Abstract:Azolylpurines and azolylpurine nucleosides have important medicinal and biological applications. They are used as adenosine receptor agonists and antagonists and also as antivirals. Several compounds of this class exhibit fluorescent properties that can be applied in biological chemistry. This review summarizes and classifies all reported classes of purine‐azole conjugates, strategies for their syntheses, and suggestions of compound classes yet to be synthesized. Synthetic methodologies directed towards purine… Show more
“…To find more efficient synthetic approach to ( S , S )- 13b , we varied the reaction conditions. Unfortunately, we did not observe the product formation neither in aqueous HCl (Liu and Robins 2007 ), nor while using DMF as a solvent (Terrier 2013 ), nor without any solvent (Novosjolova et al 2015 ). Scheme 5 Synthesis of diastereomerically pure compounds ( S , S )- 13a,b and ( S , S )- 12a,b …”
The synthesis of purine conjugates with natural amino acids is one of the promising directions in search for novel therapeutic agents, including antimycobacterial agents. The purpose of this study was to synthesize
N
-(purin-6-yl)dipeptides containing the terminal fragment of (
S
)-glutamic acid. To obtain the target compounds, two synthetic routes were tested. The first of them is based on coupling of
N
-(purin-6-yl)-(
S
)-amino acids to dimethyl (
S
)-glutamate in the presence of carbodiimide coupling agent followed by the removal of ester groups. However, it turned out that this coupling process was accompanied by racemization of the chiral center of
N
-(purin-6-yl)-α-amino acids and in all cases led to mixtures of (
S,S
)- and (
R,S
)-diastereomers (6:4). Individual (
S,S
)-diastereomers were obtained using an alternative approach based on the nucleophilic substitution of chlorine in 6-chloropurine or 2-amino-6-chloropurine with corresponding dipeptides as nucleophiles. The enantiomeric purity of the target compounds was confirmed by chiral HPLC. To test the assumption that racemization of the chiral center of
N
-(purin-6-yl)-α-amino acids occurs with the participation of nitrogen atoms of the imidazole ring via the stage of formation of a chirally labile intermediate, we obtained such structural analogs of
N
-(purin-6-yl)-(
S
)-alanine as
N
-(9-benzylpurin-6-yl)-(
S
)-alanine and
N
-(7-deazapurin-6-yl)-(
S
)-alanine. It was found that coupling of these compounds to dimethyl (
S
)-glutamate was also accompanied by racemization. This indicates that the imidazole fragment does not play a crucial role in this process. When testing the antimycobacterial activity of some of the obtained compounds, conjugates with moderate activity against the laboratory
Mycobacterium tuberculosis
H37Rv strain (MIC 3.1–6.25 μg/mL) were identified.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00726-021-02958-0.
“…To find more efficient synthetic approach to ( S , S )- 13b , we varied the reaction conditions. Unfortunately, we did not observe the product formation neither in aqueous HCl (Liu and Robins 2007 ), nor while using DMF as a solvent (Terrier 2013 ), nor without any solvent (Novosjolova et al 2015 ). Scheme 5 Synthesis of diastereomerically pure compounds ( S , S )- 13a,b and ( S , S )- 12a,b …”
The synthesis of purine conjugates with natural amino acids is one of the promising directions in search for novel therapeutic agents, including antimycobacterial agents. The purpose of this study was to synthesize
N
-(purin-6-yl)dipeptides containing the terminal fragment of (
S
)-glutamic acid. To obtain the target compounds, two synthetic routes were tested. The first of them is based on coupling of
N
-(purin-6-yl)-(
S
)-amino acids to dimethyl (
S
)-glutamate in the presence of carbodiimide coupling agent followed by the removal of ester groups. However, it turned out that this coupling process was accompanied by racemization of the chiral center of
N
-(purin-6-yl)-α-amino acids and in all cases led to mixtures of (
S,S
)- and (
R,S
)-diastereomers (6:4). Individual (
S,S
)-diastereomers were obtained using an alternative approach based on the nucleophilic substitution of chlorine in 6-chloropurine or 2-amino-6-chloropurine with corresponding dipeptides as nucleophiles. The enantiomeric purity of the target compounds was confirmed by chiral HPLC. To test the assumption that racemization of the chiral center of
N
-(purin-6-yl)-α-amino acids occurs with the participation of nitrogen atoms of the imidazole ring via the stage of formation of a chirally labile intermediate, we obtained such structural analogs of
N
-(purin-6-yl)-(
S
)-alanine as
N
-(9-benzylpurin-6-yl)-(
S
)-alanine and
N
-(7-deazapurin-6-yl)-(
S
)-alanine. It was found that coupling of these compounds to dimethyl (
S
)-glutamate was also accompanied by racemization. This indicates that the imidazole fragment does not play a crucial role in this process. When testing the antimycobacterial activity of some of the obtained compounds, conjugates with moderate activity against the laboratory
Mycobacterium tuberculosis
H37Rv strain (MIC 3.1–6.25 μg/mL) were identified.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00726-021-02958-0.
“…On the other hand, azolylpurines are an important compound class that combines two recognized structural motifs of drug design – purines and azoles. Derivatives of this class are known for their activity against Mycobacterium tuberculosis and also as agonists and antagonists of adenosine receptors [ 18 ].…”
A new method for C–N bond transformations into C–P bonds was developed using 1,2,3-triazoles as leaving groups in SNAr–Arbuzov reactions. A series of C6-phosphonated 2-triazolylpurine derivatives was synthesized for the first time, with the isolated yields reaching up to 82% in the C–P-bond-forming event. The SNAr–Arbuzov reaction of 2,6-bistriazolylpurines follows the general regioselectivity pattern of the C6-position being more reactive towards substitution, which was unambiguously proved by X-ray analysis of diethyl (9-heptyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-9H-purin-6-yl)phosphonate.
“…These transformations usually require prolonged time and elevated temperatures to be completed. Among the widely studied 1,2,3-triazolyl nucleoside conjugates [57,58], the synthesis of 2-triazolylpurine derivatives containing a designed substituent at C6 has been little discussed. 6-N-Substituted purines have been the most studied [11,[59][60][61][62], but 6-S- [14,63] or 6-O-analogues are less common [61].…”
Section: Introductionmentioning
confidence: 99%
“…Azolylpurine derivatives are important due to their potential as drug candidates. They can be used as agonists and antagonists of adenosine receptors [ 58 , 64 – 66 ] and against Mycobacterium tuberculosis [ 60 ]. They also show useful fluorescent properties [ 11 , 67 – 69 ] and can be used as metal ion sensors [ 70 ].…”
A new approach was designed for the synthesis of C6-substituted 2-triazolylpurine derivatives. A series of substituted products was obtained in SNAr reactions between 2,6-bistriazolylpurine derivatives and O- and C-nucleophiles under mild conditions. The products were isolated in yields up to 87%. The developed C–O and C–C bond forming reactions clearly show the ability of the 1,2,3-triazolyl ring at the C6 position of purine to act as leaving group.
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