Surface properties of new virginiamycin M1 derivatives

Abstract

a b s t r a c tThree kinds of derivatives of the M 1 factor of virginiamycin have been synthesised: esters with long chain fatty acids, oximes with modified polar amino acids and bis-derivatives with both the ester and oxime function. The study of the surface tension time dependence of M 1 and its derivatives has shown that it is necessary to enhance simultaneously the hydrophobicity and the hydrophilicity of M 1 to render M 1 surface-active. A structure/function relationship study of the surface-active bis-derivatives has shown that enhancing the hydrophobicity of the molecule led to slower adsorption kinetics, higher stability of the monolayers formed and a better capacity to penetrate a membrane model. The repulsive electrostatic forces due to the presence of charges on the amino acids linked to M 1 lead to higher surface tensions, a greater molecular area at the interface and lower penetration into a membrane model. This study has demonstrated that modifying systematically the hydrophobicity and hydrophilicity of a non surface-active molecule allows the production of surface-active derivatives.

Total Synthesis of (−)‐Virginiamycin M2

“…The realization that natural and synthetic derivatives of virginiamycins have displayed potent antibiotic activity against methicillin-, erythromycin-, and vancomycin-resistant S.aureus, [1] by inhibiting protein synthesis through synergistic binding of weak ribsome binders, has resulted in an active research area in both academia and industry. [2,3] These efforts resulted in the development of Synercid (Figure 1), a mixture of dalfopristin (type A) and quinupristin (type B), which was approved in the United States for the treatment of severe Gram-positive bacterial infections a little over a decade ago.[4] However, production of dalfopristin-like compounds by semisynthesis has been hampered by their sensitive functionalities and pH instability.[2] Herein, we report a concise and modular total synthesis of virginiamycin M 2 , a typical member of virginiamycin group A compounds originally isolated by Todd and co-workers. [5] Our strategy for the synthesis of virginiamycin M 2 is illustrated in Scheme 1, where we envisioned formation of the 23-membered macrocycle through a SmI 2 -mediated intramolecular Barbier/Reformatsky-type cyclization [6] from the acyclic framework 2.…”

“…natural and synthetic derivatives of virginiamycins have displayed potent antibiotic activity against methicillin-, erythromycin-, and vancomycin-resistant S.aureus, [1] by inhibiting protein synthesis through synergistic binding of weak ribsome binders, has resulted in an active research area in both academia and industry. [2,3] These efforts resulted in the development of Synercid (Figure 1), a mixture of dalfopristin (type A) and quinupristin (type B), which was approved in the United States for the treatment of severe Gram-positive bacterial infections a little over a decade ago. [4] However, production of dalfopristin-like compounds by semisynthesis has been hampered by their sensitive functionalities and pH instability.…”

Total Synthesis of (−)‐Virginiamycin M2

“…The realization that natural and synthetic derivatives of virginiamycins have displayed potent antibiotic activity against methicillin-, erythromycin-, and vancomycin-resistant S.aureus, [1] by inhibiting protein synthesis through synergistic binding of weak ribsome binders, has resulted in an active research area in both academia and industry. [2,3] These efforts resulted in the development of Synercid (Figure 1), a mixture of dalfopristin (type A) and quinupristin (type B), which was approved in the United States for the treatment of severe Gram-positive bacterial infections a little over a decade ago. [4] However, production of dalfopristin-like compounds by semisynthesis has been hampered by their sensitive functionalities and pH instability.…”

“…[4] However, production of dalfopristin-like compounds by semisynthesis has been hampered by their sensitive functionalities and pH instability. [2] Herein, we report a concise and modular total synthesis of virginiamycin M 2 , a typical member of virgin-iamycin group A compounds originally isolated by Todd and co-workers. [5] Our strategy for the synthesis of virginiamycin M 2 is illustrated in Scheme 1, where we envisioned formation of the 23-membered macrocycle through a SmI 2 -mediated intramolecular Barbier/Reformatsky-type cyclization [6] from the acyclic framework 2.…”

“…[2,3] These efforts resulted in the development of Synercid (Figure 1), a mixture of dalfopristin (type A) and quinupristin (type B), which was approved in the United States for the treatment of severe Gram-positive bacterial infections a little over a decade ago. [4] However, production of dalfopristin-like compounds by semisynthesis has been hampered by their sensitive functionalities and pH instability.…”