Cytotoxicity-boosting of kiteplatin by Pt(IV) prodrugs with axial benzoate ligands

Margiotta, Nicola; Savino, Salvatore; Marzano, Cristina; Pacifico, Concetta; Hoeschele, James D.; Gandin, Valentina; Natile, Giovanni

doi:10.1016/j.jinorgbio.2015.11.028

Cited by 20 publications

(17 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The bond lengths and angles related to the phen ligand and platinum are consistent with the previously published polyaromatic PCs. 32,33 The 1,4-dach ligand adopted a twist-boat conformation similar to that seen in previous 1,4-dach complexes, 7,15,36 with a N2-Pt1-N2 bond angle of 96.3(3)° and Pt1-N2-C7 angle of 125.6(4)°. The N-Pt-N angle is approximately 13° larger than that of previous 1,2-dach complexes that adopt a chair conformation.…”

Section: X-ray Crystal Structure Of Complexsupporting

confidence: 68%

See 1 more Smart Citation

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

et al. 2018

Self Cite

View full text Add to dashboard Cite

Platinum complexes of the type [Pt(P)(A)] where P is a derivative of 1,10-phenanthroline and A is cis-1,4-diaminocyclohexane (1,4-dach), have been synthesised and characterised by ultraviolet spectroscopy, elemental microanalysis, nuclear magnetic resonance and X-ray crystallography. The calf-thymus DNA binding affinity of these complexes was determined by isothermal titration calorimetry, revealing higher DNA affinity than their 1S,2S-diaminocyclohexane analogues. In vitro cytotoxicity was assessed in eleven human cell lines, revealing unexpectedly low activity for the 1,4-dach complexes.

show abstract

Section: X-ray Crystal Structure Of Complexsupporting

confidence: 68%

“…9,10 Research into kiteplatin has recently resurged, with many labs investigating the DNA binding activity of kiteplatin and synthesising platinum(IV) derivatives to improve cytotoxicity. [11][12][13][14][15][16][17]…”

Section: Introductionmentioning

confidence: 99%

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…In some studies, bipyridine derivatives have proven to be suitable spectator ligands to complete the metal ion coordination sphere along with cur − , and thereby improve the crystallization of the complex [36,39,40]. Acetate ions in Pt(II) complexes were shown to significantly enhance their solubility in water and chemical stability compared to the parent chlorides, while a benzoate ligand in a kiteplatin Pt(IV) analog has boosted its cytotoxicity [41,42].…”

Section: Introductionmentioning

confidence: 99%

Zn(II) Curcuminate Complexes with 2,2′-bipyridine and Carboxylates

Grabner

Modec

2019

Molecules

View full text Add to dashboard Cite

Two novel zinc(II) compounds with curcuminate (abbreviated as cur–), [Zn(CH3COO)(cur)(bpy)](1)·CH3OH·2H2O (bpy = 2,2’-bipyridine) and [Zn(PhCOO)(cur)(bpy)] (2)·CH3OH, have been synthesized and characterized. Their composition has been determined by single-crystal X-ray structure analysis. Complexes 1 and 2 are similar: in both a five-fold coordination environment of zinc(II) consists of a monodentate carboxylate, a chelating bidentate 2,2’-bipyridine, and curcuminate, which is bound via a deprotonated 1,3-dione moiety. In 1, 2,2’-bipyridine nitrogen atoms and curcuminate oxygen atoms form the base of a square pyramid, whereas the acetate oxygen occupies its apex. The O3N2 donor set in 2 defines a polyhedron which more closely resembles a trigonal bipyramid. The packing in the crystal lattices of both compounds is governed by hydrogen-bonds. Complexes 1 and 2 display higher stability than curcumin in buffered media at pH = 7.0, however, the degradation of coordinated cur– is comparable to that of yellow pigment curcumin (curH) when the pH is raised to 7.2. Both complexes 1 and 2 in DMSO exhibit fluorescence with Stokes shifts of 5367 and 4634 cm−1, respectively.

show abstract

“…In order to overcome at least some of these drawbacks, new platinum drugs based on the platinum(IV) core have been developed. In this context, we have recently focused on Pt(IV) complexes [ 22 , 23 ] derived from kiteplatin, [PtCl 2 ( cis -1,4-DACH)] (DACH = diaminocyclohexane; Scheme 2 ) including a derivative having two DCA ligands in axial positions [ 24 ]; the aim was to obtain a dual acting complex endowed with the ability to target both nuclear DNA and mitochondria. Kiteplatin contains an isomeric form of the diamine ligand 1 R ,2 R -DACH present in oxaliplatin and is effective against both cisplatin-resistant (ovarian C13*) and oxaliplatin-resistant (colon LoVo-OXP) cancer cell lines, suggesting that the spectrum of activity of this compound could be different from that of cisplatin and oxaliplatin [ 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions

Savino

Marzano

Gandin

et al. 2018

IJMS

Self Cite

View full text Add to dashboard Cite

Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis-[PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters.

show abstract

Cytotoxicity-boosting of kiteplatin by Pt(IV) prodrugs with axial benzoate ligands

Cited by 20 publications

References 36 publications

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

Zn(II) Curcuminate Complexes with 2,2′-bipyridine and Carboxylates

Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions

Contact Info

Product

Resources

About