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Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

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ABSTRACT

A series of seventeen β-hydroxyphosphonate ribonucleoside analogues containing 4-substituted-1,2,3-triazoles was synthesized and fully characterized. Such compounds were designed as potential inhibitors of the cytosolic 5’-nucleotidase II (cN-II), an enzyme involved in the regulation of purine nucleotide pools. NMR and molecular modelling studies showed that a few derivatives adopted similar structural features to IMP or GMP. Five derivatives were identified as modest inhibitors with 53 to 64% of cN-II inhibition at 1 mM.

No MeSH data available.


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Comparison of the docking poses obtained for three active derivatives in the substrate binding site of cN-II. Main interactions between derivatives (A) 1h (green stick) or (B) 1i (yellow sticks) or (C) 1j (orange sticks) and cN-II residues (depicted in thin stick representation). (D) Superimposition of the docking poses obtained for derivatives 1n (cyan sticks), 1q (pink sticks), 1h (green stick), 1i (yellow sticks), 1j (orange sticks) in the substrate binding site.
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Figure 8: Comparison of the docking poses obtained for three active derivatives in the substrate binding site of cN-II. Main interactions between derivatives (A) 1h (green stick) or (B) 1i (yellow sticks) or (C) 1j (orange sticks) and cN-II residues (depicted in thin stick representation). (D) Superimposition of the docking poses obtained for derivatives 1n (cyan sticks), 1q (pink sticks), 1h (green stick), 1i (yellow sticks), 1j (orange sticks) in the substrate binding site.

Mentions: We then compared the three analogues bearing an aminophenyl substituent on the triazole ring with all possible orientations (ortho, meta or para) for the amino group (derivatives 1h, 1i and 1j). Interestingly, all of them showed very similar binding poses with respect to the positions of the oxygens linked to the phosphorus atom (strong ionic interactions with the magnesium ion), the ribose moiety (formation of hydrogen bonds between the hydroxy groups and Lys215) and the triazole ring oriented towards the hydrophobic residues Phe157 and His209 (Fig. 8). However, the position of the phenyl group for derivative 1h (amino group in the ortho position) is clearly different than the one of derivatives 1i and 1j (these last being very similar to each other) and the rotation of the phenyl group appears to be dependent on the orientation of the amino group. According to the inhibition results, derivative 1j was less potent than expected (in view of the interaction of the para-amino phenyl with Asn158) and derivative 1h was found to be more active. This last may be explained by the interaction of the ortho-aminophenyl with His352 residue of cN-II as it represents the only difference with the others (Fig. 8). One should note that in comparison to smallest substituents on the triazole ring (compounds 1n, 1o and 1q) in compounds 1h, 1i and 1j the position of the five-membered ring is rotated by 90° (Fig. 8).


Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation
Comparison of the docking poses obtained for three active derivatives in the substrate binding site of cN-II. Main interactions between derivatives (A) 1h (green stick) or (B) 1i (yellow sticks) or (C) 1j (orange sticks) and cN-II residues (depicted in thin stick representation). (D) Superimposition of the docking poses obtained for derivatives 1n (cyan sticks), 1q (pink sticks), 1h (green stick), 1i (yellow sticks), 1j (orange sticks) in the substrate binding site.
© Copyright Policy - Beilstein
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4979751&req=5

Figure 8: Comparison of the docking poses obtained for three active derivatives in the substrate binding site of cN-II. Main interactions between derivatives (A) 1h (green stick) or (B) 1i (yellow sticks) or (C) 1j (orange sticks) and cN-II residues (depicted in thin stick representation). (D) Superimposition of the docking poses obtained for derivatives 1n (cyan sticks), 1q (pink sticks), 1h (green stick), 1i (yellow sticks), 1j (orange sticks) in the substrate binding site.
Mentions: We then compared the three analogues bearing an aminophenyl substituent on the triazole ring with all possible orientations (ortho, meta or para) for the amino group (derivatives 1h, 1i and 1j). Interestingly, all of them showed very similar binding poses with respect to the positions of the oxygens linked to the phosphorus atom (strong ionic interactions with the magnesium ion), the ribose moiety (formation of hydrogen bonds between the hydroxy groups and Lys215) and the triazole ring oriented towards the hydrophobic residues Phe157 and His209 (Fig. 8). However, the position of the phenyl group for derivative 1h (amino group in the ortho position) is clearly different than the one of derivatives 1i and 1j (these last being very similar to each other) and the rotation of the phenyl group appears to be dependent on the orientation of the amino group. According to the inhibition results, derivative 1j was less potent than expected (in view of the interaction of the para-amino phenyl with Asn158) and derivative 1h was found to be more active. This last may be explained by the interaction of the ortho-aminophenyl with His352 residue of cN-II as it represents the only difference with the others (Fig. 8). One should note that in comparison to smallest substituents on the triazole ring (compounds 1n, 1o and 1q) in compounds 1h, 1i and 1j the position of the five-membered ring is rotated by 90° (Fig. 8).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

A series of seventeen β-hydroxyphosphonate ribonucleoside analogues containing 4-substituted-1,2,3-triazoles was synthesized and fully characterized. Such compounds were designed as potential inhibitors of the cytosolic 5’-nucleotidase II (cN-II), an enzyme involved in the regulation of purine nucleotide pools. NMR and molecular modelling studies showed that a few derivatives adopted similar structural features to IMP or GMP. Five derivatives were identified as modest inhibitors with 53 to 64% of cN-II inhibition at 1 mM.

No MeSH data available.


Related in: MedlinePlus