Abstract
A new chiral organometallic nucleoside analogue containing ruthenocene is reported, in which alkylthymine and alkylhydroxyl groups are attached in adjacent positions on one cyclopentadienyl ring. The synthetic procedures for this metallocene derivative and two control compounds are described, along with their characterisation by cyclic voltammetry and X-ray crystallography. Their biological activities in a human pancreatic cancer cell line (MIA-Pa-Ca-2) were significantly lower than those of three previously reported analogous ferrocene compounds, indicating that the choice of metallocene metal atom (Fe or Ru) plays a pivotal role in determining the anticancer properties of these nucleoside analogues, which in turn suggests a different mode of action from that of a conventional nucleoside analogue.
Highlights
A topical area within the field of metal-based anticancer drug research involves examining the effect of incorporating organometallic moieties into known organic drugs and related biological molecules.[1,2] Ferrocene is a popular choice in this respect as a so-called bioisosteric group[2] because of its stability and well-understood reactivity and electrochemistry
We considered that the synthesis of 1-(S,Rp)-Ru and the two control compounds 2-(S) and 3 would allow a direct comparison with the three analogous ferrocene compounds previously reported[9] and enable similar synthetic routes to be followed
Its X-ray structure was determined for the first time from crystals grown from a solution of the racemate in DCM layered with hexane.‡ The step was to introduce planar chirality through the diastereoselective synthesis of 6-(R,Sp) via treatment with n-BuLi in diethylether and quenching with iodine in THF
Summary
A topical area within the field of metal-based anticancer drug research involves examining the effect of incorporating organometallic moieties into known organic drugs and related biological molecules.[1,2] Ferrocene is a popular choice in this respect as a so-called bioisosteric group[2] because of its stability and well-understood reactivity and electrochemistry. The three ruthenocene compounds were tested for cytotoxic activity in the pancreatic ductal adenocarcinoma cell line MIA-Pa-Ca-2 and compared with the ferrocene counterpart 1(S,Rp)-Fe as well as with cisplatin. The previously published ferrocene analogues of 2-(S) and 3, which display more positive Epa values, are less toxic than 1-(S,Rp)-Fe.[9] Overall the trend in the biological data supports the hypothesis that there is a significant relationship between the redox properties of the metallocene units in this series and cancer cell line toxicity.
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