Platinum compounds with estrogen receptor affinity

Bednarski, Patrick J.; Gust, Ronald; Spruß, Thilo; Knebel, Norbert; Otto, Angela M.; Farbel, Michael; Koop, Ronald; Holler, Eggehard; Angerer, E. von; Schönenberger, Helmut

doi:10.1016/0305-7372(90)90052-h

Cited by 15 publications

(12 citation statements)

References 13 publications

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“…A number of platinum complexes linked to steroids have been designed to take advantage of steroid transport mechanisms to increase the intracellular accumulation of drug [14,15,16,17,18,19]. In addition to affecting toxicant transport, our study was aimed at the construction of a molecule that would disrupt the processes of DNA repair and transcription.…”

Section: Resultsmentioning

confidence: 99%

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A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

Kim

Rye

Essigmann

et al. 2009

Journal of Inorganic Biochemistry

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A strategy is described for the re-design of DNA damaging platinum(II) complexes to afford elevated toxicity towards cancer cells expressing the estrogen receptor (ER). Two platinum-based toxicants are described in which a DNA damaging warhead, [Pt(en)Cl2] (en, ethylenediamine), is tethered to either of two functional groups. The first agent, [6-(2-amino-ethylamino)-hexyl]-carbamic acid 2-[6-(7α-estra-1,3,5,(10)-triene)-hexylamino]-ethyl ester platinum(II) dichloride ((Est-en)PtCl2), terminates in a ligand for the ER. The second agent is a control compound lacking the steroid; this compound, N-[6-(2-amino-ethylamino)-hexyl]-benzamide platinum(II) dichloride ((Bz-en)PtCl2)), terminates in a benzamide moiety, which lacks affinity for the ER. Using a competitive binding assay, Est-en had 28% relative binding affinity (RBA) for the ER as compared to 17β-estradiol. After covalent binding to a synthetic DNA duplex 16-mer, the compound retained its affinity for the ER; specificity of the binding event was demonstrated by the ability of free 17β-estradiol as a competitor to disrupt the DNA adduct-ER complex. The (Est-en)PtCl2 compound showed higher toxicity against the ER positive ovarian cancer cell line CAOV3 than did the control compound. (Est-en)PtCl2 was also more toxic to the ER positive breast cancer line, MCF7, than to an ER negative line, MDA-MB231.

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Section: Resultsmentioning

confidence: 99%

“…These manipulations have been intended to achieve selective transport and accumulation of platinum compounds in the DNA of tumor cells. The notion that estradiol-linked platinum complexes might be selectively enriched in ER+ tumor cells led to the design and evaluation of platinum compounds with affinity for the ER [19,18,15,27]. …”

Section: Discussionmentioning

confidence: 99%

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

Kim

Rye

Essigmann

et al. 2009

Journal of Inorganic Biochemistry

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“…[1,2] Its medical use is restricted by the relatively narrow spectrum of tumors against which it is highly active, and also in certain patients by the development of resistance. [3,4] One possible strategy in the development of more potent drugs is based on functionalization of the platinum complex with groups that have affinity for specific receptors, [5] organs, [6] or biomolecules, [7] thus allowing for targeted delivery. Following this line, Keppler et al have designed aminobisphosphonate derivatives of platinum(II) diamine complexes that possess osteotropic properties, due to the affinity of the phosphonate group for Ca 2 + .…”

Section: Cis-diamminedichloroplatinum(ii) (Cis-[ptcl 2 a C H T U N G mentioning

confidence: 99%

Study of Intramolecular Competition between Carboxylate and Phosphonate for Pt^II with the Aid of a Novel Tridentate Carboxylato‐Thioether‐Phosphonato Ligand

Rizzato¹,

Lecinq²,

Sene³

et al. 2007

Chemistry A European J

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The tridentate dianionic ligand 2-[2'-(hydroxyisopropoxyphosphoryl)phenylsulfanyl]benzoate (L(2-)) reacts with cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) to form an S,O-chelate in which the O-coordinated group is either carboxylate or phosphonate, depending on the degree of protonation of the complex. Carboxylate appears to be the stronger ligand, and the stoichiometric reaction between cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) and L(2-) yields the neutral species [Pt(L)(NH(3))(2)], with L bound by sulfanyl and carboxylate groups, both in solution and in the solid state. Upon protonation of [Pt(L)(NH(3))(2)], the stronger basicity of the carboxylate causes the Pt coordination to switch from carboxylate to phosphonate, and the uncoordinated carboxylate group becomes protonated. In methanolic solution, the first-order kinetics of this rearrangement could be observed by (31)P NMR spectroscopy. Both complexes-the carboxylate-bound neutral complex [Pt(L)(NH(3))(2)].H(2)O (triclinic, P1 (no. 2), a=9.529(6), b=9.766(6), c=12.299(7) angstroms, alpha=106.91(2), beta=101.71(2), gamma=102.05(2) degrees, Z=2) and the perchlorate salt of the phosphonate-bound complex [Pt(LH)(NH(3))(2)]ClO(4).H(2)O (monoclinic, P2(1)/c (no. 14), a=12.095(2), b=14.046(2), c=14.448(2) angstroms, beta=95.55(2) degrees, Z=4)-were characterized by X-ray crystallography.

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“…This compound, however, is toxic and in some cases not selective enough [5]. A new class of Pt(ll) compounds, designed by combining the cytotoxic PtCI2 group (the active moiety in cisplatin) and a diamine ligand with estrogen-receptor affinity has been found [6][7][8][9]. These new complexes retain the estrogen properties of the ligand that binds to the estrogen receptor which is specific for the tumor cell and thus the complexes attack selectively critical areas of the DNA [9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…These new complexes retain the estrogen properties of the ligand that binds to the estrogen receptor which is specific for the tumor cell and thus the complexes attack selectively critical areas of the DNA [9][10][11][12][13][14][15]. Such compounds are more selective and less toxic [6]. The synthetic estrogen, hexestrol (HES-nonsteroidal) ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Platinum (II) Compounds With Antitumor Activity Studied by Molecular Mechanics

1998

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A series of Pt(ll) complexes with antitumor properties: [1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]PtL2 (meso-l-PtL2) and [erythro-l-(2,6-dichloro-4-hydroxyphenyl)-2-(2-halo-4-hydroxyphenyl)ethylenediamine]PtL2, [2L 2C1-, 21-, SO42"; halo F (erythro-8-PtL2), halo = CI (erythro-9-PtL2)] has been modelled by molecular mechanics (MM). The MM calculations were carried out for different isomers and ligand conformations meso-5, meso-X, d,l-5, d,I-X. The compounds with the lowest MM energies have the same geometries as those obtained by X-ray analysis. The calculated MMX energy orders: meso-l-PtL2 < erythro-9-PtL2 < erythro-8-PtL2 for L I-, CI-and SO42-are reverse to the known antitumor activity order-the lowest energy complex (the most stable one)is the one with the highest estrogen activity (meso-l-PtL2). The type of the leaving group (L) does not alter the energy order, which is in agreement with the biological experiments that show a slight dependence of the estrogen properties on the leaving group type.

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Platinum compounds with estrogen receptor affinity

Cited by 15 publications

References 13 publications

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

Study of Intramolecular Competition between Carboxylate and Phosphonate for Pt^II with the Aid of a Novel Tridentate Carboxylato‐Thioether‐Phosphonato Ligand

Platinum (II) Compounds With Antitumor Activity Studied by Molecular Mechanics

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Platinum compounds with estrogen receptor affinity

Cited by 15 publications

References 13 publications

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

A bifunctional platinum(II) antitumor agent that forms DNA adducts with affinity for the estrogen receptor

Study of Intramolecular Competition between Carboxylate and Phosphonate for PtII with the Aid of a Novel Tridentate Carboxylato‐Thioether‐Phosphonato Ligand

Platinum (II) Compounds With Antitumor Activity Studied by Molecular Mechanics

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Study of Intramolecular Competition between Carboxylate and Phosphonate for Pt^II with the Aid of a Novel Tridentate Carboxylato‐Thioether‐Phosphonato Ligand