title: Photoactivatable prodrugs of highly potent duocarmycin analogues for a selective cancer therapy.
abstract: 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.
authors.affiliation: Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany. ltietze@gwdg.de
authors.forename: Lutz F
authors.initials: LF
authors.lastname: Tietze
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Svenia-C
authors.initials: SC
authors.lastname: Duefert
authors.forename: Kianga
authors.initials: K
authors.lastname: Schmuck
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schuberth
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use*; D000906:Antibodies / Q000737:chemistry / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D015394:Molecular Structure; D009369:Neoplasms / Q000737:chemistry* / Q000188:drug therapy*; D010777:Photochemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D000970:Antineoplastic Agents; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011760:Pyrrolidinones; C058289:duocarmycin A