TY - JOUR
T1 - Cytotoxicity and ROS production of novel Pt(IV)oxaliplatin derivatives with indole propionic acid
AU - Tolan, Dina
AU - Almotairy, Awatif Rashed Z.
AU - Howe, Orla
AU - Devereux, Michael
AU - Montagner, Diego
AU - Erxleben, Andrea
N1 - Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/6/24
Y1 - 2019/6/24
N2 - The coordination of biologically active moieties to the axial positions of Pt(IV)derivatives of Pt(II)anticancer drugs allows the co-delivery and simultaneous activation of two pro-drugs for combination therapy. Pt(IV)complexes with a redox modulator as an axial ligand can kill cancer cells by a mechanism combining DNA platination and generation of oxidative stress. In this study we evaluated the cytotoxicity of Pt(IV)complexes based on the oxaliplatin scaffold and the pro-oxidant indole-3-propionate in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. A series of five complexes was synthesized and characterized by 1H and 195Pt NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; trans-[Pt(DACH)(ox)(IPA)(OH)](1), trans-[Pt(DACH)(ox)(IPA)2](2), trans-[Pt(DACH)(ox)(IPA)(bz)](3), trans-[Pt(DACH)(ox)(IPA)(suc)](4), and trans-[Pt(DACH)(ox)(IPA)(ac)](5)(DACH = 1,2-diaminocyclohexane (1R,2R)-(−), ox = oxalate, IPA = indole-3-propionate, bz = benzoate, suc = succinate and ac = acetate). The complexes were shown to produce cellular reactive oxygen species (ROS)in a time-dependent manner. The most potent ROS producer, complex 1, also elicited the highest cytotoxicity. Complex 1 was shown to form the mono- and bis-adducts [Pt(DACH)(guanosine)(OH)]+ and [Pt(DACH)(guanosine)2]2+ in the presence of ascorbic acid, suggesting that on activation the released oxaliplatin will interact with DNA.
AB - The coordination of biologically active moieties to the axial positions of Pt(IV)derivatives of Pt(II)anticancer drugs allows the co-delivery and simultaneous activation of two pro-drugs for combination therapy. Pt(IV)complexes with a redox modulator as an axial ligand can kill cancer cells by a mechanism combining DNA platination and generation of oxidative stress. In this study we evaluated the cytotoxicity of Pt(IV)complexes based on the oxaliplatin scaffold and the pro-oxidant indole-3-propionate in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. A series of five complexes was synthesized and characterized by 1H and 195Pt NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; trans-[Pt(DACH)(ox)(IPA)(OH)](1), trans-[Pt(DACH)(ox)(IPA)2](2), trans-[Pt(DACH)(ox)(IPA)(bz)](3), trans-[Pt(DACH)(ox)(IPA)(suc)](4), and trans-[Pt(DACH)(ox)(IPA)(ac)](5)(DACH = 1,2-diaminocyclohexane (1R,2R)-(−), ox = oxalate, IPA = indole-3-propionate, bz = benzoate, suc = succinate and ac = acetate). The complexes were shown to produce cellular reactive oxygen species (ROS)in a time-dependent manner. The most potent ROS producer, complex 1, also elicited the highest cytotoxicity. Complex 1 was shown to form the mono- and bis-adducts [Pt(DACH)(guanosine)(OH)]+ and [Pt(DACH)(guanosine)2]2+ in the presence of ascorbic acid, suggesting that on activation the released oxaliplatin will interact with DNA.
KW - Cytotoxicity
KW - Indole propionic acid
KW - Oxaliplatin
KW - Pt(IV)prodrugs
KW - Redox stress
UR - http://www.scopus.com/inward/record.url?scp=85064812388&partnerID=8YFLogxK
U2 - 10.1016/j.ica.2019.04.038
DO - 10.1016/j.ica.2019.04.038
M3 - Article
AN - SCOPUS:85064812388
SN - 0020-1693
VL - 492
SP - 262
EP - 267
JO - Inorganica Chimica Acta
JF - Inorganica Chimica Acta
ER -
