Gemcitabine (dFdC) is an effective chemotherapeutic nucleoside analog in the treatment of cancers and solid tumors. Synthesis of lipophilic gemcitabine analogues via click reactions with silicon-fluoride-acceptor building blocks suitable for 18F labeling has been accomplished. The coupling of gemcitabine with carboxylic acids using peptide coupling conditions afforded 4-N-alkanoyl analogues with a terminal alkyne or azido moiety. Click reaction of these compounds with dialkylsilyl building blocks afforded 4-N-alkanoylsilanegemcitabine analogue (e.g., 1). Reaction of 4-N-tosylgemcitabine with functionalized azidoalkyl amines provided 4-N-alkylgemcitabine with a terminal azido group. Coupling of the latter with 4-(di-iso-propylsilyl)-O-propargylbenzylalcohol provided 4-N-alkylsilanegemcitabine (e.g., 3). Treatment of these trisubstituted silane derivatives with KF/18-crown-6 resulted in efficient fluorination to give 2 or 4 under conditions that are compatible with protocols for positron emission tomography (PET) 18F labeling. The cytotoxicity and antiproliferative activities against several cancer cell lines will also be discussed.

Clickable 4-N-alkanoyl and 4-N-alkylgemcitabine analogues with silicon-fluoride acceptors

253rd National Meeting (2017)

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