Tripodale, „supergeladene” Analoga von Adenosinnucleotiden: Inhibitoren des Fhit-Proteins, einer Ap3A-Hydrolase

Abstract

Methantrisphosphonsäuren bieten eine Verzweigungsstelle für synthetische Nucleotidanaloga, die entweder zu neuartigen tripodalen Nucleotiden führen oder zum Einbau zusätzlicher negativer Ladung in lineare Analoga eines Stammnucleotids genutzt werden können (im Bild ist dies für ATP und Diadenosintetraphosphat (Ap4A) gezeigt). Diese Verbindungen sollten von großem Nutzen sein, da sie als kompetitive Inhibitoren deutlich zwischen dem Tumorsuppressorprotein Fhit und einer anderen ApnA‐Pyrophosphohydrolase unterscheiden. X = H, Cl, F.

Methylidynetrisphosphonates: Promising C1 building block for the design of phosphate mimetics

“…In a fascinating series of publications, Blackburn and co-workers have realized the synthesis of “supercharged” mimics of pyrophosphoric acid capable of introducing additional anionic charge relative to simple methylenebisphosphonates when built into ATP and Ap n A analogues [7–8 27,44]. They demonstrated that methylidynetrisphosphonic acid and especially its halogenated derivatives are key structure blocks in the synthesis of the nucleotide analogues with enhanced affinity for receptors and better charge correlation with transition states for selected kinases.…”

“…The incorporation of the third adenylate moiety was found to be extremely slow; however, the use of tetrazole as catalyst allowed the preparation of P 1 , P 2 , P 3 -tris(5'-adenylyl)methylidynetrisphosphonate 48 and the tripodal P 1 -5'-adenosyl P 2 , P 3 -bis(5'-adenylyl)methylidynetrisphosphonate 49 in good yields. Compounds 48 and 49 provide the first examples of species in which three adenylate moieties are linked together by a methylidynetrisphosphonate core (Scheme 24) [8]. …”

“…By contrast, the adenylated polyphosphonates AdoPPCCl(P)PPAdo ( 47 ) and (AdoPP) 3 CH ( 48 ) strongly and competitively inhibit Fhit while they are less effective as inhibitors of the lupine enzyme. Since the detection of levels of Fhit protein is an important problem relating to cancers, Fhit-selective inhibitors such as 47 and 48 can be valuable as Fhit diagnostics [8]. …”

“…Moreover, examples of the reactivity of functionalized methylidynetrisphosphonates XC(PO 3 R 2 ) 3 shown in this review indicate that the nature of the substituent X at the central carbon atom is the key to the optimization of their acidic and coordination properties thus providing excellent possibilities for the design of effective phosphate mimetics. Especially successful so far seem to be approaches for the synthesis of trisphosphonate-modified nucleotides and nucleosides, which represent a promising class of potential drugs [8]. …”