A Subset of New Platinum Antitumor Agents Kills Cells by a Multimodal Mechanism of Action Also Involving Changes in the Organization of the Microtubule Cytoskeleton.

The substitution inert platinum agent [Pt(1 S,2 S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far.

An Anticancer Pt Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects.

Dual- or multi-action Pt prodrugs represent a new generation of platinum anticancer drugs. The important property of these Pt prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a "triple-action" prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate.

Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance.

A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells. In particular, "triple action" Pt(iv) derivatives of cisplatin, where the axial ligands are inhibitors of cyclooxygenase (COXi), histone deacetylase (HDACi) or pyruvate dehydrogenase kinase (PDKi) were developed. All compounds, ctc-[Pt(NH)(COXi)(PDKi)Cl], ctc-[Pt(NH)(COXi)(HDACi)Cl] and ctc-[Pt(NH)(HDACi)(PDKi)Cl], where COXi = aspirin or ibuprofen, PDKi = dichloroacetate and HDACi = valproate or phenylbutyrate, were significantly more cytotoxic than cisplatin against all cell lines of an in-house panel of human cancer cells.

A Quadruple-Action Platinum(IV) Prodrug with Anticancer Activity Against KRAS Mutated Cancer Cell Lines.

We developed a novel Pt prodrug that simultaneously releases four different bioactive moieties inside the cancer cell. Its cytotoxicity against monolayer cultures (2D) and spheroid (3D) cancer cells is significantly better than cisplatin. It is 200-450-fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40-fold more selective towards KRAS mutated cells compared to non-cancerous.

Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)].

This report describes the synthesis, characterization and biological activity of a series of platinum(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] (Pt56MeSS) with non-bioactive, lipophilic and bioactive axial ligands. In an attempt to explore the anticancer activity potential of the Pt(iv) derivatives, 2D and 3D cytotoxic screening and a preliminary in vivo study were performed. The average IC values of the platinum(iv) derivatives ranged from 1.

Probing the Interactions of Cytotoxic [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] and Its Pt Derivatives with Human Serum.

The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its Pt derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The Pt complex, Pt56MeSS, binds noncovalently and reversibly to slow-tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a K value of ∼1.5×10  m.

Microwave-assisted synthesis of the anticancer drug cisplatin, cis-[Pt(NH3)2Cl2].

A microwave-assisted synthesis of cisplatin, cis-[Pt(NH3)2Cl2], has been developed and optimized on both a 0.2 and 0.05 millimolar scale.

DNA fragment conformations in adducts with Kiteplatin.

The anticancer activity of cisplatin is triggered by its formation of intrastrand adducts involving adjacent G residues of DNA. To obtain information on the different conformers that can be formed, carrier ligands such as 2,2'-bipiperidine, which provide large steric bulk near the platinum coordination plane and decrease the dynamic motion about the Pt-N7 bonds, were introduced ("retro-modelling" approach). In the present study we investigate the effect of cis-1,4-diaminocyclohexane (cis-1,4-DACH) on the formation, stability, and stereochemistry of (cis-1,4-DACH)Pt(ss-oligo) adducts (ss-oligo = d(GpG) with 3'- and/or 5'-substituents).

Reactivity of kiteplatin with S-donor biomolecules and nucleotides.

Kiteplatin, (cis-1,4-DACH)dichloridoplatinum(ii), contains an isomeric form of the carrier ligand present in the successful antitumor drug oxaliplatin and has been recently found to be very active against oxaliplatin-resistant colon cancers, confirming that, by changing the nature of the amine ligand, it is possible to obtain platinum drugs that are not cross-resistant to those already in clinical use. Apart from interaction with DNA, another factor that can affect the activity of platinum drugs is their metabolic fate in the cellular environment. Therefore, kiteplatin has been reacted with S-donor biomolecules, such as glutathione, cysteine, and methionine.

Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy.

Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth.

NMR investigation of the spontaneous thermal- and/or photoinduced reduction of trans dihydroxido Pt(IV) derivatives.

The initial aim of the present work was the synthesis of the axial disuccinato Pt(IV) derivative of [PtCl2(cis-1,4-DACH)] (Kiteplatin, 1 in Figure 1 ) (DACH = diaminocyclohexane), which contains an isomeric form of the diamine ligand present in oxaliplatin (i.e., 1R,2R-DACH).

Revisiting [PtCl₂(cis-1,4-DACH)]: an underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer.

Although the encouraging antitumor activity of [PtCl(2)(cis-1,4-DACH)] (1; DACH = diaminocyclohexane) was shown in early studies almost 20 years ago, the compound has remained nearly neglected. In contrast, oxaliplatin, containing the isomeric 1(R),2(R)-DACH carrier ligand, enjoys worldwide clinic application as a most important therapeutic agent in the treatment of colorectal cancer. By extending the investigation to human chemotherapy-resistant cancer cells, we have demonstrated the real effectiveness of 1 in circumventing cisplatin and oxaliplatin resistance in LoVo colon cancer cells.