Unantimycin A, a new neoantimycin analog isolated from a microbial metabolite fraction library

Lim, Chung Liang; Nogawa, Toshihiko; Okano, Akiko; Futamura, Yushi; Kawatani, Masahito; Takahashi, Shunji; Demirtaş, İbrahim; Osada, Hiroyuki

doi:10.1038/ja.2015.124

Cited by 21 publications

(16 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the bioactivity assay, 1-4 exhibited considerable anticancer activities with IC 50 values 1.6 to 8.2 μM, comparable to the IC 50 of 1.1 to 6.3 μM detected for cisplatin ( Table 1). This is consistent with the activities previously shown for unantimycin A, which structurally differs from 1 at the C4 alkyl group, and which has shown moderate cytotoxicity (IC 50 ~10 μM) against human cervix epidermoid carcinoma, promyelocytic leukemia, and sarcoma cell lines (13). Notably, besides the exception of 3 showing IC 50 8.5 μM to 16HBE cells, 1-4 generally displayed no obvious toxicity (IC 50 >31.9 μM) towards the related normal cells, in contrast to the IC 50 of 2.7 to 4.6 μM detected for cisplatin (Table 1).…”

Section: Anticancer Activity Evaluation Of 1-4supporting

confidence: 91%

Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase

Shen

Sun

Zhang

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

show abstract

Section: Anticancer Activity Evaluation Of 1-4supporting

confidence: 91%

Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase

Shen

Sun

Zhang

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…SNA 15896 (soil, Ibaraki Prefecture, Japan) during screening for immunosuppressants. 46 Notably, the hydroxyl of the macrocyclic ring is oxidized to a ketone in 62, and other oxidized neoantimycin variants include 58, 45 prunustatin A (63) produced by S. violaceusniger, 47,48 and neoantimycin H (64) produced by S. orinoci. 43,44 Several variants of neoantimycins differing in the 3-formamidosalicylate moiety and/or oxidation have also been reported.…”

Section: Antimycin-type Depsipeptides With a 15-membered Macrocyclic mentioning

confidence: 99%

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

et al. 2016

View full text Add to dashboard Cite

Covering: up to 2016Antimycin-type depsipeptides are a family of natural products with great structural diversity and outstanding biological activities. These compounds have typically been isolated from actinomycetes and are generated from hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly lines. This review covers the literature on the four classes of antimycin-type depsipeptides, which differ by macrolactone ring size, and it discusses the discovery, biosynthesis, chemical synthesis, and biological activities of this family of compounds.

show abstract

“…To date, 13 NAT derivatives and their analogs have been isolated since the 1960s, which exhibit various biological activities of immunosuppression, anti-microbial, fungicidal, and anti-tumor effects (Li et al, 2013; Salim et al, 2014; Lim et al, 2016; Zhou et al, 2018). For example, it has been reported that the NAT derivatives SW-163A and B, isolated from the culture broth of Streptomyces sp.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, Lim et al reported that unantimycin A and SW-163A, analogues of neoantimycin, isolated from Streptomyces sp. RK88-1355, showed moderate cytotoxicity activities against several cancer cell lines, including HeLa, HL-60, and others; both of them also possessed potent antimalarial activities (Lim et al, 2016). Recently, we studied the biosynthetic pathways of Streptomyces conglobatus and isolated a series of NATs, including the known NAT-A, F, H, and a new NAT-I, and revealed that these compounds displayed interesting anti-cancer properties against multiple cell lines (Zhou et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Neoantimycin F, a Streptomyces-Derived Natural Product Induces Mitochondria-Related Apoptotic Death in Human Non-Small Cell Lung Cancer Cells

Liu

Zhu

et al. 2019

Front. Pharmacol.

View full text Add to dashboard Cite

Streptomyces-derived natural products have been become a major focus of anti-tumor drug discovery studies. Neoantimycin F (NAT-F), was isolated from Streptomyces conglobatus by our group. Here, we examined the anti-cancer activities and its underlying molecular mechanisms implicated in NAT-F–induced apoptosis of non–small cell lung cancer (NSCLC) cells. Our results showed that NAT-F exerted excellent growth-inhibitory activity against PC9 and H1299 cells in a concentration-dependent manner. NAT-F–induced cell cycle arrest at S and G0/G1 phase in PC9 and H1299 cells, respectively. Further investigation revealed that the key proteins (including cyclinD1, cyclinE1, cyclinB1, CDK2, and CDK4) were involved in the cell regulation by NAT-F. Additionally, NAT-F significantly increased the production of reactive oxygen species (ROS), induced DNA damage, nuclear condensation, and cell apoptosis in both cell lines. Moreover, loss of the mitochondrial membrane potential (MMP) was markedly induced by NAT-F. Additional results revealed that NAT-F could up-regulate pro-apoptotic protein Bax and down-regulate anti-apoptotic protein Bcl-2, Mcl-1, and Bcl-xL, resulting in cytochrome c release from mitochondria and sequential activation of caspase-9 and -3, as well as the cleavage of poly (ADP-ribose) polymerase. Meanwhile, c-Jun N-terminal kinase (JNK), p38 MAPK (p38), and extracellular signal-regulated kinase (ERK) signaling pathway were also involved in anti-cancer activity of NAT-F in NSCLC cells. Taken together, these findings indicated that NAT-F possessed anti-proliferative effect and induced apoptosis in NSCLC cells in vitro and may be conducive to promote the development of novel anti-NSCLC agents.

show abstract

Unantimycin A, a new neoantimycin analog isolated from a microbial metabolite fraction library

Cited by 21 publications

References 14 publications

Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase

Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

Neoantimycin F, a Streptomyces-Derived Natural Product Induces Mitochondria-Related Apoptotic Death in Human Non-Small Cell Lung Cancer Cells

Contact Info

Product

Resources

About