cancer diseases. Chem. Soc. Rev., 2022, 51(13), 5518-5556.
[http://dx.doi.org/10.1039/D1CS00933H] [PMID: 35699475]
[46]
Haque, R.A.; Ghdhayeb, M.Z.; Budagumpi, S.; Khadeer Ahamed, M.B.; Abdul Majid, A.M.S. Synthesis, crystal structures, and in vitro anticancer properties of new N-heterocyclic carbene (NHC) silver(I)- and gold(I)/(III)-complexes: a rare example of silver(I)–NHC complex involved in redox transmetallation. RSC Advances, 2016, 6(65), 60407-60421.
[http://dx.doi.org/10.1039/C6RA09788J]
[47]
Bonner, J.; Fisher, R.; Wilch, E.; Schutte, D.; Schutte, B. Mitochondrial haplogroups and lifespan in a population isolate. Mitochondrion, 2020, 51, 62-67.
[http://dx.doi.org/10.1016/j.mito.2019.12.004] [PMID: 31887371]
[48]
Marzo, T.; Cirri, D.; Pollini, S.; Pratesi, A.; Guerri, A.; Biver, T. Gold(III) porphyrin 1a-induced lnhibition of mitochondrial function in human breast-cancer cells. Chemistry-A Eur J., 2016, 22, 6517-6522.
[49]
Ning, P.; Huang, L.; Bao, Y.; Fu, Y.; Xu, C.; Shen, Y.; Zhou, X.; Wen, X.; Cheng, Y.; Qin, Y. Portfolio targeting strategy to realize the assembly and membrane fusion-mediated delivery of gold nanoparticles to mitochondria for enhanced NIR photothermal therapies. Bioconjug. Chem., 2020, 31(12), 2719-2725.
[http://dx.doi.org/10.1021/acs.bioconjchem.0c00518] [PMID: 33226788]
[50]
Mora, M.; Gimeno, M.C.; Visbal, R. N-Heterocyclic carbene gold(I) and silver(I) complexes bearing β-Diketonate ancillary ligands: synthesis, structure, and preliminary biological assessment. Organometallics, 2017, 36, 333-342.
[51]
Martins, E.T.; Barros, W.A.; Alegrio, L.V.; Hausmann, R.D.S.; Andó, R.A. New Gold(I) N-heterocyclic carbene complexes: Synthesis, characterization, and antiproliferative activity. Inorganics, 2018, 6, 97.
[52]
Zhang, J.J.; Abu el Maaty, M.A.; Hoffmeister, H.; Schmidt, C.; Muenzner, J.K.; Schobert, R.; Wölfl, S.; Ott, I. A multitarget gold(I) complex induces cytotoxicity related to aneuploidy in HCT-116 colorectal carcinoma cells. Angew. Chem. Int. Ed., 2020, 59(38), 16795-16800.
[http://dx.doi.org/10.1002/anie.202006212] [PMID: 32529715]
[53]
Liang, X.; Tang, M. Research advances on cytotoxicity of cadmium-containing quantum dots. J. Nanosci. Nanotechnol., 2019, 19(9), 5375-5387.
[http://dx.doi.org/10.1166/jnn.2019.16783] [PMID: 30961689]
[54]
Rigobello, M.P.; Folda, A.; Baldoin, M.C.; Scutari, G.; Bindoli, A. Effect of Auranofin on the mitochondrial generation of hydrogen peroxide. Role of thioredoxin reductase. Free Radic. Res., 2005, 39(7), 687-695.
[http://dx.doi.org/10.1080/10715760500135391] [PMID: 16036347]
[55]
Meyer, A.; Bagowski, C.P.; Kokoschka, M.; Stefanopoulou, M.; Alborzinia, H.; Can, S.; Vlecken, D.H.; Sheldrick, W.S.; Wölfl, S.; Ott, I. On the biological properties of alkynyl phosphine gold(I) complexes. Angew. Chem. Int. Ed., 2012, 51(35), 8895-8899.
[http://dx.doi.org/10.1002/anie.201202939] [PMID: 22848030]
[56]
Yan, K.; Lok, C.N.; Bierla, K.; Che, C.M. Gold(i) complex of N,N'-disubstituted cyclic thiourea with in vitro and in vivo anticancer properties—potent tight-binding inhibition of thioredoxin reductase. Chem. Commun., 2010, 46(41), 7691-7693.
[http://dx.doi.org/10.1039/c0cc01058h] [PMID: 20623063]
[57]
Zhang, J.; Zou, H.; Lei, J.; He, B.; He, X.; Sung, H.H.Y.; Kwok, R.T.K.; Lam, J.W.Y.; Zheng, L.; Tang, B.Z. Multifunctional AuI-based AIEgens: Manipulating molecular structures and boosting specific cancer cell imaging and theranostics. Angew. Chem. Int. Ed., 2020, 59(18), 7097-7105.
[http://dx.doi.org/10.1002/anie.202000048] [PMID: 32049411]
[58]
Hikisz, P.; Szczupak, Ł.; Koceva-Chyła, A.; Guśpiel, A.; Oehninger, L.; Ott, I.; Therrien, B.; Solecka, J.; Kowalski, K. Anticancer and antibacterial activity studies of gold(I)-alkynyl chromones. Molecules, 2015, 20(11), 19699-19718.
[http://dx.doi.org/10.3390/molecules201119647] [PMID: 26528965]
[59]
De Nisi, A.; Bergamini, C.; Leonzio, M.; Sartor, G.; Fato, R.; Naldi, M.; Monari, M.; Calonghi, N.; Bandini, M. Synthesis, cytotoxicity and anti-cancer activity of new alkynyl-gold(I) complexes. Dalton Trans., 2016, 45(4), 1546-1553.
[http://dx.doi.org/10.1039/C5DT02905H] [PMID: 26687209]
[60]
Mármol, I.; Castellnou, P.; Alvarez, R.; Gimeno, M.C.; Rodríguez-Yoldi, M.J.; Cerrada, E. Alkynyl Gold(I) complexes derived from 3-hydroxyflavones as multi-targeted drugs against colon cancer. Eur. J. Med. Chem., 2019, 183, 111661.
[http://dx.doi.org/10.1016/j.ejmech.2019.111661] [PMID: 31546196]
[61]
Tabrizi, L.; Romanova, J. Antiproliferative Activity of Gold(I) N-Heterocyclic Carbene and triphenylphosphine complexes with ibuprofen derivatives as effective enzyme inhibitors. Appl. Organomet. Chem., 2020, 34(5), e5618.
[http://dx.doi.org/10.1002/aoc.5618]
[62]
Moreno-Alcántar, G.; Picchetti, P.; Casini, A. Gold complexes in anticancer therapy: From new design principles to particle-based delivery systems. Angew. Chem. Int. Ed., 2023, 62(22), e202218000.
[http://dx.doi.org/10.1002/anie.202218000] [PMID: 36847211]

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