Synthesis and structural characterisation of novel platinum-based drug candidates with extended functionality by incorporation of bis(diphenylphosphino)ferrocene units as metal chelators

Haris Bjelosevic, Christer Spegel, Åse Sykfont Snygg, Lo Gorton, Sofi Elmroth, Tina Persson

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Abstract

Among the metal-based anticancer drugs, cisplatin (cis-diaminedichloroplatinum(II)) is the most widely used species in therapy. Despite its clinical success, cisplatin still suffers in generating resistance, as well as being highly toxic due to poor selectivity between healthy and sick cells. By molecular design it ought to be possible to generate new cis-platinum compounds with increased selectivity and improved cellular behaviour. In this paper, we report a synthetic pathway for construction of derivatives of 1,1'-bis(diphenylphosphino)-ferrocene, together with their corresponding cis-platinum compounds with the aim testing them for their interaction capacity with respect to various DNA models. We also report a synthetic route for a nucleoside-based cis-platinum compound containing a bidentate ferrocenylphosphine derivative connected through a succinamic-based linker to the 5-position of the heterocyclic moiety of uridine. Our preliminary kinetic investigation of 5-{N-[1-[1',2-bis(diphenylphosphino)ferrocenyl]ethyl]1-N'-[prop-2-yn-3-y l]succinamide} uridinedichloroplatinum(II) showed that this compound reacted faster with the phosphorothioate containing oligonucleotides d(T(6)p(S)T-6), with an observed first-order rate constant k(obs) = (1.4 +/- 0.1) X 10(-4) s(-1), compared with the G-N7 target in d(T(7)GGT(7)), for which the observed first-order rate constant is k(obs) = (7.2 +/- 0.5) X 10(-4) s(-1). (c) 2006 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)4519-4527
JournalTetrahedron
Volume62
Issue number18
DOIs
Publication statusPublished - 2006

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240), Analytical Chemistry (S/LTH) (011001004), Biochemistry and Structural Biology (S) (000006142)

Subject classification (UKÄ)

  • Analytical Chemistry
  • Biological Sciences
  • Organic Chemistry

Keywords

  • cisplatin
  • anticancer
  • kinetics
  • linker
  • nucleoside analogue
  • Pt(dppf)

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