Replacement of a thiourea-S with an amidine-NH donor group in a platinum-acridine antitumor compound reduces the metal's reactivity with cysteine sulfur

Zhidong Ma; Lu Rao; Ulrich Bierbach

doi:10.1021/jm900451y

Replacement of a thiourea-S with an amidine-NH donor group in a platinum-acridine antitumor compound reduces the metal's reactivity with cysteine sulfur

Zhidong Ma, Lu Rao, Ulrich Bierbach

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

The reactivity of two DNA-targeted platinum-acridine conjugates with cysteine sulfur was studied. The conjugate containing an amidine-NH donor group cis to the chloride leaving group showed considerably reduced reactivity with N-acetylcysteine compared to the prototypical derivative containing a thiourea-S linkage. The opposite scenario has been observed previously in reactions with nucleobase nitrogen. Possible consequences of the unique target-selective tuning of the substitution chemistry for the pharmacodynamic properties and biological activity of these agents are discussed.

Original language	English (US)
Pages (from-to)	3424-3427
Number of pages	4
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	10
DOIs	https://doi.org/10.1021/jm900451y
State	Published - May 28 2009
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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abstract = "The reactivity of two DNA-targeted platinum-acridine conjugates with cysteine sulfur was studied. The conjugate containing an amidine-NH donor group cis to the chloride leaving group showed considerably reduced reactivity with N-acetylcysteine compared to the prototypical derivative containing a thiourea-S linkage. The opposite scenario has been observed previously in reactions with nucleobase nitrogen. Possible consequences of the unique target-selective tuning of the substitution chemistry for the pharmacodynamic properties and biological activity of these agents are discussed.",

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AU - Rao, Lu

AU - Bierbach, Ulrich

PY - 2009/5/28

Y1 - 2009/5/28

N2 - The reactivity of two DNA-targeted platinum-acridine conjugates with cysteine sulfur was studied. The conjugate containing an amidine-NH donor group cis to the chloride leaving group showed considerably reduced reactivity with N-acetylcysteine compared to the prototypical derivative containing a thiourea-S linkage. The opposite scenario has been observed previously in reactions with nucleobase nitrogen. Possible consequences of the unique target-selective tuning of the substitution chemistry for the pharmacodynamic properties and biological activity of these agents are discussed.

AB - The reactivity of two DNA-targeted platinum-acridine conjugates with cysteine sulfur was studied. The conjugate containing an amidine-NH donor group cis to the chloride leaving group showed considerably reduced reactivity with N-acetylcysteine compared to the prototypical derivative containing a thiourea-S linkage. The opposite scenario has been observed previously in reactions with nucleobase nitrogen. Possible consequences of the unique target-selective tuning of the substitution chemistry for the pharmacodynamic properties and biological activity of these agents are discussed.

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Replacement of a thiourea-S with an amidine-NH donor group in a platinum-acridine antitumor compound reduces the metal's reactivity with cysteine sulfur

Abstract

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