A New Class of Antitumortrans-Amine-Amidine-Pt(II) Cationic Complexes: Influence of Chemical Structure and Solvent on in Vitro and in Vivo Tumor Cell Proliferation

Abstract

The reactions of cyclopropylamine, cyclopentylamine, and cyclohexylamine with trans-[PtCl2(NCMe)2] afforded the bis-cationic complexes trans-[Pt(amine)2(Z-amidine)2]2+[Cl-]2, 1-3. The solution behavior and biological activity have been studied in different solvents (DMSO, water, polyethylene glycol (PEG 400), and polyethylene glycol dimethyl ether (PEG-DME 500)). The biological activity was strongly influenced by the cycloaliphatic amine ring size, with trans-[Pt(NH2CH(CH2)4CH2)2{N(H) horizontal lineC(CH3)N(H)CH(CH2)4CH2}2]2+[Cl-]2 (3) being the most active compound. Complex 3 overcame both cisplatin and MDR resistance, inducing cancer cell death through p53-mediated apoptosis. Alkaline single-cell gel electrophoresis experiments indicated direct DNA damage, reasonably attributable to DNA adducts of trans-[PtCl(amine)(Z-amidine)2][Cl] species, which can evolve to produce disruptive and nonrepairable lesions on DNA, thus leading to the drug-induced programmed cancer cell death. Preliminary in vivo antitumor studies on C57BL mice bearing Lewis lung carcinoma highlighted that complex 3 promoted a significant and dose-dependent tumor growth inhibition without adverse side effects.

A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling

“…LoVo (10 5 ) cells were incubated for 6, 12 and 24 hrs with IC 50 of tested compounds. Subsequently, cells were processed and comet assay was performed as previously described [27].…”

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

“…224 At room temperature and with 24 h reaction times, both chlorides of trans -[PtCl 2 (NCR) 2 ] can be substituted by aliphatic amines or ammonia to form the salts, trans -[Pt(amine) 2 (amidine) 2 ]Cl 2 (Scheme 14) 235 , which also exhibit anticancer activity. 227 The greater tendency of the trans dinitrile complex to lose its chloride ligands in comparison to that of the cis is proposed to be a consequence of the greater solubility of the intermediate diamidine complex, trans -[PtCl 2 (amidine) 2 ], which makes it susceptible to further reactivity with the nucleophilic amines. For the cis complex, the diamidine complex precipitates from solution, thus impeding further substitution reactions.…”

Chemistry and Biological Activity of Platinum Amidine Complexes

“…The dicationic species 13, 15, and 17 can be obtained in high yield by performing the reactions at room temperature for extended periods of time (typically 24 h) in the presence of the corresponding amines in excess. [53] The addition of MeNH 2 to cis-and trans-[PtCl 2 (NCCH 2 Ph) 2 ] yielded the corresponding bis-benzylamidine derivatives as confirmed by an X-ray structural investigation of trans-[PtCl 2 {ZÀN(H)=C(NHMe)CH 2 Ph} 2 ]. [54] The addition of primary ali-phatic amines to cis-and trans-[PtCl 2 (NCPh) 2 ] occurred with the formation of various compounds depending on the geometry of the starting nitrile and on the entering amine (Scheme 5), for which the corresponding amidines are in the E and Z configuration as depicted in Figure 3.…”

“…[50,53] Biological tests recognized PEG400 and PEG-DME500 as suitable solvents for platinum compounds that are frequently insoluble and/or unstable in water, DMSO, and DMF. Moreover, a reasonable relationship between structure and bioactivity emerged: by progressively increasing the alicyclic ring size from cyclopropyl to cyclohexyl, an enhancement in cytotoxic activity was observed ( Table 3).…”

“…[104] The water-soluble complex trans-[Pt(NH 2 cHex) 2 {N(H)=C-(NHcHex)CH 3 } 2 ](Cl) 2 , bearing four cyclohexyl groups, distinguished itself as the most promising derivative among a series of dicationic bis-amidine trans-Pt II complexes (see Table 4). [53] With PEG400 as a solvent, it was able to overcome both cisplatin and multidrug resistance, inducing cancer cell death through p53-mediated apoptosis. 2 show low adverse systemic effects.…”