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cis-Diammine(pyridine)chloroplatinum(II), a Monofunctional platinum(II) Antitumor Agent: Uptake, Structure, Function, and Prospects

cis-Diammine(pyridine)chloroplatinum(II), a Monofunctional platinum(II) Antitumor Agent: Uptake, Structure, Function, and Prospects

Katherine S Lovejoy, Ryan C Todd, Shuzhong Zhang, Michael S McCormick, J Alejandro D'Aquino, Joyce T Reardon, Aziz Sancar, Kathleen M Giacomini, Stephen J Lippard

Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8902-7.

PMID: 18579768

Abstract:

We have identified unique chemical and biological properties of a cationic monofunctional platinum(II) complex, cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH(3))(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(NH(3))(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+). cDPCP-DNA adducts are removed by the nucleotide excision repair apparatus, albeit much less efficiently than bifunctional platinum-DNA 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP106343548	cDPCP		106343-54-8	Price
AP66900683	Oxaliplatin Related Compound B		66900-68-3	Price

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