Synthesis of Mixed Dinucleotides by Mechanochemistry

Abstract

We report the synthesis of vitamin B1, B2, and B3 derived nucleotides and dinucleotides generated either through mechanochemical or solution phase chemistry. Under the explored conditions, adenosine and thiamine proved to be particularly amenable to milling conditions. Following optimization of the chemistry related to the formation pyrophosphate bonds, mixed dinucleotides of adenine and thiamine (vitamin B1), riboflavin (vitamin B2), nicotinamide riboside and 3-carboxamide 4-pyridone riboside (both vitamin B3 derivatives) were generated in good yields. Furthermore, we report an efficient synthesis of the MW+4 isotopologue of NAD+ for which deuterium incorporation is present on either side of the dinucleotidic linkage, poised for isotopic tracing experiments by mass spectrometry. Many of these mixed species are novel and present unexplored possibilities to simultaneously enhance or modulate cofactor transporters and enzymes of independent biosynthetic pathways.

Synthesis, Detection, and Metabolism of Pyridone Ribosides, Products of NAD Overoxidation

“…We recently reported the synthesis of each isomer of the pyridone riboside series (e.g., 2-PYR, 4-PYR, and 6-PYR) . We also reported the synthesis of 4-ox-NAD from 4-PYR-monophosphate enabled by mechanochemistry, whereby we sought a versatile approach to dinucleotide synthesis via pyrophosphate bond formation . However, this chemistry is cumbersome as homodimers formed readily and required extensive purification for their removal.…”

Spiers Memorial Lecture: Mechanochemistry, tribochemistry, mechanical alloying – retrospect, achievements and challenges

“…A large variety of reactions have been documented, which are highly selective, which have yields approaching 100%, or that are ecologically friendly and economically acceptable. 19–24,27,29–43 To date, a few examples of inorganic and organic reactions have been scaled up to levels suitable for practical applications. 9,15,39,43,122,123,131–140…”

“…Mechanical treatment can result in decomposition, 7,9,11,17,19,50,111,112 or synthesis of inorganic or organic compounds. 12,17,20–24,27,29–42,78,113,116–119,141–143 Quite often these compounds can be obtained as metastable polymorphs, 144 mesophases, quasicrystals, 145 or in amorphous states. 94,96,97,146 Mechanochemical processes can be used, in order to prepare product particles not only with target composition and structure, but also with a desirable shape, e.g .…”

“…5–18 “Dry”, or liquid assisted mechanochemical organic synthesis by ball milling, grinding, extrusion, or resonant acoustic mixing (RAM) is becoming increasingly popular. 19–43 Based on what is observed today, it can be expected that more inorganic and organic syntheses will be soon conducted mechanochemically at the industrial level, alongside – and perhaps instead of – the long-standing “classical” solution thermal synthesis. However, scaling up practically relevant syntheses requires the community to achieve a better understanding of the processes that take place in a mechanoreactor during and after mechanical action.…”

Defining NAD(P)(H) Catabolism

“…This mechanism is supported by the fact that NQO2 can generate superoxide [123], that can react with the pyridium ring of NR + . One can consider that NQO1, a component of complex I, might facilitate NAD + over-oxidation (4-ox-NAD [124], Although PYR derivatives in bio-specimens have been quantified for more than 40 years, their origin remains mostly speculative. A biochemical relationship between the methylated (N-Me-PYs) and ribosylated (PYRs) forms of the pyridone species has been proposed but has yet to be identified.…”