Glycosyl Poly Ether Antibiotics On Anticancer Activity Studies

Polyether antibiotics represent a large group of natural occurring biologically active compounds produced by Streptomyces,which has been widely used as the ideal anti-coccidiosis drugs,owned with the characteristiscs of unique mechanism of action,low dosage and no residue,and difficult to drug resistance.Until now,more than 120 polyether antibiotics have been found,polyethers used in the market include:Monensin,salinomycin,Lasalocid,Maduramycin,Narasin etc.Recently,Poly ether antibiotics were found to be able to kill cancer stem cells,for example,salinomycin can selectively kill EMT-mediated breast cancer stem cells with the efficiency of more than 100 times higher than paclitaxel,and nigericin has the similar effect.Therefore,polyether antibiotics may be a class of compounds that have not yet been developed as anti-cancer agents.According to molecular structure characteristic of polyether antibiotics,salinomycin and monensin,termed non-glycosyl polyethers,have been investigated,but there exists a class of promising and characteristic glycosyl polyethers that have similar polyketide backbone owned different glycosyl groups such as nanchangmycin and maduramycin not been tested towards tumors.We first study the biological activity of salinomycin and maduramycin and nanchangmycin,the results revealed that the anticancer activity of nanchangmycin(IC50=0.28 ?M)is stronger than that of salinomycin(IC50=2.85 ?M)and marduramycin(IC50=4.54 ?M,which indicated that glycosyl polyethers represented by nanchangmycin maybe a promising library for drug development.In order to further determine whether polyether antibiotic biological activity are associated with glycosyl group,we prepared the deglycosyl-Jl-001-1(deglycosylation product of nanchangmycin)and compared the anti-cancer activity and IC50 values of deglycosyl-J1-001-1,nanchangmycin and salinomycin in 7 different tumor cells,results indicated that the glycosyl group plays an important role in the anti-cancer activity of glycosyl polyether antibiotics.We found that the glycosyl polyether antibiotics accounted for more than 1/3 of the polyether antibiotics,the number of polyether antibiotics represented by maduramycin are 29,and the number of polyether antibiotics represented by maduramycin are 16.Combination with the above results that maduramycin are less potential than nanchangmycin(J-001-1)on cancer proliferation and cell vitality.So we take nanchangmycin(J-001-1)as a model based on nanchangmycin core ring and the characteristics of sugar as template,Consequently,four glycosyl polyethers,which shared the same backbone J1-001(Nanchangmycin:J1-001-1;A-130-A:J1-001-2;Endusamycin:J1-001-3;CP-80,219:J1-001-4)were obtained and evaluated for their anti-cancer effects were evaluated.This study found that glycosyl polyether antibiotics can not only inhibit the growth of breast cancer stem cells;but also exhibit obvious antitumor activity on different tumor cells,especially A-130-A(J1-001-2)on lymphoma cells DOHH2(4.4×l10-10M),leukemia cell MV-4-11(7.2×10-10M),rhabdomyosarcoma cells A-204(3.94×10-9M),gastric cancer cell MG-63(8.5×10-9M)and Hep3B cells(8.68×10-9M)and brain cancer cells U-87-MG(8.63×10-9M)show promising anti-tumor activity.Proteomic results reveals glycosyl polyether antibiotics can influence up to 10 pathways in tumor cells leading to limit cell proliferation,induce apoptosis autophagy,inhibit cell invasion and metastasis.Immunoblotting methods verified that five signal pathways(wnt/?-catenin,Hippo,Ca2+,autophagy and apoptosis pathway)were comfirmed.Glycosyl polyether antibiotics themselves as ion carriers can enhance intracelluar calcium concentration,leads to mitochondrial ROS accumulation and cytochrome c release,activate Caspase cascade reaction in the cytoplasm to trigger apoptosis.In vivo experiments showed that the inhibitory effect of Nanchangmycin on taxol-resistant MCF7 cells was significant.These data suggests that glycosyl polyether antibiotics are a potential library that are worthy to explore into antitumor drugs.In order to obtain the chemical modification strategies of glycosyl polyethers,we first studied salinomycin as the research object.Salinomycin has been used to control coccidiosis and promote the growth of ruminants.Because of its ability to inhibit tumor stem cells,studies found that salinomycin can inhibit tumor proliferation,promote tumor apoptosis and inhibit tumor metastasis and invasion through many ways to affect cancer.In recent years,the researchers proposed several hypotheses for anti-tumor mechanism of salinomycin:target tumor stem cells to weaken its ability of self-renewal and tolerance of cytotoxic drugs,resist the high expression of ATP binding cassette transporter and P-gp,inhibit the classic Wnt/?-catenin pathway,induce intracellular ROS accumulation and downregulate the Akt/NF-B signaling pathway.Therefore,derivating highly potent,highly selective analogs of salinomycin can be used to probe the modes of mechanism of salinomycin.Based on presious work about chemical modification of salinomycin,including carboxyl,three hydroxyl and double bond sites,derivatives origined from the modificaton of C20 hydroxyl group can improve the antitumor activity.In this paper,three series of derivatives were synthesized by modifying the carboxyl group and the hydroxyl group of C20,through click chemistry.The comparisons of the in vitro biological test results for compound series 2 antiproliferative activities in two breast cancer cell lines MCF-7(ERa-positive)and MDA-MB-231(triple-negative)indicate that anticancer activity increases as the length of aliphatic acid appended on carboxyl unit of salinomycin extends was observed;antitumour activity depends on the chain length and cell line when a hydrophilic group is attached to the C20 hydroxyl group;Salinomycin triazole dimers(series 4)were 3.27-4.97 times more cytotoxic than salinomycin monomers in MCF-7 and had moderately improved toxicity in MDA-MB-231.This results could provide a basic tool to develop new antitumor drugs for glycosyl polyether antibiotics.