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Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17

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Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17 FULL PAPERS DOI:10.1002/adsc.201500250 Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17 Pramod B. Shinde,a,e Hong-Se Oh,b Hyemin Choi,c Kris Rathwell,a Yeon Hee Ban,a Eun Ji Kim,a Inho Yang,a Dong Gun Lee,c David H. Sherman,d Han-Young Kang,b,*and YeoJoon Yoona,* a Department of Chemistry andNano Science,Ewha Womans University,Seoul 120-750, Republic of Korea Fax: (+82)-2-3277-3419;phone:(+ 82)-2-3277-4446;e-mail:[email protected] b Department of Chemistry,Chungbuk National University,Cheongju 361-763, Republic of Korea Fax: (+82)-43-267-2279;phone:(+ 82)-43-261-2305;e-mail:[email protected] c School of Life Sciences,BK21Plus KNU Creative BioResearch Group,College of Natural Sciences,Kyungpook National University,Daehak-ro 80, Buk-gu, Daegu 702-701,Republic of Korea d Department of Medicinal Chemistry,Life Science Institute,DepartmentofChemistry,and Department of Microbiology &Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA e Present address:Institute of Bioinformatics and Biotechnology (IBB), Savitribai Phule Pune University (formerly University of Pune), Pune 411-007, India Received:March 12, 2015; Revised:June 15, 2015;Published online:August 19, 2015 Supporting information for this article is availableonthe WWW under http://dx.doi.org/10.1002/adsc.201500250. Abstract: YC-17 is a12-membered ring macrolide sugars for subsequent glycosylation. Some YC-17 antibiotic producedfrom Streptomyces venezuelae macrolactam analogues were active against erythro- ATCC 15439 andiscomposed of the polyketide mac- mycin-resistant bacterial pathogens and displayed rolactone10-deoxymethynolide appendedwith d- improved metabolic stability in vitro.The enhanced desosamine.Inorder to develop structurally diverse therapeutic potentialdemonstrated by these glycosy- macrolactam analoguesofYC-17 with improved lated macrolactam analogues reveals the uniquepo- therapeutic potential, acombined approach involv- tential of chemoenzymatic synthesis in antibiotic ing chemical synthesis and engineered cell-based bio- drug discoveryand development. transformation was employed. Eight new antibacteri- al macrolactam analogues of YC-17 were generated by supplying anovelchemically synthesized macro- Keywords: antibacterial activity;glycosyltransferase; lactam aglycone to S. venezuelae mutantsharboring macrolide glycosides; Streptomyces venezuelae;YC- plasmids capable of synthesizing several unnatural 17 Introduction lide esterases of resistantpathogens.While analogue generation via macrolactone structural modification is Macrocyclic polyketides are ahighly diverse and clini- necessary to increase the stability or efficacy of these cally important class of natural products that include clinically important pharmaceuticals,manyofthe antibiotics (erythromycin),[1] immunosuppressants next-generationstructures remainsusceptible to hy- (FK506),[2] antiparasitics (avermectin),[3] antifungal drolysisbythe macrolide esterases producedbysome agents (amphotericin B),[4] andantitumor agents antibiotic-resistant microbial pathogens.[6] Conse- (epothilone)[5] (Figure 1A). Their structures are char- quently,the need for bioactive molecules with newor acterizedbyamacrolactone and are often decorated improved pharmacologicalproperties that can toler- by one or more deoxyand amino sugar moieties. ate these conditions has further increasedinterest in While the macrolactone is an important pharmaco- generating novelmacrolides.[7] Forexample,semisyn- phore for the observed biological activity,many of thetic derivatives of erythromycin with modified agly- these largering systems are susceptible to degrada- cone structures,such as clarithromycin,[8] azithromy- tion by the acidicpHofthe stomach,esterases in the cin,[9] and telithromycin,[10] displayincreasedstability blood plasma, various hepatic enzymes,orthe macro- under acidic conditions (Figure 1B),[11] andthe recent- Adv.Synth. Catal. 2015, 357,2697 –2711 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 2697 Pramod B. Shindeetal. FULL PAPERS Figure 1. Representative structures of natural macrolides (A)and their semisynthetic derivatives (B). 2698 asc.wiley-vch.de 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Adv.Synth. Catal. 2015, 357,2697 –2711 FULL PAPERS Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues ly approved anticancer agent ixabepilone (Figure 1B), Pik PKS generates both the 12- and14-membered asemisynthetic lactam analogue of epothilone B, was macrolactone rings of 10-dml andnarbonolide,and developed to increase metabolic stability against es- the glycosyltransferase DesVII, along with its auxili- terasecleavage.[12] In addition to modifying the mac- ary partner DesVIII, transfer TDP-d-desosamine rolide aglycone,modificationofthe sugar moieties onto the aforementioned aglyconestogiveYC-17 and can also significantly alter biological activity profiles, narbomycin, respectively.Following glycosylation, and several chemical and enzymatic synthetic ap- narbomycin is converted to pikromycin by the action proachesfor the diversification of macrolides have of PikC cytochrome P450 monooxygenase.This P450 been employed.[13] also converts narbomycin to neopikromycin and nova- Since the synthesis of azithromycin,[9] manyazalides pikromycin, and YC-17 to methymycin, neomethymy- have been reported containing nitrogen atoms at- cin, and novamethymycin.[19] Due to inherent flexibili- tachedtoC-9, C-10, C-11, or C-12 (lactone carbonyl ty,DesVII/DesVIII can transfer arange of structural- designated as C-1), and afew macrolactam analogues ly diverse TDP-sugars,demonstrating their potential of erythromycin Ahave been synthesized(Fig- for the structural diversification of macrolide antibiot- ure 1B).[14] However, macrolactam analogues that ics both in vitro and in vivo.[17] bear structurally diverse sugar moieties have not been Theengineered strains of S. venezuelae capable of explored, and we were motivatedtoaccess and test generating desosamine andarange of alternative the biological activity and selected pharmacological sugar moieties produced newanalogueswhich exhib- properties of this newclass of molecules. ited improved in vitro antibacterial activitiesand met- Thesynthesis of 12-membered macrolides bearing abolic stabilities.Tothe best of our knowledge,this is asingle sugar group is generally more facile than the the first synthesis of diverselyglycosylated macrolac- synthesisof14-membered macrolides that contain tam analogues for amacrolide antibiotic, andthe first two sugar moieties.Inaddition,12-membered mono- report of DesVII/DesVIII recognizing and processing glycosylated macrolides still displaysignifican biologi- alactam for glycosylation. By utilizing chemical syn- cal activities. Forexample,incontrast to erythromy- thesis to supply an unnatural functional group in com- cin, clarithromycin, and roxithromycin, methymycin bination with flexible biological machinery,novel possesses a12-membered ring macrolactone,10-deox- macrolide analogues with increased therapeutic po- ymethynolide (10-dml) which is appended to asingle tential were generated. amino sugar,desosamine.Despite these chemical dif- ferences,methymycin (Figure 1A) retainsantibiotic activity against Gram-positive bacteria similar to the Results and Discussion larger polyglycosylated macrolideantibiotics.[15] Thus, YC-17(Figure 1A) produced from Streptomyces vene- Synthesis of Aza-(10-deoxymethynolide)(1) zuelae ATCC 15439 was selectedfor its relative ease of synthesis,[16] and alactam analogue of this macro- Theretrosynthetic analysisofAZDM 1 is shown in lide possessing diverse sugar moieties was envisioned. Scheme S1 (Supporting Information). Analogous to However, pathwayengineering using apolyketide our previously reported synthesis of 10-dml, AZDM synthase (PKS) to replace the oxygeninthe lactone 1 could be synthesizedfrom key amine 2 and known moiety of the aglycone core with nitrogen is not avail- carboxylic acid 3[16] using EDC coupling and ring clos- able,and both the chemical synthesis of novelsugar ing metathesis(RCM) as the key steps.Our synthesis moieties andthe subsequent glycosylationwith the of AZDM 1 is summarized in Scheme 1. Thedesired corresponding aglycone are impractical. Therefore, amine 2 was preparedinastereoselective mannerin we have employed acombined approach involving four steps starting from propanal. Crotylationof chemical synthesis and biotransformation to efficient- propanal was successfully performed to provide alco- ly generate aseries of macrolactam glycosides.First, hol 4 according to the previously reported proce- amacrolactam analogue of the YC-17 aglycone 10- dure.[20] Mesylationofalcohol 4 followed by success- dml, aza-(10-dml) (AZDM; 1), was chemically syn- ful nucleophilicsubstitution with sodium azide and re- thesized, andanengineered strain of S. venezuelae ductionofthe resultant azide with LiAlH4 afforded with its substrate-flexible glycosyltransferase was em- amine 2.This key amine wassuccessfully coupled ployed to assemble the newcompounds.[7,17] with carboxylicacid 3[16] utilizing EDC to afford 6. The S. venezuelae YJ028 mutant strain[18] in which Theprimary TBS ether was selectively cleaved yield- the entire biosynthetic gene cluster encoding the pik- ing alcohol 7,which in turn was oxidized with DMP romycin (Pik) PKS anddesosamine biosyntheticen- to yield aldehyde 8.Grignard reactionofaldehyde 8 zymes were deleted was chosen as the biotransforma- with vinylmagnesium bromidefollowed by DMPoxi- tion host, and different deoxy sugar
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