YM-216391, a Novel Cytotoxic Cyclic Peptide from Streptomyces nobilis

Abstract

YM-216391, a novel cyclic peptide, was isolated from the cultured mycelium of Streptomyces nobilis JCM 4274. It was purified by solvent extraction, silica gel and ODS flash column chromatographies, followed by preparative HPLC. YM-216391 dosedependently inhibited the growth of human cervical cancer HeLa S3 cells with an IC 50 value of 14 nM. YM-216391 also showed potent cytotoxic activity against a human cancer cell line panel.

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

“…613 NMR structure determination revealed YM-216391 to be a cyclic, pentazole-containing peptide, similar to the telomerase inhibitor telomestatin (Figure 29). 614 All but one amino acid (Val) of the core peptide have been modified; Marfey’s analysis confirmed the presence of D- allo -Ile.…”

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

“…Furthermore, when tested for its inhibitory Table 4 Structural analogues of Telomestatin and its biological activity evaluation in TRAP and PCR stop assays. activity against HDAC, YM-216391 was not active even at 10 lM [57]. Thus, the mode of action for this entire potent class of molecules remains elusive and requires further investigation.…”

“…Telomerase is an enzyme that elongates telomeres. Inhibiting telomerase shortens telomeres on the chromosomes, which ultimately leads to apoptosis as the cells can no longer produce viable daughter cells [57,[59][60][61][62][63][64]. Telomestatin forms a stable and well-studied intramolecular G-quadruplex (Fig.…”

“…YM-216391 is structurally closest to that of M5, differing only by incorporating a thiazole instead of an oxazole within the heterocyclic backbone. YM-216391, isolated from the cultured mycelium of Streptomyces nobilis JCM4274, showed an IC 50 of 14 nM against HeLa S3 cervical carcinoma [57]. Tanaka and co-workers noted that YM-216391 had 50-250 fold greater inhibitory activity on MCF-7 (breast cancer), OVCAR-3 (ovarian cancer) and SK-OV-3 (ovarian cancer) cell lines than those of Telomestatin, a known telomerase inhibitor, and like M1 and Urukthaplestatin A, appeared to act via a mechanism that did not involve telomerase.…”

Synthesis and Antitumor Activity of Mechercharmycin A Analogues

“…9 We sought to prepare analogs of 1with improved solubility and activity. The first structural modifications comprised substitution on the penta-azole system and modifications of the exocyclic methylidene ( Figure 1).…”