Synthesis and Cytotoxicity of Water-Soluble Dual- and Triple-Action Satraplatin Derivatives: Replacement of Equatorial Chlorides of Satraplatin by Acetates

Abstract

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- and 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- and 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.

IC50 Evaluation of Platinum Nanocatalysts for Cancer Treatment in Fibroblast, HeLa, and DU-145 Cell Lines

“…The behavior observed for the nanocatalyst against cancerous and normal cells indicates that the NPs are harmless to this normal cell line, in contrast with its toxicity profile in cancerous cells. The aforementioned suggests the high selectivity of the NPt for malignant cells without affecting benign cells, in contrast with cisplatin and its high cytotoxicity against all types of cells …”

“…The aforementioned suggests the high selectivity of the NPt for malignant cells without affecting benign cells, in contrast with cisplatin and its high cytotoxicity against all types of cells. 69 …”

“…The aforementioned suggests the high selectivity of the NPt for malignant cells without affecting benign cells, in contrast with cisplatin and its high cytotoxicity against all types of cells. 69 Platinum compounds, such as cisplatin, 70 are widely known for their antineoplastic properties regarding effects in DNA. 40,71,72 NPt is believed to exhibit cytotoxicity because of the platinum atoms distributed in the titania matrix, which display similar interaction with the DNA as reported by Loṕez et al (2008) 73 in a Wistar rat model.…”

Understanding the Role of Axial Ligands in Modulating the Biopharmaceutical Outcomes of Cisplatin(IV) Derivatives

“…The reaction equation C t = C 0 e – k t was used for determination of t 1/2 , where C 0 and C t were the concentrations of the test compound at times t – 0 & time – t , respectively, and k was the reaction rate constant. Subsequently, t 1/2 was determined by the equation t 1/2 = 0.693/ k …”

“…Subsequently, t 1/2 was determined by the equation t 1/2 = 0.693/k. 18 3.7. Anticancer Activity in Cell Culture.…”