Studies on the antitumor activity of group VIII transition metal complexes. Part I. Platinum (II) complexes

Cleare, M. J.; Hoeschele, James D.

doi:10.1016/s0006-3061(00)80249-5

Cited by 560 publications

(322 citation statements)

References 17 publications

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“…It should be emphasized that, apart from covalent bonding to the DNA double helix, both electrostatic interactions and formation of hydrogen bonds 37 play a very important role in the mechanism of interaction of these kinds of cationic polyamine metal complexes with DNA, which determines their antiproliferative and cytotoxic action. According to Cleare and Hoeschele's structure-activity relationships (SARs) for platinum(II) complexes, 38,39 for such compounds to display significant antitumor activity they should have a cis geometry with the general formula cis-[PtX 2 (Am) 2 ], Am being an inert amine containing at least one NH moiety and X being an anionic leaving group with a weaker trans effect than the amine. All the complexes reported in the present work comply with these conditions except for the number of X groups (which is, in some of the chelates studied, only 1).…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

et al. 2004

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Several polynuclear Pt(II) chelates with biogenic polyamines were synthesized and screened for their potential antiproliferative and cytotoxic activity in different human cancer cell lines. To gather information regarding the structure-activity relationships underlying their biological activity, the complexes studied were designed to differ in geometrical parameters such as the nature of the ligand and the number and chemical environment of the metal centers. Distinct effects were found for different cell lines and different structural characteristics of the complexes; chelates II, III, and IV displayed specificity toward the HeLa and HSC-3 epithelial-type cells, while V, VI, and VII were clearly more effective against the THP-1, MOLT-3, and CCRF-CEM leukemia cell lines. The toxicity of these Pt(II) complexes on noncancer cells was, in all cases, found to be reversed upon drug removal.

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Section: Resultsmentioning

confidence: 99%

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

et al. 2004

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“…These rules are clearly violated by cationic, monofunctional platinum compounds such as pyriplatin (4,5). Other monofunctional platinum complexes, including ½PtðdienÞCl þ , ½PtðNH 3 Þ 3 Cl þ , and trans-½PtðNH 3 Þ 2 ðpyÞCl þ , are inactive and do not arrest pol II transcription, whereas the cis-fPtðNH 3 Þ 2 ðpyÞg 2þ unit bound to guanosine blocks pol II transcription and has significant anticancer properties in mice when administered as pyriplatin (4,5,8,(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct

Wang

Zhu

Huang

et al. 2010

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

122

118

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DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cisDiammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.anticancer | chemotherapy | DNA damage | pyriplatin | transcription T he DNA template for transcription is not only the site of inborn errors of metabolism and of continuous attack by harmful environmental agents, but it also represents a major target for cancer therapy. Platinum-based anticancer drugs such as cisplatin, cis-diamminedichloroplatinum(II), are widely used and among the most effective antineoplastic treatments (1, 2). Platinum-based drugs typically form bifunctional intra-or interstrand DNA cross-links by covalent bonding to the N 7 positions of two guanosine residues, triggering a variety of cellular processes, including transcription inhibition with attendant apoptosis (1, 2). However, resistance and side effects can require withdrawal of these drugs before they can effect a cure in certain types of cancer (3).In the effort to find new compounds that circumvent resistance to conventional bifunctional platinum-based drugs, a class of monofunctional platinum compounds were synthesized and screened for anticancer activity (4-6). In contrast to other inactive monofunctional platinum(II) compounds such as ½PtðdienÞCl þ and ½PtðNH 3 Þ 3 Cl þ , cis-diammine(pyridine)chloroplatinum(II) [cDPCP or "pyriplatin" (Fig. 1)] and related complexes display significant anticancer properties and a different spectrum of activity compared to conventional platinum-based drugs. These features render them attractive candidates for treating cisplatin-refractory patients if the potency could be raised to or beyond the level of that of cisplatin (4, 5, 7). Pyriplatin exhibits unique chemical and biological properties, forming monofunctional DNA adducts ( Fig. 1 and Fig. S1) that can inhibit transcription an...

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“…Consequently, pyriplatin is expected to form only one covalent bond with DNA, precluding the bending induced by bifunctional platinum complexes such as cisplatin. Monofunctional platinum complexes had long been considered inactive [30]. The possibility that a significantly different type of DNA adduct would be formed by pyriplatin, however, suggested that it might have a novel spectrum of activity.…”

Section: Monofunctional Platinum Anti-cancer Agents (A) Pyriplatin: Rmentioning

confidence: 99%

“…Although other researchers have investigated the anti-cancer potential of complexes of these metals, we long refrained from doing so. One reason was that, based on studies of cisplatin, DNA base cross-linking as encountered with bifunctional Pt(II) complexes appeared to be essential for activity [25,30]. The bending of DNA induced by cross-linking blocks the areas above and below the coordination plane and precludes DNA cross-linking by octahedral complexes.…”

Section: Other Third Row Transition Metal Complexesmentioning

confidence: 99%

Third row transition metals for the treatment of cancer

Johnstone

Suntharalingam

Lippard

2015

Phil. Trans. R. Soc. A.

103

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Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving platinum. But there is a great need for improvement. Major features of the cisplatin mechanism of action involve cancer cell entry, formation mainly of intrastrand cross-links that bend and unwind nuclear DNA, transcription inhibition and induction of cell-death programmes while evading repair. Recently, we discovered that platinum cross-link formation is not essential for activity. Monofunctional Pt compounds such as phenanthriplatin, which make only a single bond to DNA nucleobases, can be far more active and effective against a range of tumour types. Without a cross-link-induced bend, monofunctional complexes can be accommodated in the major groove of DNA. Their biological mechanism of action is similar to that of cisplatin. These discoveries opened the door to a large family of heavy metal-based drug candidates, including those of Os and Re, as will be described.

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Studies on the antitumor activity of group VIII transition metal complexes. Part I. Platinum (II) complexes

Cited by 560 publications

References 17 publications

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

X-ray structure and mechanism of RNA polymerase II stalled at an antineoplastic monofunctional platinum-DNA adduct

Third row transition metals for the treatment of cancer

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