Stereoselective synthesis of structurally simplified cephalostatin analogues by multiple Heck reactions and their biological evaluation.
The stereoselective synthesis of structurally simplified heptacyclic cephalostatin analogues 2, 3, 18-21, 31, 32 and 33 by multiple Heck reactions is described. The key step of the synthesis is a selective Heck reaction of hydrindene 7 with 12 and 25, respectively at the vinyl bromide moiety followed by the introduction of a second molecule of 7 and a twofold intramolecular Heck reaction. The obtained bissteroidal heptacyclic compounds 2 and 3, in which the central octahydrophenazine moiety of 1 is replaced by a benzene ring, contain an unusual cis-annulation of the two newly generated rings. The cytotoxicity of some of the derivatives was determined on human lung cancer cell line A 549 in HTFCA tests (Human tumor colony forming ability). They show a rather high activity with an ED(50) in the micro molar range.
Tietze
Lutz F
LF
Institut für Organische Chemie Georg-August-Universität Göttingen Tammannstrasse 2, 37077 Göttingen, Germany. ltietze@gwdg.de
Krahnert
Wolf-Rüdiger
WR
D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010619:Phenazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D010619:Phenazines; D013141:Spiro Compounds