Over eighty iV-alkyl vancomycins were synthesized by reductive alkylation of vancomycin with the appropriate aldehydes. The 7V-alkyl vancomycins exhibit greater antibacterial activity than the corresponding iV-acyl vancomycins and the parent antibiotic.Some of these semisynthetic vancomycins are five times more active than vancomycin. The AT-alkyl vancomycins also show longer elimination half-lives in rats than vancomycin.For the past 30 years, vancomycin has been the drug of choice to treat severe Gram-positive infections caused by methicillin-resistant Staphylococcus aureus. Recent reports have described glycopeptides with acylamido side chains on a sugar residue,2~6) and some of these compounds, e.g. teicoplanin, have been claimed to have more favorable antibacterial and pharmacokinetic properties than vancomycin.70 Synthesis of several iV-acyl vancomycins and structure activity relationship studies revealed no substantial advantage of these iV-acyl vancomycins over the parent antibiotic.8) As an extension to the structure-activity relationship (SAR) of the iV-acyl vancomycin research, we undertook the synthesis and evaluation of iV-alkyl vancomycins. ChemistryThe AT-alkyl vancomycins were obtained by reductive alkylation of vancomycin with the appropriate aldehydes. This reaction could yield two mono-7V-alkyl derivatives substituted at the amino groups of vancosamine sugar and iV-methyl leucine residue, respectively, and one di-N-alkyl vancomycin. The reaction products were monitored by analytical HPLC. Not all reactions produced all the three possible products. However, if all three iV-alkyl vancomycins were available in a series, the retention times of the iV-alkyl vancomycins were diagnostic of the site of alkylation as previously observed for the iV-acyl derivatives.50 The mono-iV-alkyl derivative substituted on vancosamine eluted first, then the second mono-iV-alkyl vancomycin functionalized on JV-methyl leucine, and finally the di-iV-alkyl vancomycin (see Table 1).The ratio of the three 7V-alkyl vancomycins from the reductive alkylation reaction depended on the reaction conditions which could be adjusted to yield the desired iV-alkyl derivative as the major product. The reaction mixture was purified by preparative HPLC.The structures of the iV-alkyl vancomycins were confirmed by fast atom bombardment mass spectrometry (FAB-MS). The molecular ion indicates if the derivatives is a mono-or di-iV-alkyl vancomycin. The fragmentation pattern of the mono-7V-alkyl derivative clearly establishes the site of substitution between the two alternative amino groups in vancomycin. Thus, the mono-iV-alkyl vancomycin alkylated on the JV-methyl leucine affords the disaccharide, vancosaminyl-O-glucose and vanf Seerefl.
Gram-positive bacteria resistant to vancomycin are rare; but they include members of the genera Leuconostoc, Lactobacillus, and Pediococcus, as well as recently emerging vancomycin-resistant strains of Enterococcus faecium and Enterococcus faecalis. Vancomycin, teicoplanin, and several vancomycin derivatives were tested for their activities against vancomycin-resistant gram-positive bacteria. Vancomycin-resistant E. faecium and E. faecalis were generally cross-resistant to other glycopeptides, but some N-substituted vancomycin derivatives were active against the resistant strains, with MICs of 2 to 32 micrograms/ml. These vancomycin derivatives also had significant levels of activity against intrinsically vancomycin-resistant organisms such as Leuconostoc sp. While vancomycin resistance in E. faecium and E. faecalis was inducible, resistance in members of the genera Leuconostoc, Lactobacillus, and Pediococcus appeared to be expressed constitutively. Antibody to a vancomycin-induced membrane protein found in membranes of resistant enterococci did not detect a cross-reacting protein in other vancomycin-resistant species.
Several glycopeptides containing N-acyl groups have been isolated recently. We undertook the synthesis of Ar-acyl vancomycins, using the active ester method. The in vitro and in vivo antibacterial activity were evaluated, and structure-activity relationship of this series of semisynthetic vancomycins is discussed.Vancomycin is produced by Amycolatopsis orientalist (previously designated Nocardia orientalis and Streptomyces orientalis). The antibiotic has been marketed for the past 30 years and continues to be marketed as the hydrochloride salt to treat deep-seated Gram-positive infections. It is the drug of choice for Staphylococcus aureus strains especially those resistant to methicillin (MRSA). Vancomycin is bactericidal to most Gram-positive organisms, but Gram-negative organisms are resistant. Cross resistance with other antibiotics is unknownand there have been few, if any, reports of the emergence of resistant organisms2) during therapy, in spite of its long usage. Vancomycin is not absorbed from the gastrointestinal tract, and the antibiotic is used to treat enterocolitis caused especially by Clostridium difficile in the gut.Several glycopeptides containing a long chain aliphatic acyl residue on one of the amino sugars have been reported3~7). Someof these compounds have been claimed to be superior in antibacterial activity and pharmacokinetics to vancomycin. These glycopeptide antibiotics contain seven aromatic rings and belong to the ristocetin class of glycopeptide antibiotics. Vancomycincontains five aromatic rings and is structurally unique in having JV-methyl leucine as the TV-terminal residue. However, the recently discovered orienticins also contain a iV-methyl leucine as the N-terminal amino acid8). Until nowno iV-acyl vancomycins have been reported. In this paper we report the synthesis and antibacterial activity of this new class of semisynthetic iV-acyl vancomycins. ChemistrySeveral methods are available for the synthesis of iV-acyl vancomycins. Wechose the reaction of vancomycin base with the 2,4,5-trichlorophenyl active ester due to the versatility of the reaction and its mild reaction conditions. Twomono-iV-acyl derivatives substituted at the amino groups of the vancosamine and iV-methyl leucine moieties, respectively, and one di-7V-acyl derivative were obtained. The ratio of these three iV-acyl vancomycins obtained depended on the reaction conditions. These semi-synthetic vancomycins were purified by preparative HPLC.The HPLCretention time of these iV-acyl vancomycins were diagnostic of the site of substitution. Accordingly, the mono-iV-substituted vancomycin on the sugar eluted first, followed by the mono-iVf The SARof 7V-acyl vancomycins were presented at the 26th Intersci. Conf. on Antimicrob. Agents Chemother., Sept. 26-Oct. 1, 1986, New Orleans, LA., U.S.A., abstract No. 224.
Reaction of vancomycin and related antibiotics with trifluoroacetic acid at -15°C for 40 h selectively cleaved the amino sugar vancosamine; the second sugar, glucose, was removed b y reaction with trifluoroacetic acid at 50°C for 3 h, and the N-terminal leucine moiety was cleaved using the Edman degradation procedure.
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