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. 2025 Feb 28;15(3):351.
doi: 10.3390/biom15030351.

Synthesis, Antiproliferative Activity, and ADME Profiling of Novel Racemic and Optically Pure Aryl-Substituted Purines and Purine Bioisosteres

Martina Piškor  1 , Astrid Milić  2 , Sanja Koštrun  2 , Maja Majerić Elenkov  3 , Petra Grbčić  4 , Sandra Kraljević Pavelić  5 , Krešimir Pavelić  4 , Silvana Raić-Malić  1
Affiliations

Synthesis, Antiproliferative Activity, and ADME Profiling of Novel Racemic and Optically Pure Aryl-Substituted Purines and Purine Bioisosteres

Martina Piškor et al. Biomolecules. .

Abstract

The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded R- and S-enantiomers of purine and pyrrolo[2,3-d]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a N-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine 40a and pyrrolo[2,3-d]pyrimidine 45a derivatives with p-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound 45a exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability.

Keywords: ADME profiling; antiproliferative activity; purine; purine bioisosteres.

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Conflict of interest statement

Although the authors Sanja Koštrun and Astrid Milić are employees of Selvita d.o.o., they declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. The remaining authors also declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Figures

Figure 1
Figure 1
Chiral purine and purine isostere derivatives as antitumor drugs.
Figure 2
Figure 2
Design of novel racemic α- and β-regioisomers and optically pure aryl-substituted purine bioisosteres.
Scheme 1
Scheme 1
Cu(I)-catalyzed synthesis of novel racemic aryl-substituted derivatives of purines and purine isosteres. Reagents and conditions: (i) propargyl bromide, NaH, DMF, r.t., overnight; (ii) NaN3, NH4Cl, MeOH/H2O (8:1), 75 °C, overnight; (iii) NaN3, DMF, r.t, 0.5 h; (iv) NaBH4, MeOH, r.t., 1 h; and (v) Cu(OAc)2, MeOH, 2 h, under ultrasound irradiation.
Scheme 2
Scheme 2
Cu(I)-catalyzed synthesis of novel optically enriched (R)- and (S)-aryl-substituted derivatives of 6-chloropurine and 4-chloropyrrolo[2,3-d]pyrimidine. Reagents and conditions: (i) MeOH, Cu(OAc)2, 2 h, under ultrasound irradiation.
Figure 3
Figure 3
Electrostatic potential calculated from molecular fields for p-bromophenyl-substituted derivatives from explored subseries aligned on the minimum energy conformation of the p-(trifluoromethyl)phenyl-substituted 6-chloropurine 40a.
Figure 4
Figure 4
Conformational analysis of compound 40a: left—conformational distribution, middle—energy histogram of generated conformations, and right—minimum energy conformation.
Figure 5
Figure 5
Graphical presentation of measured ADME parameters.
Figure 6
Figure 6
Insight into structure–antiproliferative activity relationship of the racemic and enantioenriched aryl-substituted N-heterocycles.
See this image and copyright information in PMC

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