1. http://pubs.acs.org/doi/abs/10.

1021/ic00030a021
Marijo Van Beusichem , Nicholas Farrell

Inorg. Chem., 1992, 31 (4), pp 634639 DOI: 10.1021/ic00030a021 Publication Date: February 1992

2. http://www.pnas.org/content/105/26/8902.short

cis-Diammine(pyridine)chloroplatinum(II), a monofunctional platinum(II) antitumor agent: Uptake, structure, function, and prospects
pnas> vol. 105 no. 26 > Katherine S. Lovejoy, 89028907 Abstract
We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH3)2(py)Cl]+ or cDPCP, a coordination compound previously identified to have significant anticancer activity in a mouse tumor model. This compound is an excellent substrate for organic cation transporters 1 and 2, also designated SLC22A1 and SLC22A2, respectively. These transporters are abundantly expressed in human colorectal cancers, where they mediate uptake of oxaliplatin, cis-[Pt(DACH)(oxalate)] (DACH = trans-R,R-1,2-diaminocyclohexane), an FDA-approved first-line therapy for colorectal cancer. Unlike oxaliplatin, however, cDPCP binds DNA monofunctionally, as revealed by an x-ray crystal structure of cis-{Pt(NH3)2(py)}2+ bound to the N7 atom of a single guanosine residue in a DNA dodecamer duplex. Although the quaternary structure resembles that of B-form DNA, there is a base-pair step to the 5 side of the Pt adduct with abnormally large shift and slide values, features characteristic of cisplatin intrastrand cross-links. cDPCP effectively blocks transcription from DNA templates carrying adducts of the complex, unlike DNA lesions of other monofunctional platinum(II) compounds like {Pt(dien)}2+. cDPCPDNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinumDNA intrastrand cross-links. These exceptional characteristics indicate that cDPCP and related complexes merit consideration as therapeutic options for treating colorectal and other cancers bearing appropriate cation transporters.

3. http://pubs.acs.org/doi/abs/10.1021/jm00350a013

Synthesis and antitumor activity of new platinum complexes

David B. Brown , A. R. Khokhar , M. P. Hacker , L. Lokys , J. H. Burchenal , R. A. Newman , J. J. McCormack , David Frost

J. Med. Chem., 1982, 25 (8), pp 952956 DOI: 10.1021/jm00350a013 Publication Date: August 1982

4. http://pubs.acs.org/doi/abs/10.1021/jm00170a021

Cytotoxicity and antitumor activity of bis(platinum) complexes. A novel class of platinum complexes active in cell lines resistant to both cisplatin and 1,2-diaminocyclohexane complexes

Nicholas Farrell , Yun Qu , Miles P. Hacker

J. Med. Chem., 1990, 33 (8), pp 21792184 DOI: 10.1021/jm00170a021 Publication Date: August 1990

5. http://www.sciencedirect.com/science/article/pii/1040842893900423

Critical Reviews in Oncology/Hematology

Volume 15, Issue 3, December 1993, Pages 191219

Abstract
Over the past two decades, platinum-based drugs (cis-platin and, latterly, the less toxic analogue carboplatin) have conferred significant therapeutic benefit to a large number of cancer suffers. However, there remains scope for substantial improvement in the clinical utility of metal coordination complexes through the discovery of additional platinum-based complexes (or possibly alternative metals). Future drug discovery strategies should focus on tumor resistance and its circumvention. To date, only one series of compounds, those containing a 1,2-diaminocyclohexane carrier ligand (e.g., oxaliplatin, tetraplatin), has entered clinical trial based on their circumvention of acquired cisplatin resistance in some (mainly murine) preclinical tumor models. At present these agents are in early clinical trial and thus their true clinical utility in cisplatin/carboplatin refractory disease is not yet determinable (and may not be due to dose-limiting neurotoxicity). Over the past few years, our understanding of mechanisms of resistance to cisplatin and its interaction with DNA has vastly increased. This new information will undoubtedly guide the development of new strategies aimed at the circumvention of intrinsic and acquired tumor resistance to cisplatin. Approaches to circumvent resistance will probably involve not only the rational development of a new generation of platinum-based drugs (e.g., compounds designed to overcome reduced cisplatin accumulation or enhanced removal of cisplatin-induced DNA adducts) but also non-platinum drugs which are capable of modulating resistance (e.g., modulators of signal transduction pathways, ras and myc oncogene expression and glutathione biosynthesis). One may look forward with a great deal of optimism that these promising new approaches will result in clinical benefit by the end of the century. Nevertheless, cis-platin and carboplatin remain the standard anticancer drugs to which novel platinum-based complexes must be compared.

6. http://www.ncbi.nlm.nih.gov/pubmed/12779240 Biometals. 2003 Dec;16(4):553-60.

Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex, a selective inhibitor of telomerase enzyme.

Abstract
Since it has been widely demonstrated that platinum-based drugs, like cisplatin, carboplatin and oxaliplatin, bind preferentially to guanine in N7 position and that telomerase assemblage includes a RNA portion rich in guanine, we previously designed and synthesized a series of new complexes with a cytotoxic [Pt(II)Cl2] moiety, with the aim of selecting carrier ligands able to inhibit telomerase enzyme. Among these compounds, [cis-dichloropyridine-5-isoquinolinesulfonic acid Pt(II)], named Ptquin8, showed the most significant inhibition of telomerase in a cell-free biochemical assay. In this paper, we report the biological effects of Ptquin8 on in vitro tumor model (MCF-7). This complex is able to reduce telomerase activity from 12 to 46%, in a concentration range between 10(-9) and 10(-5) M after 24 h continuous treatment. Moreover, Ptquin8 shows significant cytotoxicity after 10 days of continuous treatment only at concentrations higher than 10(-5) M. The determination of residual telomere length confirmed the inhibition of telomerase action. This induced a progressive reduction of the cell proliferative capacity, and the appearance of an elevated number of apoptotic cells after 18 days. RT-PCR analysis of telomerase RNA components excluded any interaction of the compound at genomic level. The biochemical effects of Ptquin8 were also evaluated on non-neoplastic NIH3T3 cells, that are able to down-regulate telomerase activity as a consequence of the confluence contact inhibition. In this cell model, the reactivation of telomerase due to re-seeding at lower density was significantly inhibited by Ptquin8 in a dose-dependent manner. These results highlight a possible role of Ptquin8 as a selective anti-telomerase tool for cancer treatment.