Natural nucleotide antibiotics such as Agrocin 84, Dinoguellin, Microcin C
and Phosmidosine have a N-acylphosphoramidate linkage at the 5’-hydroxyl of the
adenosine derivatives (Fig. 1, 2) [1–3]. They exhibit interesting antifungal, antiemetics
and anticancer properties. To synthesize these products, the construction
of the N-acylphosphoramidate linkages seems to be a key step. Many groups have
described the preparation of such a type of analogues but none of those methods
was general. Grandas has for the first time reported the synthesis, of N-acylphosphoramidate
peptide-oligonucleotide hybrids via condensation of N-phosphitylated
carboxyamides with alcohols in the presence of 1H-tetrazole [9]. Based on this
strategy Sekine synthesized aminoacyl adenylate (aa-AMP) analogues which could
be useful in the studies on the recognition mechanism of the aminoacylation of
tRNA and other biochemical reactions [10]. Since aa-AMPs are extremely unstable
under aqueous conditions more stable analogues were required. Aminoacyl-adenylate
analogues having an N-acylphosphoramidate linkage (aa-AMPN) could behave
as potent, selective asparagine synthetase (AS) inhibitors because of its structural
similarity to β-aspartyl-AMP (β AspAMP) which is natural product of AS [17].
Among natural N-acylphosphormiadates, Phosmidosine which connects
a nucleoside analogue, 8-oxoadenosine, with an L-proline residue is unique because
of its significant antitumor activities and property of stopping cell growth at the G1
phase in the cell cycle (Fig. 2) [2, 13]. The main difficulty during the synthesis of
this compound is an extreme instability under weak basic conditions which excludes
the use of labile protecting group of basic properties [14]. Stability studies have
shown that under basic conditions phosphoryl group of Phosmidosine underwent
rapid N–N migration (Scheme 9) [16]. Many modifications have been introduced
to improve Phosmidosine properties [16]. Analogues such as demethylated species
(Phosmidosine B) have proven to be stable under both basic and acid conditions
and are also potential candidates for antitumor drugs [14].
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