Abstract
HIV infection is known for replicating in proliferating CD+ T-cells. Treatment of these cells with cytostatic (anti-proliferation) compounds such as hydroxyurea interferes with the cells’s ability support HIV replication. Combinations of such cytostatic compounds with proven anti-retroviral drugs (like ddI) are known as virostatic, and have been shown to aid in the control of the infection. The use of two different drugs in virostatic combinations however, carries the risk of adverse effects including drug–drug interactions, which could lead to augmented toxicities and reduced efficacy. Here, a novel digold(I) complex of ferrocene–quinoline (3) was investigated for cytostatic behaviour as well as anti-viral activity which if demonstrated would eliminate concerns of drug–drug interactions. The complex was synthesized and characterized by NMR, FT-IR and mass spectroscopy and the molecular structure was confirmed by X-ray crystallography. Bio-screening involved viability dyes, real time electronic sensing and whole virus assays. The complex showed significant (p = 0.0092) inhibition of virus infectivity (83 %) at 10 ug/mL. This same concentration caused cytostatic behaviour in TZM-bl cells with significant (p < 0.01) S and G2/M phase cell cycle arrest. These data supports 3 as a virostatic agent, possessing both anti-viral and cytostatic characteristics.
Graphical Abstract
In the absence of 3, TZM-bl cells were infected by a pseudovirus and this was demonstrated through luminescence in a luciferase assay. Pre-incubation of the virus with 3 decreased luminescence, indicating the anti-viral activity of 3. Complex 3 also showed cytostatic behavior with increased S-phase and G2/M phase cell cycle arrest.
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References
Abid Masood M, Farrant E, Morao I et al (2012) Lead diversification. Application to existing drug molecules: mifepristone 1 and antalarmin 8. Bioorg Med Chem Lett 22:723–728. doi:10.1016/j.bmcl.2011.10.066
Atienzar FA, Tilmant K, Gerets HH et al (2011) The use of real-time cell analyzer technology in drug discovery: defining optimal cell culture conditions and assay reproducibility with different adherent cellular models. J Biomol Screen 16:575–587. doi:10.1177/1087057111402825
Bjelosevic H, Spégel C, Snygg ÅS et al (2006) Synthesis and structural characterisation of novel platinum-based drug candidates with extended functionality by incorporation of bis(diphenylphosphino)ferrocene units as metal chelators. Tetrahedron 62:4519–4527. doi:10.1016/j.tet.2006.02.057
Boelaert JR, Sperber K, Piette J (1999) Chloroquine exerts an additive in vitro anti-HIV type 1 effect when associated with didanosine and hydroxyurea. AIDS Res Hum Retrovir 15:1241–1247. doi:10.1089/088922299310133
Brenchley JM, Schacker TW, Ruff LE et al (2004) CD4 + T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200:749–759. doi:10.1084/jem.20040874
Briz V, Poveda E, Soriano V (2006) HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother 57:619–627. doi:10.1093/jac/dkl027
d’Ettorre G, Paiardibi M, Ceccareli G et al (2011) HIV-associated immune activation: from bench to bedside. AIDS Res Hum Retrovir 27:355–364. doi:10.1089/aid.2010.0342
Derdeyn CA, Decker JM, Sfakianos JN et al (2000) Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol 74:8358–8367
Desai M, Iyer G, Dikshit RK (2012) Antiretroviral drugs: critical issues and recent advances. Indian J Pharmacol 44:288–298. doi:10.4103/0253-7613.96296
Fonteh PN, Keter FK, Meyer D (2011) New bis(thiosemicarbazonate) gold(III) complexes inhibit HIV replication at cytostatic concentrations: potential for incorporation into virostatic cocktails. J Inorg Biochem 105:1173–1180. doi:10.1016/j.jinorgbio.2011.05.011
Fonteh P, Elkhadir A, Omindi B et al (2015) Impedance technology reveals correlations between cytotoxicity and lipophilicity of mono and bimetallic phosphine complexes. Biometals. doi:10.1007/s10534-015-9851-y
García F, Plana M, Arnedo M et al (2003) A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study. AIDS 17:43–51. doi:10.1097/01.aids.0000042953.95433.79
Krogstad DJ, Gluzman IY, Kyle DE et al (1987) Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238:1283–1285
Kustermann S, Boess F, Buness A et al (2013) A label-free, impedance-based real time assay to identify drug-induced toxicities and differentiate cytostatic from cytotoxic effects. Toxicol Vitr 27:1589–1595. doi:10.1016/j.tiv.2012.08.019
Lori F, Jessen H, Lieberman J et al (1999) Immune restoration by combination of a cytostatic (didanosine and indinavir). AIDS Res Hum Retrovir 15:619–624
Lori F, Foli A, Groff A et al (2005) Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic (“virostatic”) mechanisms. AIDS 19:1173–1181
Meijer L, Borgne A, Mulner O et al (1997) Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem 243:527–536. doi:10.1111/j.1432-1033.1997.t01-2-00527.x
Montefiori DC (2005) Evaluating neutralizing antibodies against HIV, SIV, and SHIV in luciferase reporter gene assays. Curr Protoc Immunol Ed by John E Coligan al Chapter 12:Unit 12.11
Montessori V, Press N, Harris M et al (2004) Adverse effects of antiretroviral therapy for HIV infection. CMAJ 170:229–238
Mufhandu HT, Gray ES, Madiga MC et al (2012) UCLA1, a synthetic derivative of a gp120 RNA aptamer, inhibits entry of human immunodeficiency virus type 1 subtype C. J Virol 86:4989–4999. doi:10.1128/JVI.06893-11
Muthyala R (2011) Orphan/rare drug discovery through drug repositioning. Drug Discov Today Ther Strateg 8:71–76. doi:10.1016/j.ddstr.2011.10.003
Palatinus L, Chapuis G (2007) SUPERFLIP—a computer program for the solution of crystal structures by charge flipping in arbitrary dimensions. J Appl Crystallogr 40:786–790
Platt EJ, Wehrly K, Kuhmann SE et al (1998) Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J Virol 72:2855–2864
Platt EJ, Bilska M, Kozak SL et al (2009) Evidence that ecotropic murine leukemia virus contamination in TZM-bl cells does not affect the outcome of neutralizing antibody assays with human immunodeficiency virus type 1. J Virol 83:8289–8292
Pollack TM, Mccoy C, Pharm D, Stead W (2009) Clinically significant adverse events from a drug interaction between quetiapine and atazanavir-ritonavir in two patients. Pharmacotherapy 29:1386–1391
Sánchez-Delgado RA, Anzellotti A (2004) Metal complexes as chemotherapeutic agents against tropical diseases: trypanosomiasis, malaria and leishmaniasis. Mini Rev Med Chem 4:23–30
Savarino A, Gennero L, Sperber K, Boelaert JR (2001) The anti-HIV-1 activity of chloroquine. J Clin Virol 20:131–135
Schneider Y, Vincent F, Duranton B et al (2000) Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells. Cancer Lett 158:85–91. doi:10.1016/S0304-3835(00)00511-5
Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr 64:112–122
Spek AL (2009) Structure validation in chemical crystallography. Acta Crystallogr D 65:148–155
Takeuchi Y, McClure MO, Pizzato M (2008) Identification of γ-retroviruses constitutively released from cell lines used for HIV research. J Virol 82:12585–12588
Tsai WP, Nara PL, Kung HF, Oroszlan S (1990) Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res Hum Retrovir 6:481–489
Uson R, Laguna A, Laguna M et al (1989) (Tetrahydrothiophene)gold(I) or gold(III) complexes. Inorg Synth 26:85–91
Wang W, Heideman L, Chung CS et al (2000) Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol Carcinog 28:102–110
Wei X, Decker J, Liu H et al (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46:1896–1905. doi:10.1128/AAC.46.6.1896
Williams DBG, Traut T, Kriel FH, van Zyl WE (2007) Bidentate amino- and iminophosphine ligands in mono- and dinuclear gold(I) complexes: synthesis, structures and AuCl displacement by AuC6F5. Inorg Chem Commun 10:538–542. doi:10.1016/j.inoche.2007.01.022
World Health Organization (2015) Media centre—HIV/AIDS
Yearick K, Ekoue-kovi K, Iwaniuk DP et al (2008) Overcoming drug resistance to heme-targeted antimalarials by systematic side chain variation of 7-chloro-4-aminoquinolines. J Med Chem 51:1995–1998
Zhang Q, Hua G, Bhattacharyya P et al (2003) Syntheses and coordination chemistry of aminomethylphosphine derivatives of adenine. Eur J Inorg Chem 2003:2426–2437. doi:10.1002/ejic.200300037
Acknowledgments
We would like to thank the National Research Foundation (NRF) and the Technology Innovation Agency (TIA), South Africa for funding the project as well as the NRF Innovation Doctoral Scholarship for N. Gama. K. Kumar would like to thank the European Commission (Erasmus Mundus Europe Asia, EMEA) and University of Johannesburg, South Africa for a postdoctoral fellowship.
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Gama, N., Kumar, K., Ekengard, E. et al. Gold(I) complex of 1,1′-bis(diphenylphosphino) ferrocene–quinoline conjugate: a virostatic agent against HIV-1. Biometals 29, 389–397 (2016). https://doi.org/10.1007/s10534-016-9921-9
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DOI: https://doi.org/10.1007/s10534-016-9921-9