Platinum Complexes with Cytotoxic Activity: Models for Structure‐Activity Relationship Studies

Mier-Vinué, Jordi de; Montaña, Ángel M.; Moreno, Virtudes

doi:10.1002/chin.200709277

Cited by 5 publications

(4 citation statements)

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“…Over time thousands of platinum compounds have been screened for their cytostatic properties, and empirical structure–activity rules/relationships (SAR) have been established . According to SAR, activity can be expected for neutral planar Pt(II) complexes of the general formula cis -Pt(II)A 2 X 2 in which A represents a neutral amine ligand bearing 1–3 protons and X (X 2 , respectively) represents an anionic leaving group such as halide, oxalate, and malonate, which slowly hydrolyzes.…”

Section: Introductionmentioning

confidence: 99%

9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

2017

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As part of a comprehensive study of N-unsubstituted bispidines, the novel 9,9-difluorobispidine (D) has been synthesized. The compound crystallizes from pentane below 0 °C in the ordered-crystalline phase D-II and undergoes at 0-30 °C a stepwise endothermic phase transition to a dynamically disordered crystalline phase D-I; melting occurs at 227 °C. Single crystalline D-II has been subjected to X-ray structure analysis, revealing association of the molecules to form chains. Reaction of (1,5-hexadiene)PtCl with D affords {CHF(NH)}PtCl (D1), which can be converted by conventional routes to {CHF(NH)}Pt(cbdca)·5HO (D2) and {CHF(NH)}Pt(CO) (D3). Compound D1 crystallizes solvent-free from water and is isomorphous to the solvent-free parent bispidine analogue (A1). The pentahydrate D2 is isomorphous to the bispidine and 9-oxabispidine homologues (A2 and C2), as shown by X-ray structure analyses. An increased polarity of the bispidine skeleton as a consequence of the high electronegativity of fluorine is seen as the reason for low cytotoxic potency of D1-D3.

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Section: Introductionmentioning

confidence: 99%

9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

2017

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“…In the quest to overcome the problems associated with cisplatin-based therapy, countless platinum complexes have been tested for their cytostatic activity. On the basis of such empirical studies, structure–activity rules (SARs) have been established and were first formulated by Cleare and Hoeschele . According to SARs, activity is generally found for platinum(II) complexes that are neutral and planar and adhere to the general formula cis -Pt II A 2 X 2 , in which A represents a neutral amine ligand bearing 1–3 protons.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structures of 9-Oxabispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

2016

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The literature synthesis of 9-oxabispidine [OC6H10(NH)2, C] has been revisited and optimized, which includes determination of the crystal structures of C, the secondary component trans-(PhSO2)NC4H6O(CH2I)2 (trans-III), and the unexpected solute intermediate OC6H10(NSO2Ph)2·(1)/2py (V·(1)/2py). The reaction of (1,5-hexadiene)platinum dichloride with C yields {OC6H10(NH)2}PtCl2 (C1), which is converted to {OC6H10(NH)2}Pt(cbdca)·5H2O (C2) and {OC6H10(NH)2}Pt(C2O4) (C3). In the crystal, C1 forms a planar 2D network by N-H··Cl and N-H··O hydrogen bonding. In the crystal structure of C2, which is isomorphous to the parent bispidine compound (A2), all complex molecules are encapsulated by a water shell. While complexes C1 and C3 are virtually insoluble in water, C2 dissolves quite well. The low cytotoxicity of compounds C1-C3 is explained by an increased polarity of the bonds in the C skeleton as a consequence of the electronegative O atom.

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“…So far, relatively little is known about the effect of secondary amines such as cyclic monoamines, chelating acyclic diamines, and chelating cyclic diamines as possible carrier ligands for Pt(II). Based on the established structure–activity relationships (SARs), , Pt(II) complexes with secondary amine ligands are expected to be less potent.…”

Section: Introductionmentioning

confidence: 99%

Bispidin-9,9-diol Analogues of Cisplatin, Carboplatin, and Oxaliplatin: Synthesis, Structures, and Cytotoxicity

et al. 2016

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3,7-Diallyl-bispidin-9-one (6) (bispidin-9-one = 3,7-diazabicyclo[3.3.1]nonan-9-one) is converted to N-unsubstituted spiro[bispidin-9,2'-[1,3]dioxolane] (12; 35%). The ketal crystallizes in the forms of anhydrous 12a and the dihydrate 12b. The molecules in anhydrous 12a are linked to each other, forming N1-H1···N2-H2···N1* hydrogen-bond chiral helices of alternating chirality. In the dihydrate 12b, the ketal molecules are connected to a central string of water molecules by O3-H···O1 and O4-H···N1 hydrogen bonds, but not to themselves. Reaction of 12 with (1,5-hexadiene)PtCl2 affords almost quantitatively spiro[bispidin-9,2'-[1,3]dioxolane]PtCl2 (13). Cleavage of the ketal to retrieve the ketone produces the geminal diol (bispidin-9,9-diol)PtCl2 (14; 85%). Compound 14 reacts with Ag2cbdca (cbdca = 1,1-cyclobutanedicarboxylate) to give the dihydrate (bispidin-9,9-diol)Pt(cbdca)·2H2O (15b), which can be dehydrated to obtain anhydrous (bispidin-9,9-diol)Pt(cbdca) (15a). Similarly, anhydrous (bispidin-9,9-diol)Pt(oxalate) (16) is obtained. Crystal structures of 14 and 15b reveal association by various forms of O-H···O, O-H···Cl, N-H···Cl, and N-H···O hydrogen bonds. Biological studies showed a moderate cytotoxic activity of the bispidin-9,9-diol complexes 14-16, compared to the 9,9-unsubstituted bispidine complexes. No unspecific cytotoxicity of 14-16 up to 316 μM was found against the noncancer cell line HEK293.

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Platinum Complexes with Cytotoxic Activity: Models for Structure‐Activity Relationship Studies

Cited by 5 publications

References 0 publications

9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

Synthesis and Structures of 9-Oxabispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin

Bispidin-9,9-diol Analogues of Cisplatin, Carboplatin, and Oxaliplatin: Synthesis, Structures, and Cytotoxicity

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