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

• Published in: Tetrahedron Vol. 62; no. 18; pp. 4519 - 4527
• Main Authors: Bjelosevic, Haris, Spégel, Christer, Snygg, Åse Sykfont, Gorton, Lo, Elmroth, Sofi K.C., Persson, Tina
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2006; Elsevier
• Subjects: Analytical Chemistry; Analytisk kemi; Anticancer; Biologi; Biological Sciences; Chemical Sciences; Chemistry; Chemistry, Organic; Cisplatin; Kemi; Kinetics; Linker; Natural Sciences; Naturvetenskap; Nucleoside analogue; Organic Chemistry; Organisk kemi; Physical Sciences; Pt(dppf); Science & Technology; Nucleoside analogue; Pt(dppf); Kinetics; Anticancer; Linker; Cisplatin; linker; ANATION; FERROCENE; CRYSTAL-STRUCTURE; REDOX BEHAVIOR; CIS-DIAMMINEDICHLOROPLATINUM(II); anticancer; HYDROLYSIS PRODUCTS; nucleoside analogue; DNA; HETEROPOLYMETALLIC COMPLEXES; cisplatin; kinetics
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2006.02.057

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]- N′-[prop-2-yn-3-yl]succinamide} uridinedichloroplatinum(II) showed that this compound reacted faster with the phosphorothioate containing oligonucleotides d(T 6p(S)T 6), with an observed first-order rate constant k obs=(1.4±0.1)×10 −4 s −1, compared with the G-N7 target in d(T 7GGT 7), for which the observed first-order rate constant is k obs=(7.2±0.5)×10 −4 s −1. We here report a synthetic pathway for the construction of several unique dppf-based platinum compounds with chemical modifications introduced in the ferrocenyl moiety. A nucleoside-based cis-platinum compound showed both improved water solubility and promising kinetics with DNA models with a reactivity similar to cisplatin.