Effect of the Diamine Nonleaving Group in Platinum−Acridinylthiourea Conjugates on DNA Damage and Cytotoxicity

Guddneppanavar, Rajsekhar; Choudhury, Jayati Roy; Kheradi, Alexander R; Steen, Bartlett D; Saluta, Gilda; Kucera, Gregory L.; Day, Cyn­thia S.; Bierbach, Ulrich

doi:10.1021/jm0614376

Cited by 44 publications

(60 citation statements)

References 28 publications

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“…Azido and hydroxido ligands can dissociate from trans , trans , trans -[Pt(N 3 ) 2 (OH) 2 (Am1)(Am2)] complexes upon irradiation with light, and Am1 and Am2 remain as non-leaving groups 38. The current work reveals the similarities between 1 and 5 , and between 2 and 6 (Table 4).…”

Section: Discussionmentioning

confidence: 54%

Diazido Mixed‐Amine Platinum(IV) Anticancer Complexes Activatable by Visible‐Light Form Novel DNA Adducts

Zhao

Woods

Farrer

et al. 2013

Chemistry A European J

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Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable PtIV prodrugs offer the potential of targeted drug release and new mechanisms of action. We report the synthesis, X-ray crystallographic and spectroscopic properties of photoactivatable diazido complexes trans,trans,trans-[Pt(N3)2(OH)2(MA)(Py)] (1; MA=methylamine, Py=pyridine) and trans,trans,trans-[Pt(N3)2(OH)2(MA)(Tz)] (2; Tz=thiazole), and interpret their photophysical properties by TD-DFT modelling. The orientation of the azido groups is highly dependent on H bonding and crystal packing, as shown by polymorphs 1 p and 1 q. Complexes 1 and 2 are stable in the dark towards hydrolysis and glutathione reduction, but undergo rapid photoreduction with UVA or blue light with minimal amine photodissociation. They are over an order of magnitude more potent towards HaCaT keratinocytes, A2780 ovarian, and OE19 oesophageal carcinoma cells than cisplatin and show particular potency towards cisplatin-resistant human ovarian cancer cells (A2780cis). Analysis of binding to calf-thymus (CT), plasmids, oligonucleotide DNA and individual nucleotides reveals that photoactivated 1 and 2 form both mono- and bifunctional DNA lesions, with preference for G and C, similar to transplatin, but with significantly larger unwinding angles and a higher percentage of interstrand cross-links, with evidence for DNA strand cross-linking further supported by a comet assay. DNA lesions of 1 and 2 on a 50 bp duplex were not recognised by HMGB1 protein, in contrast to cisplatin-type lesions. The photo-induced platination reactions of DNA by 1 and 2 show similarities with the products of the dark reactions of the PtII compounds trans-[PtCl2(MA)(Py)] (5) and trans-[PtCl2(MA)(Tz)] (6). Following photoactivation, complex 2 reacted most rapidly with CT DNA, followed by 1, whereas the dark reactions of 5 and 6 with DNA were comparatively slow. Complexes 1 and 2 can therefore give rapid potent photocytotoxicity and novel DNA lesions in cancer cells, with no activity in the absence of irradiation.

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Section: Discussionmentioning

confidence: 54%

Diazido Mixed‐Amine Platinum(IV) Anticancer Complexes Activatable by Visible‐Light Form Novel DNA Adducts

Zhao

Woods

Farrer

et al. 2013

Chemistry A European J

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“…282–287 Polymerase stop assays and flow cytometric assays showed that the hybrid adducts inhibited RNA polymerase II and DNA synthesis. 285,286,288 Inhibition of DNA synthesis led to S phase cell cycle arrest as opposed to G2/M phase cell cycle arrest, as is customary following cisplatin treatment. 288 Although Pt-ACRAMTU maintained sub-micromolar activity in cell lines with aberrant p53 and k-ras expression, because of their inability to stop tumor growth in corresponding tumor mouse models, preclinical development was halted and other Pt-ACRAMTU analogues have been subsequently investigated.…”

Section: Platinum(ii) Compounds With a Mechanism Of Action Differementioning

confidence: 99%

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

2016

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The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive.

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“…201,202 Although the first generation analogues of these complexes with underivatized thiourea ligands exhibit only poor to moderate in vitro cytotoxicity, 203 the second generation compounds with acridine-functionalized thioureas are typically more cytotoxic than cisplatin. 174,204,205 These Pt-acridinylthiourea, or PT-ACRAMTU, conjugates form hybrid DNA adducts; 206 the Pt center binds preferentially to N 7 of guanine bases and the acridine intercalates between base pairs. Several dichloridoplatinum(II) complexes tethered to acridine through a modified ethylenediamine ligand, first reported in the late 1980s, also exhibit dual intercalation and covalent DNA-binding modes.…”

Section: Synthesis Of Platinum(ii) Complexesmentioning

confidence: 99%

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

2013

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Effect of the Diamine Nonleaving Group in Platinum−Acridinylthiourea Conjugates on DNA Damage and Cytotoxicity

Cited by 44 publications

References 28 publications

Diazido Mixed‐Amine Platinum(IV) Anticancer Complexes Activatable by Visible‐Light Form Novel DNA Adducts

Diazido Mixed‐Amine Platinum(IV) Anticancer Complexes Activatable by Visible‐Light Form Novel DNA Adducts

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

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