Synthesis and Characterization of Partially and Fully Saturated Menaquinone Derivatives

Abstract

Menaquinones (MKs) contain both a redox active quinone moiety and a hydrophobic repeating isoprenyl side chain of varying lengths and degrees of saturation. This characteristic structure allows MKs to play a key role in the respiratory electron transport system of some prokaryotes by shuttling electrons and protons between membrane-bound protein complexes, which act as electron acceptors and donors. Hydrophobic MK molecules with partially and fully saturated isoprenyl side chains are found in a wide range of eubacteria and archaea, and the structural variations of the MK analogues are evolutionarily conserved but poorly understood. For example, Mycobacterium tuberculosis , the causative agent of tuberculosis, uses predominantly MK-9(II-H 2 ) (saturated at the second isoprene unit) as its electron carrier and depends on the synthesis of MK-9(II-H 2 ) for survival in host macrophages. Thus, MKs with partially saturated isoprenyl side chains may represent a novel virulence factor. Naturally occurring longer MKs are very hydrophobic, whereas MK analogues that have a truncated (i.e., one to three isoprenes) isoprenyl side chain are less hydrophobic. This improves their solubility in aqueous solutions, allowing rigorous study of their structure and biological activity. We present the synthesis and characterization of two partially saturated MK analogues, MK-2(II-H 2 ) and MK-3(II-H 2 ), and two novel fully saturated MK derivatives, MK-2(I,II-H 4 ) and MK-3(I,II,III-H 6 ).

Allosteric regulation of menaquinone (vitamin K2) biosynthesis in the human pathogen Mycobacterium tuberculosis

“…MK-1 was obtained from Santa Cruz Biotechnology, Inc. (Dallas, TX). MK-2, MK-2 H2, and MK-3 were kindly provided by Prof. Debbie Crans (Colorado State University) as characterized previously (51). SHCHC was produced enzymatically using MenH and used as a crude mixture after removal of the enzyme.…”

Synthesis of Naphthoquinone Derivatives: Menaquinones, Lipoquinones and Other Vitamin K Derivatives

“…Recently, we synthesized fully and partially saturated MK-derivatives in an effort to understand their structural and electrochemical properties in model membranes [ 12 , 37 , 38 ]. For the synthesis of MK-2(II-H 2 ), the condensation of isophytol 22 and menadiol 2 was accomplished in 11% yield using MgF 2 -48, a Coman et al inspired catalyst ( Scheme 11 ).…”

“…In 2019, we continued our pursuit to synthesize menaquinone analogs with various levels of saturation within the side chain [ 38 ]. For analogs with the first isoprene unit saturated, we employed chemistry developed by Coppa et al in 1991.…”

“…Despite the polarity of the quinone group, these molecules are very hydrophobic, even though this property does vary with the length and the nature of the isoprene side group. We have recently found by synthesis of truncated MK-derivatives that only MK-1, MK-2, and MK-3, including derivatives with fully or partially saturated counterparts, are soluble in aqueous solution [ 12 , 37 , 38 ]. This means that assays with MK-4, even though it is known as an enzyme substrate in vivo , may not demonstrate enzyme activity even if the aqueous assay includes surfactants [ 39 ].…”

“…Contemplating the many synthetic strategies available, consideration of the structure and the application of the MK-derivatives may be important when choosing the appropriate method for synthesis. So far, our group has focused on the preparation of truncated MK-derivatives, where the syntheses are relatively short and direct [ 12 , 37 , 38 ]. Therein, we used Friedel-Crafts alkylation using BF 3 ∙OEt 2 as a Lewis acid catalyst.…”