Solid- and Solution-Phase Synthesis of Vancomycin and Vancomycin Analogues with Activity against Vancomycin-Resistant Bacteria

Abstract

Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries. Biological evaluation of these compound libraries led to the identification of a number of in vitro highly potent antibacterial agents effective against vancomycin-resistant bacteria. In addition to aiding these investigations, the solid-phase chemistry described herein is expected to enhance the power of combinatorial chemistry and facilitate chemical biology and medicinal chemistry studies.

Synthesis and Biological Evaluation of Vancomycin Dimers with Potent Activity against Vancomycin-Resistant Bacteria: Target-Accelerated Combinatorial Synthesis

“…As depicted in Scheme 1, saponification of the vancomycin-derived thioacetates (2, prepared as described in the preceding article) [3] with NaOH (10.0 equiv) in H 2 O at 238C proceeded smoothly to give, after spontaneous aerial oxidation, disulfides 3. Special care was necessary in this procedure in order to balance the increased rate of reaction under basic conditions with the decomposition which appeared to take place at high pH.…”

“…Thus, as shown in Scheme 2, vancomycin-derived thioacetate 2 a was converted, in 80 % yield, to the mixed disulfide 4 by the action of NaOMe and pyS-Spy in MeOH. Treatment of a 1:1 mixture of this mixed disulfide 4 and a binding pocket modified thioacetate (5, R various amino acid residues, see Table 4) synthesized as previously described [3] with NaOMe in MeOH gave smoothly, and in 65 ± 90 % yield, the desired heterodimers 6. The latter compounds 6 were screened against a panel of vancomycin-resistant bacteria revealing a number of interesting data (Table 4).…”

“…[3] General procedure for the conversion of thioacetates 2 to disulfides 3 (Scheme 1): A solution of thioacetate 2 (10 mg, % 6.2 mmol) in water (1.0 mL) was treated with NaOH (2.5 mg, 10.0 equiv, 62.5 mmol) and stirred for 24 ± 48 h at ambient temperature. Purification by reverse-phase HPLC (VYDAC C18, 25 mm  250 mm, flow rate 6.5 mL min À1 , 0 3 100 % CH 3 CN (0.05 % TFA) in H 2 O (0.05 % TFA) over 30 min) provided the desired disulfide 3 in yields ranging from 50 ± 90 % (analytical HPLC given below for LiChrospher C18, 6 mm  250 mm, flow rate 1.0 mL min À1 , 0 3 100 % CH 3 CN (0.05 % TFA) in H 2 O (0.05 % TFA) over the time indicated).…”

“…[1] In particular, the rise of bacterial resistance to vancomycin (1, Figure 1), the drug of last resort for the treatment of many Gram-positive infections, has spurred vigorous research activities into discovering new classes of antibacterial agents, as well as toward modifying existing types of antibiotics [2] in order to check the latest bacterial moves. In the preceding paper [3] we described the synthesis and biological evaluation of a series of monomeric vancomycin derivatives, some of which exhibited good to excellent activity against vancomycin-intermediate susceptible Staphylococcus aureus (VISA) and vancomycin-resistant Enterococci (VRE). In this article we describe the synthesis and biological evaluation of dimeric derivatives of vancomycin (1) by parallel and target-accelerated combinatorial synthesis in a study that led to the identification of a number of highly potent antibiotics effective against vancomycinresistant bacteria.…”

Dynamic Combinatorial Diversity in Drug Discovery

“…Each of them has its own characteristics, advantages and drawbacks. For the construction of DCLs in the presence of a biological target imine, acylhydrazone formation [13,[22][23][24][25][26][27][28][29], disulfide exchange [30][31][32][33], transamidation [34], transthioesterification [35], enzyme-catalyzed aldol reaction [36,37], cross-metathesis [38,39] and boronate transesterification [40] have been reported. The C=N bond formation processes, by condensation of an amino group with carbonyl functionalities, are (besides disulfide exchange) the most important class of DCC reactions and have proven to be efficient when biological systems are targeted.…”