Synthesis of novel isoindole-containing phakellistatin 2 analogs and the conformation features affecting their antitumor activities

Abstract

Two novel phakellistatin 2 analogs were synthesized and the conformational features affecting their antitumor activities were studied.

Photoinduced Synthesis of Methylated Marine Cyclopeptide Galaxamide Analogs with Isoindolinone as Anticancer Agents

“…We found that after removing the two N-methyl groups of galaxamide and introducing a rigid isoindolinone fragment into the skeleton by intramolecular photoinduced single electron transfer cyclization reaction (IPETC), the obtained cyclic peptide analogs still maintained significant antitumor activity against HepG-2 cells, and the peptide containing the D-leucine fraction showed stronger bioactivity than that with L-leucine residues, suggesting that the isoindolinone fragment together with the D-residues may play an important role in treatment. A similar phenomenon has been observed in our research on analogs of the natural cyclic peptide phakellistatin 2 [13]. Inspired by the previous findings, we tried to further modify galaxamide to explore novel antitumor cyclopeptides here.…”

“…After coupling, the C 3 carbonyl peak of phthalimido at δ 180 ppm disappeared in the 13 C NMR spectrum, followed by a new sp 3 hybridized C 3 peak at δ 85 ± 5 ppm, which is the characteristic NMR peak position of C 3 after the IPETC reaction. The chemical shifts of C-3 in 13 C NMR of all peptides 1-8 were around δ 85 ± 5 ppm in our paper, which suggested the successful preparation of the cyclopeptides. The resulting mixture was purified by column chromatography to give the galaxamide analogs 3-hydroxy-isoindolinone-cyclopeptides (1-8).…”

“…Galaxamide is defined as cyclo-(L-Leu-L-N-Me-Leu-L-Leu-L-Leu-L-N-Me-Leu Leu). The structural modification of galaxamide is initiated by splitting the amide bond the peptide sequence, followed by the introduction of phthalimide and photoinduced clization of linear peptides, as reported in our previous research [12,13]. In the pres study, the photoinduced substrate linear peptide is prepared by a liquid-phase metho as shown in Scheme 1.…”

“…N-Me-leucine used here was prepared by adopting the t-BOC-l cine and iodomethane as raw materials in the presence of TEA. Then, the nitrogen-term nal amino groups were masked with phthaloylglycyl chloride to obtain N-phthalimid During the photoinduced process, the chain-like molecule (linear peptide) was excited and formed intramolecular zwitterionic biradicals after the departure of MeOSiMe 3 , and then the donator-and acceptor-free radicals at each end connected with each other to produce the cyclic compound [12,13]. After coupling, the C 3 carbonyl peak of phthalimido at δ 180 ppm disappeared in the 13 C NMR spectrum, followed by a new sp 3 hybridized C 3 peak at δ 85 ± 5 ppm, which is the characteristic NMR peak position of C 3 after the IPETC reaction.…”

“…Mass spectra were recorded on a JEOL JMS-700 spectrometer. AMX400 NMR (Bruker, Bremen, Germany) was used to record 1 H and 13 C NMR spectra. A 450 W medium-pressure mercury lamp (HANOVIA Specialty Lighting LLC, Fairfield, NJ, USA) filtered by Pyrex glass (λ > 290 nm) was used for photoinduced excitation in a JRS-7825-34 photoreactor (Julabo, Seelbach, Germany).…”