TY - JOUR
T1 - Synthesis and Cytotoxicity of Water-Soluble Dual- A nd Triple-Action Satraplatin Derivatives
T2 - Replacement of Equatorial Chlorides of Satraplatin by Acetates
AU - Karmakar, Subhendu
AU - Poetsch, Isabella
AU - Kowol, Christian R.
AU - Heffeter, Petra
AU - Gibson, Dan
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/12/16
Y1 - 2019/12/16
N2 - Pt(II) complexes, such as cisplatin and oxaliplatin, are in widespread use as anticancer drugs. Their use is limited by the toxic side effects and the ability of tumors to develop resistance to the drugs. A popular approach to overcome these drawbacks is to use their kinetically inert octahedral Pt(IV) derivatives that act as prodrugs. The most successful Pt(IV) complex in clinical trials to date is satraplatin, cct-[Pt(NH3)(c-hexylamine)Cl2(OAc)2], that upon cellular reduction releases the cytotoxic cis-[Pt(NH3)(c-hexylamine)Cl2]. In an attempt to obtain water-soluble and more effective cytotoxic Pt(IV) complexes, we prepared a series of dual- A nd triple-action satraplatin analogues, where the equatorial chlorido ligands were replaced with acetates and the axial ligands include innocent and bioactive ligands. Replacement of the chlorides with acetates enhanced the water solubility of the compounds and, with one exception, all of the compounds were very stable in buffer. In general, compounds with one or two axial hydroxido ligands were reduced by ascorbate significantly more quickly than compounds with two axial carboxylates. While replacement of the chlorides with acetates in satraplatin led to a reduction in cytotoxicity, the dual- A nd triple-action analogues with equatorial acetates had low-to sub-micromolar IC50 values in a panel of eight cancer cells. The triple-action compound cct-[Pt(NH3)(c-hexylamine)(OAc)2(PhB)(DCA)] was active in all cell lines, causing DNA damage that induced cell cycle inhibition and apoptosis. Its good activity against CT26 cells in vitro translated into good in vivo efficacy against the CT26 allograft, an in vivo model with intrinsic satraplatin resistance. This indicates that multiaction Pt(IV) derivatives of diamine dicarboxylates are interesting anticancer drug candidates.
AB - Pt(II) complexes, such as cisplatin and oxaliplatin, are in widespread use as anticancer drugs. Their use is limited by the toxic side effects and the ability of tumors to develop resistance to the drugs. A popular approach to overcome these drawbacks is to use their kinetically inert octahedral Pt(IV) derivatives that act as prodrugs. The most successful Pt(IV) complex in clinical trials to date is satraplatin, cct-[Pt(NH3)(c-hexylamine)Cl2(OAc)2], that upon cellular reduction releases the cytotoxic cis-[Pt(NH3)(c-hexylamine)Cl2]. In an attempt to obtain water-soluble and more effective cytotoxic Pt(IV) complexes, we prepared a series of dual- A nd triple-action satraplatin analogues, where the equatorial chlorido ligands were replaced with acetates and the axial ligands include innocent and bioactive ligands. Replacement of the chlorides with acetates enhanced the water solubility of the compounds and, with one exception, all of the compounds were very stable in buffer. In general, compounds with one or two axial hydroxido ligands were reduced by ascorbate significantly more quickly than compounds with two axial carboxylates. While replacement of the chlorides with acetates in satraplatin led to a reduction in cytotoxicity, the dual- A nd triple-action analogues with equatorial acetates had low-to sub-micromolar IC50 values in a panel of eight cancer cells. The triple-action compound cct-[Pt(NH3)(c-hexylamine)(OAc)2(PhB)(DCA)] was active in all cell lines, causing DNA damage that induced cell cycle inhibition and apoptosis. Its good activity against CT26 cells in vitro translated into good in vivo efficacy against the CT26 allograft, an in vivo model with intrinsic satraplatin resistance. This indicates that multiaction Pt(IV) derivatives of diamine dicarboxylates are interesting anticancer drug candidates.
UR - http://www.scopus.com/inward/record.url?scp=85076291112&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.9b02796
DO - 10.1021/acs.inorgchem.9b02796
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C2 - 31790216
AN - SCOPUS:85076291112
SN - 0020-1669
VL - 58
SP - 16676
EP - 16688
JO - Inorganic Chemistry
JF - Inorganic Chemistry
IS - 24
ER -