A main problem of common cancer chemotherapy is the occurrence of severe side effects caused by insufficient selectivity of the applied drugs. A possible concept to overcome this limitation is light-driven prodrug monotherapy. The synthesis as well as photochemical and biological evaluation of new photoactivatable prodrugs is described. Best results were obtained with prodrug (S,S)-7a. The photochemical labile protecting groups in (S,S)-7a can easily be removed by irradiation with UV-A light in 30 min with a power of only 2 J cm(-2). The determination of the in vitro cytotoxicity by using an HTCFA-test reveals a QIC(50) value of 8200 and the prodrug is more than two million times less cytotoxic than the corresponding seco-drug (-)-(S,S)-5 with an IC(50) value of about 110 fM. The big therapeutic window makes (S,S)-7a very suitable for its use in selective cancer therapy.
Konvergent und elegant: Linoxepin (siehe Bild), ein neues Lignan mit einer ungewöhnlichen Oxepin‐Einheit, wurde in nur 10 Stufen synthetisiert. Die Totalsynthese beinhaltet eine Palladium‐katalysierte Sonogashira‐Reaktion und eine Domino‐Carbopalladierung/Heck‐Reaktion eines Allysilans und verzichtet vollständig auf die Verwendung von Schutzgruppen.
An enantioselective total synthesis of the natural (+)-linoxepin (1) was accomplished in eleven steps from bromovanin (24). Key steps are a domino carbopalladation/ Mizoroki-Heck reaction with the formation of a pentacyclic system, an asymmetric hydroboration as well as an oxidative lactonization.
Experimental procedures ______________________________________________________ 3 NMR spectra of rac-3 ________________________________________________________ 8 Biological Test 10 General methods Experimental methods: All air-sensitive reactions were performed under an argon atmosphere in flame-dried flasks and the reactants were introduced by syringe or transfer cannula. All solvents were dried by standard methods and the reagents obtained from commercial sources were used without further purification. Thin-layer chromatography was performed on precoated silica gel plates (TLC silica gel 60 F254, Merck). Silica gel 60 (0.032-0.064 mm, Merck) was used for column chromatography. Flash column chromatography was performed using the Isolera™ One flash purification system by Biotage with pre-packed silica cartridges (SNAP 10, 25, 50, 100 g). NMR spectroscopy: NMR spectra were recorded with a Varian Mercury-300, Unity-300, Inova-500 and Inova-600 spectrometer and a Bruker AMX-300 spectrometer in CDCl 3 ; chemical shifts are given in ppm relative to tetramethylsilane (TMS), coupling constants J in Hertz. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CHCl 3 : δH = 7.24 ppm, δC = 77.36 ppm). The multiplicities of first order were assigned as: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), etc. Signals of higher orders were assigned as m (multiplet). IR spectroscopy: IR spectra were recorded with a JASCO FT/IR-4100 spectrometer. All substances were applied neat on an ATR unit. UV spectroscopy: UV spectra were recorded with a JASCO V-630 spectrometer.
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