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

Abstract

The methylation of amino acid residues has played an important role in the biological function of bioactive peptides. In this paper, various methyl-modified and stereostructural-modified marine cyclopeptide galaxamide analogs with isoindolinone were synthesized by a photoinduced single electron transfer cyclization reaction. It was found that the single-methyl substitution was beneficial for the bioactivity of cyclic analogs with isoindolinone fragments, and the influence of methylation on bioactivity is uncertain and is sometimes case-specific. The compound with a single methyl group at Gly5 (compound 8) showed the strongest antiproliferative activity against HepG-2 cells. The tumor cell apoptosis, cell cycle, mitochondrial membrane potential, intracellular Ca2+ concentration and lactate dehydrogenase activity have been studied extensively to evaluate the antitumor potential of compound 8. Western blotting tests showed that compound 8 could decrease the MDM2 level and increase p53 levels efficiently. Careful molecular docking suggested that cyclic peptide 8 could bind firmly with MDM2 oncoprotein, indicating that MDM2 may be a potential drug target of the prepared peptides.

Photo-induced synthesis, stereochemistry and antitumor activity of valine-based small cyclopeptides

“…For cyclotripeptides, we found that compound (3) with two L-amino acid residues displays relatively stronger antitumor activity than compounds 4, 5, and 6 containing D-amino acids. For cyclotetrapeptides (7)(8)(9)(10)(11)(12)(13)(14), we fortunately found that cyclic peptide 7 showed promising antitumor activity (IC 50 = 40 mM), which can be considered as a potential leading compound for future modification. Structurally, compound 7 also has pure L-valine residues, similar to compound 3.…”

“…The L-valine residue is important in the present case, yet it is case-specific, for we have previously found that the cyclopeptides with D-amino acids sometimes present stronger bioactivity. [12][13][14] Some researchers also have found that the cyclopeptides with interlaced D/L amino acid residues show promising biological activity. 25 Some other examples can also be found in a recent review of small cyclic peptides.…”

“…Our team focused on the structural modification of various a Key Laboratory for Photonic and Electronic Bandgap Materials (Ministry of natural peptides by IPETC reactions to develop novel antitumor agents. [11][12][13] We found that many of the compounds with an isoindolinone moiety showed good antitumor activitiy. We have also observed that the IPETC synthesis of cyclic peptides starting from chiral pure amino acids can generate chiral pure products (mainly the C-3 chiral center), since the chiral starting material may significantly affect the spatial properties of the precursor in the cyclization reaction.…”

“…It has been reported that introduction of rigid isoindolinone into natural cyclopeptides (such as galaxamide) greatly affected their antitumor activities, and those with unnatural D-amino acids exhibited stronger anti-liver cancer activity. 12,14 The structural modification of natural cyclic peptides phakellistatin 2, phakellistatin 6 and fenestin A also showed that the compounds with the same amino acid sequence yet different spatial structural features presented disparate antitumor activities. 11,13,15 It has been reported that introduction of methylated Pro residues into the peptide would increase the percentage of the cis conformation of Pro and rescue the biological activity from synthetic cyclopeptides.…”

Phthalylglycyl Chloride as a Derivatization Agent for UHPLC-MS/MS Determination of Adrenaline, Dopamine and Octopamine in Urine

“…Phthalylglycyl chloride (PG-Cl) is a commonly used reagent for amido-alkylation for the synthesis of benzofuran derivatives, remote C-H bond functionalization and photoinduced single electron transfer cyclization for the preparation of cyclic peptides [ 33 , 34 , 35 , 36 ]. At the same time, it could be used as a derivatization reagent for amines.…”