Angucyclines From Two Streptomyces Sp.and Their Antitumor Effects

Angucyclines natural products which own the core structure of benzanthracene,belong to the type Ⅱ polyketide compounds,and mainly produced by the actinomycete Streptomyces.Their have the rich diversity of structures and wide range of biological activities,especially in the aspect of anti-tumor activity.Angucyclines,compared with anthracyclines,which also belong to the type Ⅱ polyketides,showed higher anti-tumor activity.It is expected to be developed into a new clinical antitumor drug.Marine-derived Streptomyces sp.OC1610.4 was cultured in S-medium and four angucyclines were identified.One of the isolates,saquayamycin B,displayed potent cytotoxicity on human hepatoma carcinoma cells,meanwhile,it also induced apoptosis of SMMC-772 cells in a dose-dependent manner.In this paper,large-scale fermentation using GAU and isolation resulted in the identification of another seven angucyclines including two new angucyclines vineomycin E,F(1-2)and five known homologues,grincamycin L(3),vineomycinone B2(4),fridamycin D(5),moromycin B(7)and saquayamycin B1(8).We evaluated the cytotoxic activity of isolated angucyclines on MCF-7,MDA-MB-231,and BT-474 cell lines employing the MTT method.Among the tested compounds,moromycin B(7),saquayamycin B1(8),and saquayamycin B(9)displayed remarkable cytotoxicity to breast cancer cells,with IC50 values ranging from 0.16 to 0.67 μM.Vineomycin E(1)and fridamycin D(5)displayed medium cytotoxicity on the tested cells.After treatment of the aggressive triple-negative cell line MDA-MB-231 with saquayamycin B(9)at concentrations of 25 and 50 nM for 12 hours,the invasion and migration capabilities of MDA-MB-231 cells were found to be depressed by Transwell and wound-healing assaysIn order to obtain more angucyclines producing strains,in this paper,based on the TLC information,we screened the potential angucyclines producing strains from the laboratory bacterial library.Then,using the angucyclines cyclase gene(AC)as a template,a potential angucyclines producing strain was further screened by PCR.AntiSMASH was used to predict its biosynthetic gene cluster after its whole genome was sequenced.The results showed that this strain have the potential to produce angucyclines.After fermentation with GAU medium,five angucyclines were isolated including one new angucycline 6-hydroxyfridamycin E(14),four known homologues grincamycin L(3),fridamycin D(5),dehydrorabelomycin(12),SS-228R(13).MTT assay was used to study their antitumor activities.It was found that dehydrorabelomycin(12)displayed remarkable cytotoxicity to hepatoma cell HepG-2,SMMC-7721,Hepal-6 and breast cancer cell MCF-7,MDA-MB-453,BT-20 with IC50 values from 0.69 μm to 2.69 μm.