Total Synthesis of Quinaldopeptin and Its Analogues

Abstract

The first total synthesis of quinaldopeptin (1) was accomplished. Our approach to the synthesis of 1 includes the solid-phase peptide synthesis of the linear decapeptide 4 followed by macrocyclization and introduction of the quinoline chromophores 2 at a late stage of the synthesis. As for the preparation of 4, a fragment coupling approach was applied considering the C2 symmetrical structure of 1. Chromophore analogues 22 and 23 and desmethyl analogue 27 were also prepared in a manner similar to the synthesis of 1. Synthetic 1 exhibits a strong cytotoxicity with the IC50 value of 3.2 nM. On the other hand, the activity of 23 and 27 was largely reduced.

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

“…Ichikawa and co-workers have reported the synthesis of Quinaldopeptinrelated macrocycles by the macrocyclization of the open-chain peptide containing the less sterically hindered Gly residue as the N-terminus and L-Pip as the C-terminus, using diphenylphosphoryl azide (DPPA) and NaHCO 3 in DMF (5 mM) for 6 days, although this procedure provided the desired cyclic peptide in low yields (18%) along with its epimer (27%). 340 As could be expected, the macrocyclization is facilitated when the transition state geometry has a nonstrained geometry leading to the formation of the macrocycle. 341 Therefore, a computational analysis can allow planning the synthetic route that has a less strained transition state to obtain the desired macrocycle with the optimum yields.…”

Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

“…Diverse strategies for bisintercalators chemical synthesis have been described, as generation of triostin (and its N -demethylated derivative), luzopeptins, quinoxapeptins, sandramycin, quinaldopeptin, BE-22179, TANDEM, thiocoraline and echinomycin derivatives [33,89,120,121,122,123,124,125]. In many cases, these synthetic analogues have shed light into elucidation of the correct structure of the natural compounds.…”

Application of multicomponent reactions in the total synthesis of natural peptides

“…In 1985, Williard and Laszlo performed the total synthesis of optically pure diastereomers 49 and 50 through the Ugi reaction (Scheme 8). 47 Two novel polychlorinated metabolites, demethyldysidenin (49) and demethylisodysidenin (50), were extracted from the marine sponge Dysidea herbacea. 48 The one pot condensation reaction of aldehyde 46 with methylamine 37, the isonitrile 47 and acid 48 gave the desired (+)-13-demethyldysidenin (49) in 17% yield and (-)-13-demethyldysidenin (50) in 13% yield.…”