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We describe the synthesis of 6-phosphonic acid 4 (TMP), 6-(methylene)phosphonic acid 5 (TEP), and 6-((TPP most strongly, with TMP (IC50 = 288 32 M) inhibiting most strongly, followed by TNP (IC50 = 421 24 M) and TEP (IC50 = 1959 261 M)
We describe the synthesis of 6-phosphonic acid 4 (TMP), 6-(methylene)phosphonic acid 5 (TEP), and 6-((TPP most strongly, with TMP (IC50 = 288 32 M) inhibiting most strongly, followed by TNP (IC50 = 421 24 M) and TEP (IC50 = 1959 261 M). 1. Routes for the synthesis and recycling of trehalose, as well as its conversion to TMM/TDM in is definitely reduced to trehalose monomycolate (TMM) by CmrA which is definitely transported to the cell wall by MmpL3 (Number 1). The Antigen 85 Complex (Ag85) transfers the mycolic acids to the cell wall arabinogalactan (AG) or to a second molecule of TMM to form trehalose dimycolate (TDM) a key virulence element. Free trehalose produced by the action of Ag85s on TMM is salvaged from the action of the ABC transporter LpqY-SugABC.[6a] It is also known that can enter an antibiotic resistant state under the stress of low oxygen. Intriguingly, trehalose has been linked to the ability of to adapt its rate of metabolism under these conditions. Thus, chemical substances interfering with the various trehalose-producing pathways may present fresh approaches for more effective treatments against TPP while aryl-D-glucopyranoside 6-sulfates were also reported as mimics of T6P with activity against TPP. Based on the activity of these ,-trehalose derivatives against TPP we developed heptabenzyl ,-trehalose derivative 3 and synthetic routes to access 6-phosphonic acid 4 (TMP), 6-(methylene)phosphonic acid 5 (TEP), 6-and TPP. The and TPP homologs were included in this study because of the high sequence identity with the TPP, 72% and 71%, respectively, and the 100% identity in catalytic residues. Additionally, the relative paucity of available TPP structural info suggests protein structural dynamics that hinder crystallization. The and TPP homologs lack two large loops Rabbit Polyclonal to TK (phospho-Ser13) indicated in the TPP sequence and are becoming pursued as TPP surrogates to afford structural dedication of mycobacterial TPP enzymes. Finally, the TPP enzymes with this study show TPP; however, no microbiological evaluation was reported. That data, in addition to the know growth inhibition data of 6-altered derivatives of ,-trehalose against mycobacteria,[14b, 22] prompted us to investigate the synthesis of additional 6-altered derivatives. In the current work we focused on synthesis and study of 6-phosphonate ,-trehalose TMP, an alternate route to 6-(methylene)phosphonate analogue TEP, a 6-TPP inhibitors (Number 2). The prospective 6-phosphonate analog TMP was accessible through a heptabenzyl ,-trehalose intermediate 3[22c] prepared by our reported route.[22d] The route allows gram scale access to unsymmetrical 6-altered ,-trehalose analogues. In order to access 6-phosphonate TMP, heptabenzyl ,-trehalose derivative 3 was converted to the 6-iodo-6-deoxy-,-trehalose derivative 9 in 70% yield by treatment with triphenylphosphine in the presence of iodine and imidazole (Plan 1). Iodide 9 was subjected to PF-06447475 MichaelisCArbuzov conditions by treatment with trimethyl phosphite to afford 6-phosphonate derivative 10 in 58% yield. The phosphonate ester 10 was deprotected with bromotrimethylsilane (TMSBr) to afford the 6-phosphonic acid derivative 11. The second option was debenzylated by hydrogenolysis with 20% Pd(OH)2 on carbon under 1 atm. of H2 to afford 6-phosphonate TMP. Open in a separate window Plan 1. Synthesis of 6-phosphonic acid-,-trehalose derivative TMP. The prospective 6-(methylene)phosphonic acid analog TEP was also accessible through intermediate 3. Intermediate 3 was first subjected to a Swern oxidation to PF-06447475 afford aldehyde 12 in 62% yield (Plan 2). Aldehyde 12 was converted to the phosphonate 13 in 49% yield via a HornerCWadsworthCEmmons reaction utilizing tetramethyl methylenediphosphonate and sodium hydride. The phosphonate ester 13 was deprotected with bromotrimethylsilane (TMSBr) to afford the 6-(vinylphosphonic acid) derivative 14. The second option was debenzylated by hydrogenolysis with 20% Pd(OH)2 on carbon under 1 atm. of H2 to afford 6-(methylene)phosphonic acid TEP. The route is a minor changes of reported work which used tetraethyl methylenediphosphonate in the HornerCWadsworthCEmmons PF-06447475 reaction along with other modifications in reagents and reaction sequence. Open in a separate window Plan 2. Synthesis of 6-(methylenephosphonic acid)-,-trehalose derivative TEP. The prospective.