Design, Preparation of 3‐Hydroxy Isoindolinone Cyclotripeptides, and the In Vitro Antitumor Activities Against Cervical Carcinoma HeLa Cells

Abstract

Photoinduced single electron transfer cyclization processes for synthesis of a series of 3‐hydroxy isoindolinone cyclotripeptides containing double pharmacophores (cyclotripeptides and phthalimide moiety) are described to develop novel antitumor cyclopeptide drugs. The results showed that our proposed method could be used to synthesize various isoindolinone cyclotripeptides highly regioselectively at a moderate rate. Moreover, the inhibitory potency toward human cervical carcinoma HeLa cells of the target cyclopeptides and the linear tripeptide precursors were evaluated, and most of the compounds were observed with potent inhibition ability against tumor growth. Specifically, compound 6c was found to inhibit HeLa cells with an IC50 value of 32 μM, which may serve as a potential candidate for drug development. In addition, 3‐hydroxy isoindolinone‐cyclo‐Gly‐Ala‐Pro (6a1) was chosen from the obtained cyclopeptides for the absolute configuration research, and an S configuration of C‐3 was established by experimental electronic circular dichroism with the aid of theoretical calculations.

Efficient synthesis of bisulfide-bridged bicyclopeptides by intramolecular photoinduced electron transfer cycloreaction

“…In fact, the oligomerization phenomenon has also been found by other researchers, 17,21 and is consistent with our previously reported result. 22 It is also conceivable that the position of the N-substituted amino acids in the sequence may also influence inter-or intramolecular hydrogen bonding and consequently affect the cyclization yield, which is worthy of further investigation.…”