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

Harper, Benjamin W. J.; Petruzzella, Emanuele; Sirota, Roman; Faccioli, Fernanda Fabiola; Aldrich‐Wright, Janice R.; Gandin, Valentina; Gibson, Dan

doi:10.1039/c7dt01054k

Cited by 44 publications

(33 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Treatment of cancer cells with numerous antitumor metallodrugs cause mitochondrial transmembrane potential disruption and activates the mitochondrial apoptotic pathway. − The previous investigation of the MoA of the Pt(IV) derivatives of 5 containing some nonbioactive, lipophilic, and bioactive axial ligands showed that some of these compounds effectively induced the hypopolarization of the mitochondrial membrane of 2008 ovarian tumor cells. However, the role of the 5,6-Me 2 phen ligand in the mechanisms of the hypopolarization of the mitochondrial membrane remained elusive.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

The substitution inert platinum agent [Pt(1S,2Sdiaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] 2+ (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. Here, we show that 5 and its Pt(IV) derivatives exhibit an intriguing potency in the triple-negative breast cancer cells MDA-MB-231. Moreover, we show that the Pt(IV) derivatives of 5 act by multimodal MoA resulting in the global biological effects, that is, they damage nuclear DNA, reduce the mitochondrial membrane potential, induce the epigenetic processes, and last but not least, the data provide evidence that changes in the organization of cytoskeleton networks are functionally important for 5 and its derivatives, in contrast to clinically used platinum cytostatics, to kill cancer cells.

show abstract

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Kasparkova et al recently reported a photoactivatable platinum(IV) complex with axial suberoylanilide hydroxamic acid ligands [37]. Gibson and coworkers attached the HDACi 4phenylbutyric acid (PBA) and valproate to the axial positions of Pt(IV) derivatives of cisplatin and oxaliplatin [38,39]. Cis,trans,cis-[Pt (NH 3 ) 2 (PBA) 2 Cl 2 ] was found to be up to 100-fold more potent than cisplatin [38].…”

Section: Introductionmentioning

confidence: 99%

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

Almotairy

Gandin

Morrison

et al. 2017

Journal of Inorganic Biochemistry

Self Cite

View full text Add to dashboard Cite

Five new platinum(IV) derivatives of carboplatin each incorporating the histone deacetylase inhibitor 4-phenylbutyrate in axial position were synthesized and characterized by H andPt NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis, namely cis,trans-[Pt(CBDCA)(NH)(PBA)(OH)] (1), cis,trans-[Pt(CBDCA)(NH)(PBA)] (2), cis,trans-[Pt(CBDCA)(NH)(PBA)(bz)] (3), cis,trans-[Pt(CBDCA)(NH)(PBA)(suc)] (4) and cis,trans-[Pt(CBDCA)(NH))(PBA)(ac)] (5) (PBA=4-phenylbutyrate, CBDCA=1,1-cyclobutane dicarboxylate, bz=benzoate, suc=succinate and ac=acetate). The reduction behavior in the presence of ascorbic acid was studied by high performance liquid chromatography. The cytotoxicity against a panel of human tumor cell lines, histone deacetylase (HDAC) inhibitory activity, cellular accumulation and the ability to induce apoptosis were evaluated. The most effective complex, compound 3, was found to be up to ten times more effective than carboplatin and to decrease cellular basal HDAC activity by approximately 18% in A431 human cervical cancer cells.

show abstract

“…Its Pt IV derivative Pt56MeSS(PhB) 2 showed both in vitro and in vivo activity. [14] Compound 3a was prepared by coupling 1a and 2a. Compound 3b was prepared to compare with 3a to assess the influence of the added inhibitors.T he detailed synthesis and characterization of all compounds appears in the Supporting Information (Figure S1-S7 and Table S1).…”

mentioning

confidence: 99%

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

et al. 2017

Self Cite

View full text Add to dashboard Cite

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. This is important since RAS proteins play a role in regulating cell differentiation, proliferation, and survival and KRAS is mutated in 90 % of pancreatic adenocarcinomas, 45 % of colorectal cancers, and 35 % of lung adenocarcinomas. The selectivity index, determined by dividing the IC value in non-cancerous cells by that of a cancerous cell line, is two-fold better than cisplatin, attesting to preferential cytotoxicity towards neoplastic cells.

show abstract

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)]

Cited by 44 publications

References 38 publications

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

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

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

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

Contact Info

Product

Resources

About