Synthesis and biological activity of novel bicyclic octadepsipeptides

Abstract

Echinomycin is well known as a natural product and shows strong antibiotic activity. Its outer quinoxaline rings have an important role of bis-intercalating around the DNA, and the $C_2-symmetric$ peptide also has an interesting biological activity. Connection with the synthesis of echinomycin analogue, new quinoxaline antibiotics which have a cyclic octadepsipeptide but different inner bridge $(-CH_2-S-CH_2-S-CH_2-)$ have been synthesized. $C_2-symmetric$ cyclic octadepsipeptide have been prepared from tetradepsipeptide, Cbz-D-Ser[Ala-MeCys(Bam)-Me-Val]-OPa, as a key intermediate. New quinoxalyl compounds (66 and 69) were prepared from 55 through 3 steps. Their oxidized forms (67, 68, 70 and 71) were also prepared by oxidation with m-CPBA or dimethyldioxirane. 72-75 were modified by changing outer ring for increasing solubility. It is noteworthy that 66 had comparable cytotoxicity against solid cancer cells compared to echinomycin via novel signaling pathway but showed lower toxicity. Moreover, 66 is active VRE (vancomycin-resistant enterococci) within MIC range 0.5 -8.0 μg/ml (cf. echinomycin: 0.25 μg/ml). The disadvantage of echinomycin may be overcome by 66, analogues of echinomycin. The chiral ligands containing proline moiety was synthesized from (S)-proline (S)-indoline carboxylic acids. These chiral ligands have been examined in the catalytic asymmetric cyanation of aldehydes to give the corresponding cyanohydrin. The asymmetric cyanosilylation of aldehydes has been achieved by the catalysis of 10 mol % of chiral ligands and $Ti(OiPr)_4$ complex giving the corresponding O-TMS ethers of cyanohydrins in good yields with high enantioselectivities (R, up to 95% ee) under the mild reaction conditions. The catalyst complex of 101 and $110/Ti(OiPr)_4$ would be Lewis acids/base catalysis and the $C_2-symmetric$ ligands showed the best results and the opposite configuration (R).