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Synthesis and Biological Investigation of New 400-Malonyl Tethered Derivatives of Erythromycin and Clarithromycin Daniel Sherman,A Liqun Xiong,B Alexander S

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Synthesis and Biological Investigation of New 400-Malonyl Tethered Derivatives of Erythromycin and Clarithromycin Daniel Sherman,A Liqun Xiong,B Alexander S Bioorganic & Medicinal Chemistry Letters 16 (2006) 1506–1509 Synthesis and biological investigation of new 400-malonyl tethered derivatives of erythromycin and clarithromycin Daniel Sherman,a Liqun Xiong,b Alexander S. Mankinb and Artem Melmana,* aDepartment of Organic Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel bCenter for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607, USA Received 25 August 2005; accepted 12 December 2005 Available online 4 January 2006 Abstract—A new approach to 400-substituted derivatives of erythromycin and clarithromycin was developed by converting them into corresponding 400-malonic monoesters. Subsequent carbodiimide coupling with alcohols and amines provided new macrolide deriv- atives that are capable of binding to 50S ribosomal subunits and inhibiting protein synthesis in cell-free system. Ó 2005 Elsevier Ltd. All rights reserved. Erythromycin 1a and other macrolide antibiotics X 1 OR (Scheme 1) have been used for the treatment of a variety R 2 of bacterial infections for the past 50 years. Low toxicity R HO NMe2 O 2' and cost as well as low incidence of side effects resulted 3 O R4 O in extensive use of erythromycin both for treatment of O R3 infections and prophylactic purposes.1 The active use 1a R=H, R1=R2=OH, R3=H, R4= cladinose, X= C=O of the drug resulted in a wide spread of macrolide resis- 1b R=Me, R1=R2=OH, R3=H, R4= cladinose, X= C=O tance in a number of pathogenic strains. As an example, 1 2 3 4 1c R=H, R =R =OH, R =H, R = cladinose, X= N(Me)CH2 in Asia the majority (up to 80% in Hong Kong) of Strep- 1 2 3 4 tococcus pneumoniae strains carry resistance to macro- 1d R=H, R =R =OH, R =H, R = cladinose, 2 X= C=NOCH2OCH2CH2OMe lide antibiotics. Attempts to improve relatively poor 1 2 bioavailability of erythromycin, increase its spectrum 1e R=Me, R ,R = -OC(O)N(CH2)3 N 3 -Pyridyl, R3, R4=O, X= C=O N of activity, and overcome bacterial resistance resulted 1 2 1f R=CH2CH=CH-3-Quinolinyl, R ,R = -OC(O)NH- , in synthesis and investigation of a number of semisyn- 3 4 thetic macrolide derivatives such as clarithromycin 1b, R , R =O, X= C=O azithromycin 1c, and roxithromycin 1d. The most recent Scheme 1. Erythromycin and semisynthetic macrolide antibiotics. generation of macrolide antibiotics, such as telithromy- cin (KETEKÒ) 1e and ABT-773 1f,3 possesses enhanced growth.4a–i X-ray structures showed that desosamine su- biological activity; however, their synthesis is much gar at position 5 of the macrolide lactone ring provides more complicated. very important contribution to the overall binding ener- gy of the drug.4a,i,5 Indeed, acylation of 2 -hydroxy All macrolide antibiotics share a similar mechanism of 0 group of desosamine drastically decreases antibacterial action which involves selective binding to the 50S sub- activity.6 Newer macrolide derivatives such as telithro- unit of bacterial ribosome resulting in inhibition of pro- mycin, ABT-733 or bridged ketolides possess additional tein synthesis. Genetic, biochemical, and more recent heterocyclic arm which is most likely responsible for crystallographic studies of ribosome–macrolide com- their enhanced antibacterial activity.3 plexes have indicated that macrolides bind in nascent peptide exit tunnel thus blocking polypeptide chain The extent of involvement of the cladinose sugar in ribo- some binding is less clear. While a simple removal of the Keywords: Macrolides; Ribosome; Antibiotics; Tethering. cladinose moiety was found to substantially decrease the 7 * Corresponding author. Tel.: +97226585279; fax: +97226585345; activity of erythromycin, a number of highly active e-mail: [email protected] macrolide derivatives, such as acylides8 and ketolides,9 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.12.033 D. Sherman et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1506–1509 1507 do not contain cladinose. There were relatively few our synthetic approach to 400-tethered macrolide deriva- attempts to modify cladinose residues to increase the tives of type 5 (Scheme 2) involved the use of one bioavailability or activity of erythromycin. Attempts to common intermediate of type 4. introduce simple alkanoyl6,10 and polyunsaturated alke- 11 noyl substituents into 400 position of erythromycin In line with this approach, 20-acetyl erythromycin 2a involved either diacylation at 20 and 400 positions fol- was prepared by a treatment of 1a with acetic anhydride lowed by a selective hydrolysis, or selective formylation in the absence of acylation catalysts.16 No acylation of of 20-position followed by the acylation of 400-position other hydroxyl groups was detected even in the presence 6 and selective hydrolysis of 20 formyl group. Resultant of a large excess of acetic anhydride. This is possible due 10 12 compounds exhibited lower or substantially lower to the vicinity of NMe2 group in desosamine residue than erythromycin antibacterial activity,13 most proba- which substantially increases rates of both introduction 6 bly due to decreased bioavailability. High nucleotide and removal of 20-acyl group. In contrast, acylation of content of ribosome gives rise to a number of possible 1a with an excess of acetic anhydride in the presence of interactions such as hydrogen bonding, p-stacking as DMAP yielded a complex mixture in which products well as electrostatic interactions. Erythromycin and possessing one to four acetyl groups were detected by clarithromycin derivatives carrying cladinose sugar ESI-MS. Compound 2a was then acylated by DCC cou- modified with functional groups capable of such types pling through non-symmetric malonate method15,17 of interaction have a potential to exhibit increased affin- using tert-butyldiphenylsilyl and benzyl malonates. ity toward ribosomes including mutant ribosomes of The reaction of 20-acetyl erythromycin 2a with tert- resistant bacteria. Indeed, Fernandes and co-authors butyldiphenylsilyl malonate and DCC was found to demonstrated substantial enhancing of antibacterial provide a mixture of starting material, mono-, and dia- activity through alteration of 400-position of erythromy- cylation products. In contrast, acylation of 2a with cin oxime derivatives with heteroatom-functionalized benzyl malonate/DCC system proceeded smoothly to side chains.14 This type of derivatization, however, is give benzyl ester 3b without diacylation. Reasons for relatively difficult and laborious to perform by previous- such a different reactivity are not clear since tert-butyldi- ly described methods.6 phenylsilyl malonate was found to be less reactive than benzyl malonate in acylation of other sterically hindered We recently reported on a new one-pot method for teth- alcohols. The structure of 3b was verified by the ering of organic molecules through the formation of ESI MS–MS technique. Fragmentation of MH+ of 3a 15 + non-symmetric malonate derivatives. This method en- produced MH -cladinose-C(O)CH2CO2Bn cations. No ables efficient binding of alcohols and amines under very traces of MH+-cladinose ions that would indicate the mild conditions in the absence of acylation catalysts. presence of isomers other than 400-benzylmalonylery- Since malonate linker is biocompatible and reasonably thromycin were observed. stable, we were attracted by the possibility to derivatize cladinose sugar of macrolide antibiotics by introducing We initially planned to remove the 20-acyl group by functional groups that could influence binding of the methanolysis of ester 3b. However, there was a consider- drug to the ribosome. In contrast to all previous able decrease in the methanolysis rates of malonyl deriv- attempts for selective 400-derivatization of macrolides, ative 3b in comparison to 20-acetyl erythromycin 2a O O O O R1 O R1 HO OR HO OR HO OR 1a a OH O NMe2 b OH O NMe2 c OH HO NMe2 d 1b O O 2' O O 2' O O 2' 3 O 3 O 3 O O O O O O O OMe OMe 2 OMe O O OR O OH 4'' 4'' 4'' OH O O O O O O 2a: R = H, R1= Me 3a: R = H, R1= Me, R2=SiPh tBu 4a: R = H 1 1 2 2 2b: R = H, R = CH2OMe 3b: R = H, R = Me, R =CH2Ph 4b: R = Me 1 1 2 2c: R = Me, R = CH2OMe 3c: R = H, R = CH2OMe, R =CH2Ph 1 2 O 3d: R = Me, R = CH2OMe, R =CH2Ph HO OR OH HO NMe2 O O 2' 3 O O O 3 5a: R = H, XR =OCH2Ph OMe 3 5b: R = CH3, XR =OCH2Ph O 3 4'' O 5c: R = CH3, XR =OCH2C6H4p-OMe 3 3 O XR 5d: R = CH3, XR =OCH2C6H44-N3 3 O 5e: R = H, XR =N(Me)CH2CH2NMe2 1 Scheme 2. Preparation of cladinose tethered derivatives of erythromycin and clarithromycin. Reagents and conditions: (a) (R CO)2O, DCM, rt; 2 3 (b) R OCOCH2CO2H, DCC, rt; (c) MeOH, rt, 24 h, then H2/Pd/MeOH/acetate buffer; (d) HXR , DCC, DCM, rt. 1508 D. Sherman et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1506–1509 which resulted in competing methanolysis of 400-ben- significantly reduced uptake of the compounds 4a,b by zylmalonyl functions thus contaminating the desired the cell reflected in their high MICs. 20-deacetylated product 4a with erythromycin. A num- ber of alternative 20-protecting groups were evaluated. Interaction of several new compounds with the ribo- Acylation of erythromycin with anhydrides of chloro- some was further studied using RNA footprinting tech- 4g acetic and dichloroacetic acids as well as HCO2COMe nique. Ribosomes were complexed with erythromycin failed to provide the desired 20-acylation products. In or telithromycin (as controls) or with one of the newly contrast, reaction with methoxyacetic anhydride pre- synthesized compounds: 4a, 4b or 5e, and rRNA was pared by the treatment of methoxyacetic acid with modified with dimethyl sulfate (DMS).
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