An androgenic steroid delivery vector that imparts activity to a non-conventional platinum(ii) metallo-drug

Huxley, Martin; Sanchez‐Cano, Carlos; Browning, Michael; Navarro‐Ranninger, Carmen; Quiroga, Adoración G.; Rodger, Alison; Hannon, Michael J.

doi:10.1039/c0dt00838a

Cited by 65 publications

(45 citation statements)

References 51 publications

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“…Targeting the drugs to a specific organ or tumor type is highly desirable in order to maximize the delivery of the anticancer agent into the cell and onto the DNA [6][7][8][9]. This can be achieved by applying drug carrier strategy instead of free drug solution.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

Heng

Sinniah

Teoh

et al. 2015

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, (1)H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV-Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism.

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Section: Introductionmentioning

confidence: 99%

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

Heng

Sinniah

Teoh

et al. 2015

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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“…The cellular accumulation of platinum was determined as previously described (27,28), with some modifications. The detailed procedure is described in the SI Appendix.…”

Section: Methodsmentioning

confidence: 99%

Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile

Park

Wilson

Song

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

289

311

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Monofunctional platinum(II) complexes of general formula cis-[Pt(NH 3 ) 2 (N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH 3 ) 2 (phenanthridine)Cl]NO 3 , which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links. (Fig. 1), are currently among the most effective chemotherapies in clinical use for the treatment of cancers (1). These Pt-based anticancer agents typically form bifunctional intra-and interstrand DNA cross-links through covalent bonds with purine nucleobases. These cross-links inhibit transcription and result in cell death (2, 3). Platinum-based drugs are limited by side effects and poor activity in certain types of cancer resulting from acquired or intrinsic resistance (1-3). These limitations evoke a need for new platinum-based chemotherapeutics with novel mechanisms of action.One approach that we have used to circumvent the shortcomings of classic bifunctional platinum-based drugs has been to revisit cationic, monofunctional platinum complexes previously demonstrated to display significant anticancer activity in animal tumor models (4). In contrast to monofunctional platinum(II) compounds, such as [Pt(dien)Cl] + (dien = diethylenetriamine) (5) and [Pt(NH 3 ) 3 Cl] + (6), which early work proved to be inactive, the compound pyriplatin [cis-diamminepyridinechloroplatinum(II)] (Fig. 1) and several of its analogs have significant antineoplastic activity. Moreover, the profile of cellular response to thes...

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“…These disadvantages have driven the development of improved 50 platinum-based anticancer drugs different from the traditional cisplatin 51 structure and which could probably have different DNA-binding modes 52 as well as exhibit different biological profiles [6][7][8][9][10].…”

mentioning

confidence: 99%

Palladium(II) and platinum(II) bis(thiosemicarbazone) complexes of the 2,6-diacetylpyridine series with high cytotoxic activity in cisplatin resistant A2780cisR tumor cells and reduced toxicity

Matesanz¹,

Leitao²,

Souza³

2013

Journal of Inorganic Biochemistry

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An androgenic steroid delivery vector that imparts activity to a non-conventional platinum(ii) metallo-drug

Cited by 65 publications

References 51 publications

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile

Palladium(II) and platinum(II) bis(thiosemicarbazone) complexes of the 2,6-diacetylpyridine series with high cytotoxic activity in cisplatin resistant A2780cisR tumor cells and reduced toxicity

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