Cytotoxic and antibacterial polyketide-indole hybrids synthesized from indole-3-carbinol by Daldinia eschscholzii
|
摘要
Two skeletally undescribed polyketide-indole hybrids(PIHs), named indolchromins A and B,were generated from indole-3-carbinol(I3 C) in the fungal culture(Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1 D and 2 D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism(CD) spectra with the electronic CD(ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions,including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase(AONS),C(sp3)-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3–8.6 μmol/L,(2 S,4 R)-and(2 R,4 S)-indolchromin A and(2 R,4 S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp.,Bacteroides fragilis, and Streptococcus pyogenes.(2 R,4 S)-Indolchromin A and(2 S,4 S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7(IC_(50)94.4 nmol/L).
Two skeletally undescribed polyketide-indole hybrids(PIHs), named indolchromins A and B,were generated from indole-3-carbinol(I3 C) in the fungal culture(Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1 D and 2 D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism(CD) spectra with the electronic CD(ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions,including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase(AONS),C(sp~3)-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3–8.6 μmol/L,(2 S,4 R)-and(2 R,4 S)-indolchromin A and(2 R,4 S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp.,Bacteroides fragilis, and Streptococcus pyogenes.(2 R,4 S)-Indolchromin A and(2 S,4 S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7(IC_(50)94.4 nmol/L).
Two skeletally undescribed polyketide-indole hybrids(PIHs), named indolchromins A and B,were generated from indole-3-carbinol(I3 C) in the fungal culture(Daldinia eschscholzii). The indolchromin structures were elucidated mainly by their 1 D and 2 D NMR spectra with the former confirmed by the single-crystal X-ray crystallographic analysis. Each indolchromin alkaloid was chirally separated into four isomers, whose absolute configurations were assigned by comparing the recorded circular dichroism(CD) spectra with the electronic CD(ECD) curves computed for all optional stereoisomers. Furthermore, the indolchromin construction pathways in fungal culture were clarified through enzyme inhibition, precursor feeding experiment, and energy calculation. The cascade reactions,including decarboxylative Claisen condensation catalyzed by 8-amino-7-oxononanoate synthase(AONS),C(sp~3)-H activation, double bond migration, and Michael addition, all undergone compatibly during the fungal cultivation. In an MIC range of 1.3–8.6 μmol/L,(2 S,4 R)-and(2 R,4 S)-indolchromin A and(2 R,4 S)-indolchromin B are inhibitory against Clostridium perfringens, Clostridium difficile, Veillonella sp.,Bacteroides fragilis, and Streptococcus pyogenes.(2 R,4 S)-Indolchromin A and(2 S,4 S)-indolchromin B were cytotoxic against the human breast cancer cell line MDA-MB-231 with IC50 values of 27.9 and131.2 nmol/L, respectively, with the former additionally active against another human breast cancer cell line MCF-7(IC_(50)94.4 nmol/L).
引文
1.Meng L,Guo Q,Liu Y,Chen M,Li Y,Jiang J,et al.Indole alkaloid sulfonic acids from an aqueous extract of Isatis indigotica roots and their antiviral activity.Acta Pharm Sin B 2017;7:334-41.
2.Liu Y,Wang X,Chen M,Lin S,Li L,Shi J.Three pairs of alkaloid enantiomers from the root of Isatis indigotica.Acta Pharm Sin B2016;6:141-7.
3.Xu W,Gavia DJ,Tang Y.Biosynthesis of fungal indole alkaloids.Nat Prod Rep 2014;31:1474-87.
4.Butler MS,Robertson AA,Cooper MA.Natural product and natural product derived drugs in clinical trials.Nat Prod Rep 2014;31:1612-1661.
5.Mishra BB,Tiwari VK.Natural products:an evolving role in future drug discovery.Eur J Med Chem 2011;46:4769-807.
6.Lin LP,Yuan P,Jiang N,Mei YN,Zhang WJ,Tan RX,et al.Geneinspired mycosynthesis of skeletally new indole alkaloids.Org Lett2015;17:2610-3.
7.Xu J,Lacoske MH,Theodorakis EA.Neurotrophic natural products:chemistry and biology.Angew Chem Int Ed 2014;53:956-87.
8.Lyssiotis CA,Lairson LL,Boitano AE,Wurdak H,Zhu ST,Schultz PG.Chemical control of stem cell fate and developmental potential.Angew Chem Int Ed 2011;50:200-42.
9.Pan Z,Qin XJ,Liu YP,Wu T,Luo XD,Xia C.Alstoscholarisines H-J,indole alkaloids from Alstonia scholaris:structural evaluation and bioinspired synthesis of alstoscholarisine H.Org Lett 2016;18:654-7.
10.Leng L,Zhou X,Liao Q,Wang F,Song H,Zhang D,et al.Asymmetric total syntheses of Kopsia indole alkaloids.Angew Chem Int Ed 2017;56:3703-7.
11.Chen W,Yang XD,Tan WY,Zhang XY,Liao XL,Zhang H.Total synthesis of(-)-vindorosine.Angew Chem Int Ed 2017;56:12327-31.
12.Zhang Q,Pang B,Ding W,Liu W.Aromatic polyketides produced by bacterial iterative type I polyketide synthases.ACS Catal 2013;3:1439-1447.
13.Liang X,Zhang TY,Zeng XY,Zheng Y,Wei K,Yang YR.Ircatalyzed asymmetric total synthesis of(-)-Communesin F.J Am Chem Soc 2017;139:3364-7.
14.Li Y,Zhang Q,Du Q,Zhai H.Rh-catalyzed[3t2]cycloaddition of1-sulfonyl-1,2,3-triazoles:access to the framework of aspidosperma and kopsia indole alkaloids.Org Lett 2016;18:4076-9.
15.Tang XD,Wu WQ,Zeng W,Jiang HF.Copper-catalyzed oxidative carbon-carbon and/or carbon-heteroatom bond formation with O2or internal oxidants.Acc Chem Res 2018;51:1092-105.
16.Bietti M.Activation and deactivation strategies promoted by medium effects for selective aliphatic C3H bond functionalization.Angew Chem Int.Ed.2018 http://dx.doi.org/10.1002/anie.201804929.
17.Wang X,Lerchen A,Gensch T,Knecht T,Daniliuc CG,Glorius F.Combination of Cp*RhIII-catalyzed C-H activation and a WagnerMeerwein-type rearrangement.Angew Chem Int Ed 2017;56:1381-4.
18.Adwas AA,Elkhoely AA,Kabel AM,Abdel-Rahman MN,Eissa AA.Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice.J Infect Chemother 2016;22:36-43.
19.Palani K,Harbaum-Piayda B,Meske D,Keppler JK,Bockelmann W,Heller KJ,et al.Influence of fermentation on glucosinolates and glucobrassicin degradation products in sauerkraut.Food Chem2016;190:755-62.
20.Ciska E,Drabin?ska N,Honke J,Narwojsz A.Boiled Brussels sprouts:a rich source of glucosinolates and the corresponding nitriles.J Funct Foods 2015;19:91-9.
21.Anderton MJ,Manson MM,Verschoyle RD,Gescher A,Lamb JH,Farmer PB,et al.Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice.Clin Cancer Res 2004;10:5233-41.
22.Hertweck C.The biosynthetic logic of polyketide diversity.Angew Chem Int Ed 2010;48:4688-716.
23.Zhang YL,Zhang J,Jiang N,Lu YH,Wang L,Tan RX,et al.Immunosuppressive polyketides from mantis-associated Daldinia eschscholzii.J Am Chem Soc 2011;133:5931-40.
24.Weems JM,Yost GS.3-Methylindole metabolites induce lung CYP1A1 and CYP2F1 enzymes by AhR and non-AhR mechanisms,respectively.Chem Res Toxicol 2010;23:696-704.
25.Dai JQ,Krohn K,Draeger S,Schulz B.New naphthalene-chroman coupling products from the endophytic fungus,Nodulisporium sp.from Erica arborea.Eur J Org Chem 2009;10:1564-9.
26.Alvarez-Cisneros C,Mu?oz MA,Suárez-Castillo OR,PérezHernández N,Cerda-García-Rojas CM,Morales-Ríos MS,et al.Stereospecific5JHortho,OMecouplings in methoxyindoles,methoxycoumarins,and methoxyflavones.Magn Reson Chem2014;52:491-9.
27.Kakita VM,Hosur RV.Hadamard homonuclear broadband decoupled TOCSY NMR:improved efficacy in detecting long-range chemical shift correlations.Chemphyschem 2016;17:4037-42.
28.Fridkin SK,Hageman JC,Morrison M,Sanza LT,Como-Sabetti K,Jernigan JA,et al.Methicillin-resistant Staphylococcus aureus disease in three communities.Engl J Med 2005;352:1436-44.
29.Esposito S,Bianchini S,Fastiggi M,Fumagalli M,Andreozzi L,Rigante D.Geoepidemiological hints about Streptococcus pyogenes strains in relationship with acute rheumatic fever.Autoimmun Rev2015;14:616-21.
30.A?imovi?SG,Zeng Q,McGhee GC,Sundin GW,Wise JC.Control of fire blight(Erwinia amylovora)on apple trees with trunkinjected plant resistance inducers and antibiotics and assessment of induction of pathogenesis-related protein genes.Front Plant Sci2015;6:16.
31.Wiegand I,Hilpert K,Hancock RE.Agar and broth dilution methods to determine the minimal inhibitory concentration(MIC)of antimicrobial substances.Nat Protoc 2008;3:163-75.
32.Clocchiatti A,Cora E,Zhang Y,Dotto GP.Sexual dimorphism in cancer.Nat Rev Cancer 2016;16:330-9.
33.Han WB,Lu YH,Zhang AH,Zhang GF,Mei YN,Tan RX,et al.Curvulamine,a new antibacterial alkaloid incorporating two undescribed units from a Curvularia species.Org Lett 2014;16:5366-5369.
34.Hwang IT,Choi JS,Song HY,Cho SJ,Lim HK,Park NJ,et al.Validation of 7-keto-8-aminopelargonic acid synthase as a potential herbicide target with lead compound triphenyltin acetate.Pestic Biochem Phys 2010;97:24-31.
35.Asai T,Tsukada K,Ise S,Shirata N,Hashimoto M,Fujii I,et al.Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides.Nat Chem 2015;7:737-43.
36.Song YN,Jiao RH,Zhang WJ,Zhao GY,Dou H,Jiang R,et al.New ansamycin derivatives generated by simultaneous mutasynthesis.Org Lett 2015;17:556-9.
37.Yan W,Ge HM,Wang G,Jiang N,Mei YN,Jiang R,et al.Pictet-Spengler reaction-based biosynthetic machinery in fungi.Proc Natl Acad Sci U S A 2014;111:18138-43.
38.Bruhn T,Schauml?ffel A,Hemberger Y,Bringmann G.SpecDis:quantifying the comparison of calculated and experimental electronic circular dichroism spectra.Chirality 2013;25:243-9.
39.Frisch MJ,Trucks GW,Schlegel HB,Scuseria GE,Robb MA,Cheeseman JR,et al.Gaussian 09,Revision D.01.Wallingford,CT:Gaussian,Inc;2013.
40.Périllaud C,Pilmis B,Diep J,Péan de Ponfilly G,Vidal B,Couzigou C.Prospective evaluation of rapid antimicrobial susceptibility testing by disk diffusion on Mueller-Hinton rapid-SIR directly on blood cultures.Diagn Microbiol Infect Dis 2018 pii:S0732-8893(18)30252-9.
41.Menicagli R,Samaritani S,Signore G,Vaglini F,Dalla Via L.In vitro cytotoxic activities of 2-alkyl-4,6-diheteroalkyl-1,3,5-triazines:new molecules in anticancer research.J Med Chem 2004;47:4649-52.
42.Ge HM,Yu ZG,Zhang J,Wu JH,Tan RX.Bioactive alkaloids from endophytic Aspergillus fumigatus.J Nat Prod 2009;72:753-5.
2.Liu Y,Wang X,Chen M,Lin S,Li L,Shi J.Three pairs of alkaloid enantiomers from the root of Isatis indigotica.Acta Pharm Sin B2016;6:141-7.
3.Xu W,Gavia DJ,Tang Y.Biosynthesis of fungal indole alkaloids.Nat Prod Rep 2014;31:1474-87.
4.Butler MS,Robertson AA,Cooper MA.Natural product and natural product derived drugs in clinical trials.Nat Prod Rep 2014;31:1612-1661.
5.Mishra BB,Tiwari VK.Natural products:an evolving role in future drug discovery.Eur J Med Chem 2011;46:4769-807.
6.Lin LP,Yuan P,Jiang N,Mei YN,Zhang WJ,Tan RX,et al.Geneinspired mycosynthesis of skeletally new indole alkaloids.Org Lett2015;17:2610-3.
7.Xu J,Lacoske MH,Theodorakis EA.Neurotrophic natural products:chemistry and biology.Angew Chem Int Ed 2014;53:956-87.
8.Lyssiotis CA,Lairson LL,Boitano AE,Wurdak H,Zhu ST,Schultz PG.Chemical control of stem cell fate and developmental potential.Angew Chem Int Ed 2011;50:200-42.
9.Pan Z,Qin XJ,Liu YP,Wu T,Luo XD,Xia C.Alstoscholarisines H-J,indole alkaloids from Alstonia scholaris:structural evaluation and bioinspired synthesis of alstoscholarisine H.Org Lett 2016;18:654-7.
10.Leng L,Zhou X,Liao Q,Wang F,Song H,Zhang D,et al.Asymmetric total syntheses of Kopsia indole alkaloids.Angew Chem Int Ed 2017;56:3703-7.
11.Chen W,Yang XD,Tan WY,Zhang XY,Liao XL,Zhang H.Total synthesis of(-)-vindorosine.Angew Chem Int Ed 2017;56:12327-31.
12.Zhang Q,Pang B,Ding W,Liu W.Aromatic polyketides produced by bacterial iterative type I polyketide synthases.ACS Catal 2013;3:1439-1447.
13.Liang X,Zhang TY,Zeng XY,Zheng Y,Wei K,Yang YR.Ircatalyzed asymmetric total synthesis of(-)-Communesin F.J Am Chem Soc 2017;139:3364-7.
14.Li Y,Zhang Q,Du Q,Zhai H.Rh-catalyzed[3t2]cycloaddition of1-sulfonyl-1,2,3-triazoles:access to the framework of aspidosperma and kopsia indole alkaloids.Org Lett 2016;18:4076-9.
15.Tang XD,Wu WQ,Zeng W,Jiang HF.Copper-catalyzed oxidative carbon-carbon and/or carbon-heteroatom bond formation with O2or internal oxidants.Acc Chem Res 2018;51:1092-105.
16.Bietti M.Activation and deactivation strategies promoted by medium effects for selective aliphatic C3H bond functionalization.Angew Chem Int.Ed.2018 http://dx.doi.org/10.1002/anie.201804929.
17.Wang X,Lerchen A,Gensch T,Knecht T,Daniliuc CG,Glorius F.Combination of Cp*RhIII-catalyzed C-H activation and a WagnerMeerwein-type rearrangement.Angew Chem Int Ed 2017;56:1381-4.
18.Adwas AA,Elkhoely AA,Kabel AM,Abdel-Rahman MN,Eissa AA.Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice.J Infect Chemother 2016;22:36-43.
19.Palani K,Harbaum-Piayda B,Meske D,Keppler JK,Bockelmann W,Heller KJ,et al.Influence of fermentation on glucosinolates and glucobrassicin degradation products in sauerkraut.Food Chem2016;190:755-62.
20.Ciska E,Drabin?ska N,Honke J,Narwojsz A.Boiled Brussels sprouts:a rich source of glucosinolates and the corresponding nitriles.J Funct Foods 2015;19:91-9.
21.Anderton MJ,Manson MM,Verschoyle RD,Gescher A,Lamb JH,Farmer PB,et al.Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice.Clin Cancer Res 2004;10:5233-41.
22.Hertweck C.The biosynthetic logic of polyketide diversity.Angew Chem Int Ed 2010;48:4688-716.
23.Zhang YL,Zhang J,Jiang N,Lu YH,Wang L,Tan RX,et al.Immunosuppressive polyketides from mantis-associated Daldinia eschscholzii.J Am Chem Soc 2011;133:5931-40.
24.Weems JM,Yost GS.3-Methylindole metabolites induce lung CYP1A1 and CYP2F1 enzymes by AhR and non-AhR mechanisms,respectively.Chem Res Toxicol 2010;23:696-704.
25.Dai JQ,Krohn K,Draeger S,Schulz B.New naphthalene-chroman coupling products from the endophytic fungus,Nodulisporium sp.from Erica arborea.Eur J Org Chem 2009;10:1564-9.
26.Alvarez-Cisneros C,Mu?oz MA,Suárez-Castillo OR,PérezHernández N,Cerda-García-Rojas CM,Morales-Ríos MS,et al.Stereospecific5JHortho,OMecouplings in methoxyindoles,methoxycoumarins,and methoxyflavones.Magn Reson Chem2014;52:491-9.
27.Kakita VM,Hosur RV.Hadamard homonuclear broadband decoupled TOCSY NMR:improved efficacy in detecting long-range chemical shift correlations.Chemphyschem 2016;17:4037-42.
28.Fridkin SK,Hageman JC,Morrison M,Sanza LT,Como-Sabetti K,Jernigan JA,et al.Methicillin-resistant Staphylococcus aureus disease in three communities.Engl J Med 2005;352:1436-44.
29.Esposito S,Bianchini S,Fastiggi M,Fumagalli M,Andreozzi L,Rigante D.Geoepidemiological hints about Streptococcus pyogenes strains in relationship with acute rheumatic fever.Autoimmun Rev2015;14:616-21.
30.A?imovi?SG,Zeng Q,McGhee GC,Sundin GW,Wise JC.Control of fire blight(Erwinia amylovora)on apple trees with trunkinjected plant resistance inducers and antibiotics and assessment of induction of pathogenesis-related protein genes.Front Plant Sci2015;6:16.
31.Wiegand I,Hilpert K,Hancock RE.Agar and broth dilution methods to determine the minimal inhibitory concentration(MIC)of antimicrobial substances.Nat Protoc 2008;3:163-75.
32.Clocchiatti A,Cora E,Zhang Y,Dotto GP.Sexual dimorphism in cancer.Nat Rev Cancer 2016;16:330-9.
33.Han WB,Lu YH,Zhang AH,Zhang GF,Mei YN,Tan RX,et al.Curvulamine,a new antibacterial alkaloid incorporating two undescribed units from a Curvularia species.Org Lett 2014;16:5366-5369.
34.Hwang IT,Choi JS,Song HY,Cho SJ,Lim HK,Park NJ,et al.Validation of 7-keto-8-aminopelargonic acid synthase as a potential herbicide target with lead compound triphenyltin acetate.Pestic Biochem Phys 2010;97:24-31.
35.Asai T,Tsukada K,Ise S,Shirata N,Hashimoto M,Fujii I,et al.Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides.Nat Chem 2015;7:737-43.
36.Song YN,Jiao RH,Zhang WJ,Zhao GY,Dou H,Jiang R,et al.New ansamycin derivatives generated by simultaneous mutasynthesis.Org Lett 2015;17:556-9.
37.Yan W,Ge HM,Wang G,Jiang N,Mei YN,Jiang R,et al.Pictet-Spengler reaction-based biosynthetic machinery in fungi.Proc Natl Acad Sci U S A 2014;111:18138-43.
38.Bruhn T,Schauml?ffel A,Hemberger Y,Bringmann G.SpecDis:quantifying the comparison of calculated and experimental electronic circular dichroism spectra.Chirality 2013;25:243-9.
39.Frisch MJ,Trucks GW,Schlegel HB,Scuseria GE,Robb MA,Cheeseman JR,et al.Gaussian 09,Revision D.01.Wallingford,CT:Gaussian,Inc;2013.
40.Périllaud C,Pilmis B,Diep J,Péan de Ponfilly G,Vidal B,Couzigou C.Prospective evaluation of rapid antimicrobial susceptibility testing by disk diffusion on Mueller-Hinton rapid-SIR directly on blood cultures.Diagn Microbiol Infect Dis 2018 pii:S0732-8893(18)30252-9.
41.Menicagli R,Samaritani S,Signore G,Vaglini F,Dalla Via L.In vitro cytotoxic activities of 2-alkyl-4,6-diheteroalkyl-1,3,5-triazines:new molecules in anticancer research.J Med Chem 2004;47:4649-52.
42.Ge HM,Yu ZG,Zhang J,Wu JH,Tan RX.Bioactive alkaloids from endophytic Aspergillus fumigatus.J Nat Prod 2009;72:753-5.