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

Piškor, Martina; Milić, Astrid; Koštrun, Sanja; Majerić Elenkov, Maja; Grbčić, Petra; Kraljević Pavelić, Sandra; Pavelić, Krešimir; Raić-Malić, Silvana (2025) Synthesis, Antiproliferative Activity, and ADME Profiling of Novel Racemic and Optically Pure Aryl-Substituted Purines and Purine Bioisosteres. Biomolecules, 15 (3). ISSN 2218-273X

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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.

Item Type:	Article
Uncontrolled Keywords:	purine; purine bioisosteres; antiproliferative activity; ADME profiling
Subjects:	NATURAL SCIENCES > Chemistry
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Novel N-heterocycles and their metal complexes with anticancer and antitrypanosomal activity Silvana Raić-Malić IP-2022-10-9420 HRZZ
Depositing User:	Lorena Palameta
Date Deposited:	27 Mar 2025 10:44
URI:	http://fulir.irb.hr/id/eprint/9674
DOI:	10.3390/biom15030351

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