Staurosporine and ent-Staurosporine:  The First Total Syntheses, Prospects for a Regioselective Approach, and Activity Profiles¹

Abstract

The total syntheses of staurosporine and ent-staurosporine have been achieved. Both glycosidic bonds were built from glycal precursors. The first was constructed by intermolecular coupling of an indole anion with a 1,2-anhydrosugar derived from an endo-glycal by direct epoxidation. The second bond was assembled from an exo-glycal by intramolecular iodoglycosylation.

From Imide to Lactam Metallo-pyridocarbazoles: Distinct Scaffolds for the Design of Selective Protein Kinase Inhibitors

“…First, the TBS group of 15 was replaced by an ethyl group through treatment with 0.1% ethanol in the presence of 10% TFA to afford heterocycle 17 in near quantitative yield. This ether derivative could then smoothly be reduced to lactam 5 in 77% yield using phenylselenol and a slight excess of TFA in refluxing methylene chloride 22,23. It is noteworthy, that initial attempts to directly convert TBS-protected ligand 15 to lactam 5 failed and we attributed this to the size of the TBS ether, precluding the necessary nucleophilic attack of phenylselenol.…”

Organic Synthesis and Biological Signal Transduction

“…[301,302] It proved to be a suitable glycosyl donor for linkage with the aglycon precursor 229, which was obtained from N-BOM-masked dibromomaleinimide in a three-step sequence. The heterocycle was N-deprotonated and subsequently coupled with the epoxide 228 formed in situ.…”

“…Investigation of staurosporin and isomeric compounds in two cell lines, on three human PKC isoenzymes, and on topoisomerase I showed that the spatial conformation of the lactam C5 carbonyl group and the pyranosyl C4' methylamino functionality are more important for biological activity than the conformation of the pyranosyl C3' methoxy functionality and the pyranosyl C2' methyl group. [302] Owing to the highly conserved structure of the catalytic domain of different protein kinases, staurosporin (221) and K-252a (222) are only unselective inhibitors, however, [305] so further analogues were synthesized to try to find more selective enzyme inhibitors. Examples are the analogues 223 ± 225 (Scheme 66).…”

Organische Synthese und biologische Signaltransduktion

“…Das dafür eingesetzte Monosaccharid-Epoxid 228 wurde ausgehend von Tri-O-acetyl-l-glucal 227 aufgebaut (Schema 67). [301,302] …”