Total Synthesis of Malformin C, an Inhibitor of Bleomycin-Induced G2 Arrest

Kojima, Yasuhiro; Sunazuka, Toshiaki; Nagai, Kazuo; Julfakyan, Khachatur; Fukuda, Takashi; Tomoda, Hiroshi; Ōmura, Satoshi

doi:10.1038/ja.2008.42

Cited by 18 publications

(11 citation statements)

References 7 publications

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“…1D and 2D-NMR spectra were measured on a Bruker ARX-300 spectrometer (300 MHz for 1 H, 75 MHz for 13 C). The pure compound was identified as malformin C via comparison of data with those previously reported [ 16 ].…”

Section: Methodsmentioning

confidence: 93%

Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug

et al. 2015

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Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.27±0.07μM and 0.18±0.023μM respectively. This inhibition was explicated by Malformin C’s effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug.

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Section: Methodsmentioning

confidence: 93%

Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug

et al. 2015

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“…Our study also demonstrated that MA1 treatment induced cell cycle arrest at the sub-G1 phase in human colorectal cancer cells. Previously, MA1 and Malformin C were found to abrogate bleomycin-induced G2 arrest, resulting in a drastic decrease in cells at the G2 phase and increase in cells in the sub-G1 phase (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…Malformin A1 (MA1) is a bicyclic pentapeptide containing five amino acids: L-isoleucine, L-valine, D-leucine, and two D-cysteines (12). MA1 is the most well-studied out of the malformin subtypes, and its various biological activities have been reported previously, including causing malformations in plants, having some antibacterial effects (13)(14)(15), enhancing cellular fibrinolytic activity (16 -18), preventing IL-1-induced procoagulant reaction (19,20), and inhibiting the cell cycle at G2 checkpoint followed by DNA damage (21,22). Additionally, the anticancer activity of MA1 has been reported in various human cancer cells including colorectal cancer (9,22-24).…”

Section: Introductionmentioning

confidence: 99%

Malformin A1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through stimulation of the p38 signaling pathway

Park

et al. 2017

International Journal of Oncology

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Malformin A1 (MA1), a cyclic pentapeptide isolated from Aspergillus niger, has been found to possess a range of bioactive properties including antibacterial activity. However, it is unclear whether MA1 exerts an anticancer effect or not. In this study, we conducted in vitro experiments to investigate its anticancer properties in human colorectal cancer cells. The effect of MA1 on human colorectal cancer cells, SW480 and DKO1, was examined by the WST-1 cell viability assay, inverted microscopy, 5-bromo-2-deoxyuridine (BrdU) incorporation, flow cytometry, DNA fragmentation, wound healing, Transwell assays, and western blotting. MA1 treatment showed potent cytotoxic activities on human colorectal cancer cells. MA1 treatment induced apoptosis by activating the poly(ADP-ribose) polymerase (PARP), caspase‑3, -7, and -9. MA1 treatment led to the increase in p53 upregulated modulator of apoptosis (PUMA) and the decrease in X-linked inhibitor of apoptosis protein (XIAP) and Survivin. In addition, MA1 treatment induced cell cycle arrest in the sub-G1 phase. The pan-caspase inhibitor, Z‑VAD‑FMK, attenuated these MA1-induced apoptotic effects on human colorectal cancer cells. Moreover, MA1 treatment suppressed tumor cell migration and invasion. The phosphorylation level of p38 was upregulated by MA1 treatment, and the inhibitor of p38, SB203580, attenuated the MA1-induced p38 phosphorylation as well as caspase‑3 and PARP activation. These results indicate that MA1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through the stimulation of the p38 signaling pathway.

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“…22 Since then, malformin A has been shown to possess antibiotic activity 23 and inhibit mitosis and the premitotic phase in animal cultures. 24,25 The eight-membered ring consisting of the atoms from the disulfide of the vicinal D-Cys residues is a particularly noteworthy feature of the malformins because the energetic barrier to cis/trans-isomerization of the D-Cys-D-Cys amide could be reduced by the eight-membered ring strain. Theoretical calculations, 26,27 IR studies, 28 and X-ray crystallography 29,30 of L-Cys-L-Cys disulfides suggest that the amide in the dipeptide is cis, but it was unknown if this is maintained in bicyclic systems such as the malformins.…”

Section: Malforminmentioning

confidence: 99%

Disulfide-bridged peptide macrobicycles from nature

Chung

Yudin

2015

Org. Biomol. Chem.

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Disulfide-bridged peptide bicycles (DBPBs) are molecules that contain a transannular disulfide bridge within a macrocyclic framework. While DBPBs are precedented in nature, the development of synthetic analogues and their use as therapeutic agents has yet to realize their full potential. A series of naturally-occurring DBPBs and their respective structural and biological features is presented, followed by a description of synthetic methods used to prepare and understand these unique bicyclic systems. The synergy of high-throughput biology and synthetic chemistry should facilitate the development of novel DBPBs in the near future.

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Total Synthesis of Malformin C, an Inhibitor of Bleomycin-Induced G2 Arrest

Abstract: Total synthesis of a fungal cyclic peptide, malformin C, recently rediscovered as a G2 checkpoint inhibitor was completed. Our synthesis involved a convergent approach with respect to a linear pentapeptide, cyclization, and oxidative disulfide formation.

Cited by 18 publications

References 7 publications

Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug

Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug

Malformin A1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through stimulation of the p38 signaling pathway

Disulfide-bridged peptide macrobicycles from nature

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