Cancer represents one of the most important and often fatal threats in the human population. Regarding the natural products, the purine scaffold appears in the purine bases in nucleic acids. Purine and its natural derivatives display a number of pharmacological effects. Previous investigations revealed that different compounds bearing the purine scaffold in their molecules belong to a group of potent agents for cancer treatment. Therefore, this review focuses on summarizing recently designed agents for potential cancer treatment bearing the purine scaffold as the key structural motif in the molecules. The reviewed structures clearly show the advantages and disadvantages of different substituents of the key scaffold that affect the final cytotoxic effects of the studied structures. The structure-activity relationship analysis shows a summary of different but potent compounds mentioned in this review and identifies the compounds receiving priority importance due to their high cytotoxicity and exceptional physicochemical characteristics. The effects of metal coordination, the formation of convenient conjugated molecules, and supramolecular self-assembly resulting in the production of biologically active nanovesicles and other nanoassemblies are also demonstrated. The reviewed original studies clearly showed the possible advantages of (a) metal ion coordination, (b) the formation of conjugates, and (c) designing smart and biocompatible nanoassemblies for biological activity in comparison with the characteristics of the parent compounds. This review is based on the most recent articles published in the last two years, 2023-2024, and it represents work with a highly interdisciplinary nature. Even if these original articles are not too numerous within the given period, the investigations published therein have clearly documented the importance of the purine scaffold in pharmacology and in medicinal and supramolecular chemistry.

Institute of Experimental Botany of the Czech Academy of Sciences Isotope Laboratory Vídeňská 1083 CZ 14220 Prague 4 Czech Republic

University of Chemistry and Technology Prague Department of Chemistry of Natural Compounds Technická 5 CZ 16610 Prague 6 Czech Republic

Zobrazit více v PubMed

Saenger W. In Principles of nucleic acid structure; Springer, New York, NY, 1984.

Strauss B. S. Why is DNA double stranded? The discovery of DNA excision repair mechanisms. Genetics 2018, 209, 357–366. 10.1534/genetics.118.300958. PubMed DOI PMC

Wong X. K.; Yeong K. Y. From nucleic acids to drug discovery: Nucleobases as emerging templates for drug candidates. Curr. Med. Chem. 2021, 28, 7076–7121. 10.2174/0929867328666210215113828. PubMed DOI

Das S. K.; Behera B.; Purohit C. S. Scaffolds of purine privilege for biological cytotoxic targets: A review. Pharm. Chem. J. 2023, 57, 777–792. 10.1007/s11094-023-02952-8. DOI

Dar M. O.; Mir R. H.; Mohiuddin R.; Masoodi M. H.; Sofi F. A. Metal complexes of xanthine and its derivatives: Synthesis and biological activity. J. Inorg. Biochem. 2023, 246, 112290.10.1016/j.jinorgbio.2023.112290. PubMed DOI

Chaurasiya A.; Wahan S. K.; Sahu C.; Chawla P. A. An insight into the rational design of recent purine-based scaffolds in targeting various cancer pathways. J. Mol. Struct. 2023, 1274, 134308.10.1016/j.molstruc.2022.134308. DOI

Chaurasiya A.; Sahu C.; Wahan S. K.; Chawla P. A. Targeting cancer through recently developed purine clubbed heterocyclic scaffolds: An overview. J. Mol. Struct. 2023, 1280, 134967.10.1016/j.molstruc.2023.134967. DOI

Bilget Guven E.; Durmaz Sahin I.; Altiparmak D.; Servili B.; Essiz S.; Cetin-Atalay R.; Tuncbilek M. Newly synthesized 6-substituted piperazine/phenyl-9-cyclopentyl containing purine nucleobase analogs act as potent anticancer agents and induce apoptosis via inhibiting Src in hepatocellular carcinoma cells. RSC Med. Chem. 2023, 14, 2658–2676. 10.1039/D3MD00440F. PubMed DOI PMC

Polat M. F.; Sahin I. D.; Atalay R.; Tuncbilek M. Exploration of novel 6,8,9-trisubstituted purine analogues: synthesis, in vitro biological evaluation, and their effect on human cancer cells. Turk. J. Chem. 2024, 48, 108–115. 10.55730/1300-0527.3643. PubMed DOI PMC

Fatih Polat M.; Durmaz Sahin I.; Kul P.; Cetin Atalay R.; Tuncbilek M. Synthesis and cytotoxicity of novel 6,8,9-trisubstituted purine analogs against liver cancer cells. Bioorg. Med. Chem. Lett. 2024, 106, 129775.10.1016/j.bmcl.2024.129775. PubMed DOI

Yun J. I.; Kim H. R.; Park H.; Kim S. K.; Lee J. Small molecule inhibitors of the Hedgehog signaling pathway for the treatment of cancer. Arch. Pharm. Res. 2012, 35, 1317–1333. 10.1007/s12272-012-0801-8. PubMed DOI

Ahadi H.; Emami S. Modification of 7-piperazinylquinolone antibacterials to promising anticancer lead compounds: Synthesis and in vitro studies. Eur. J. Med. Chem. 2020, 187, 111970.10.1016/j.ejmech.2019.111970. PubMed DOI

Tuncbilek M.; Bilget Guven E.; Onder T.; Cetin Atalay R. Synthesis of novel 6-(4-substituted piperazine-1-yl)-9-(β-d-ribofuranosyl)purine derivatives, which lead to senescence-induced cell death in liver cancer cells. J. Med. Chem. 2012, 55, 3058–3065. 10.1021/jm3001532. PubMed DOI

Tuncbilek M.; Kucukdumlu A.ıg.; Guven E. B.; Altiparmak D.; Cetin-Atalay R. Synthesis of novel 6-substituted amino-9-(β-d-ribofuranosyl)purine analogs and their bioactivities on human epithelial cancer cells. Bioorg. Med. Chem. Lett. 2018, 28, 235–239. 10.1016/j.bmcl.2017.12.070. PubMed DOI

Kucukdumlu A.; Tuncbilek M.; Guven E. B.; Atalay R. C. Design, Synthesis and in vitro cytotoxic activity of new 6,9-disubstituted purine analogues. Acta Chim. Slov. 2020, 67, 70–82. 10.17344/acsi.2019.5196. PubMed DOI

Delgado T.; Veselá D.; Dostálová H.; Kryštof V.; Vojáčková V.; Jorda R.; Castro A.; Bertrand J.; Rivera G.; Faundez M.; Strnad M.; Espinosa-Bustos C.; Salas C. O. New inhibitors of Bcr-Abl based on 2,6,9-trisubstituted purine scaffold elicit cytotoxicity in chronic myeloid leukemia-derived cell lines sensitive and resistant to TKIs. Pharmaceutics 2024, 16, 649.10.3390/pharmaceutics16050649. PubMed DOI PMC

Bertrand J.; Dostalova H.; Krystof V.; Jorda R.; Castro A.; Mella J.; Espinosa-Bustos C.; Maria Zarate A.; Salas C. O. New 2,6,9-trisubstituted purine derivatives as Bcr-Abl and Btk inhibitors and as promising agents against leukemia. Bioorg. Chem. 2020, 94, 103361.10.1016/j.bioorg.2019.103361. PubMed DOI

Espinosa-Bustos C.; Bertrand J.; Villegas-Menares A.; Guerrero S.; Di Marcotullio L.; Navacci S.; Schulte G.; Kozielewicz P.; Bloch N.; Villela V.; Paulino M.; Kogan M. J.; Cantero J.; Salas C. O. New smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer. Bioorg. Chem. 2024, 151, 107681.10.1016/j.bioorg.2024.107681. PubMed DOI

Honselmann K. C.; Pross M.; Jung C. M.; Wellner U. F.; Deichmann S.; Keck T.; Bausch D. Regulation mechanisms of the hedgehog pathway in pancreatic cancer: a review. J. Pancreas Online (JOP) 2015, 16 (1), 25–32. 10.6092/1590-8577/2894. PubMed DOI

Espinosa-Bustos C.; Mella J.; Soto-Delgado J.; Salas C. O. State of the art of Smo antagonists for cancer therapy: advances in the target receptor and new ligand structures. Future Med. Chem. 2019, 11, 617–638. 10.4155/fmc-2018-0497. PubMed DOI

Narra S.; Munirathinam N. Synthesis, structure analysis, Hirshfeld surface studies, molecular docking studies against cyclin-dependent kinases (CDKs) of sulfonamide decorated N6-benzyl aminopurines for cancer treatment. Res. Chem. 2024, 8, 101592.10.1016/j.rechem.2024.101592. DOI

Sakakibara H. Cytokinins: activity, biosynthesis, and translocation. Annu. Rev. Plant Biol. 2006, 57, 431–449. 10.1146/annurev.arplant.57.032905.105231. PubMed DOI

Šmeringai J.; Schrumpfová P. P.; Pernisová M. Cytokinins - regulators of de novo shoot organogenesis. Front. Plant Sci. 2023, 14, 1239133.10.3389/fpls.2023.1239133. PubMed DOI PMC

Zahajská L.; Nisler J.; Voller J.; Gucký T.; Pospíšil T.; Spíchal L.; Strnad M. Preparation, characterization and biological activity of C8-substituted cytokinins. Phytochem. 2017, 135, 115–127. 10.1016/j.phytochem.2016.12.005. PubMed DOI

Kubiasová K.; Mik V.; Nisler J.; Hönig M.; Husičková A.; Spíchal L.; Pěkná Z.; Šamajová O.; Doležal K.; Plíhal O.; Benková E.; Strnad M.; Plíhalová L. Design, synthesis and perception of fluorescently labeled isoprenoid cytokinins. Phytochem. 2018, 150, 1–11. 10.1016/j.phytochem.2018.02.015. PubMed DOI

Voko M. P.; Aremu A. O.; Makunga N. P.; Nisler J.; Dolezal K.; Masondo N. A. The potential applications of cytokinins and cytokinin oxidase/ dehydrogenase inhibitors for mitigating abiotic stresses in model and non-model plant species. Curr. Plant Biol. 2024, 40, 100398.10.1016/j.cpb.2024.100398. DOI

Husseiny E. M.; Abulkhair H. S.; Saleh A.; Altwaijry N.; Zidan R. A.; Abdulrahman F. G. Molecular overlay-guided design of new CDK2 inhibitor thiazepinopurines: Synthesis, anticancer, and mechanistic investigations. Bioorg. Chem. 2023, 140, 106789.10.1016/j.bioorg.2023.106789. PubMed DOI

Attia R. T.; Ewida M. A.; Khaled E.; Fahmy S. A.; Fawzy I. M. Newly synthesized anticancer purine derivatives inhibiting p-EIF4E using surface-modified lipid nanovesicles. ACS Omega 2023, 8, 37864–37881. 10.1021/acsomega.3c02991. PubMed DOI PMC

Sedky N. K.; Abdel-Kader N. M.; Issa M. Y.; Abdelhady M. M. M.; Shamma S. N.; Bakowsky U.; Fahmy S. A. Co-delivery of Ylang Ylang oil of Cananga odorata and oxaliplatin using intelligent pH-sensitive lipid-based nanovesicles for the effective treatment of triple-negative breast cancer. Int. J. Mol. Sci. 2023, 24, 8392.10.3390/ijms24098392. PubMed DOI PMC

Schleser S. W.; Krytovych O.; Ziegelmeier T.; Gross E.; Kasparkova J.; Brabec V.; Weber T.; Schobert R.; Mueller T. Palladium and platinum complexes of the antimetabolite fludarabine with vastly enhanced selectivity for tumour over non-malignant cells. Molecules 2023, 28, 5173.10.3390/molecules28135173. PubMed DOI PMC

Wang Q.; Pan S.; Lei S.; Jin J.; Deng G.; Wang G.; Zhao L.; Zhou M.; Frenking G. Octa-coordinated alkaline earth metal-dinitrogen complexes M(N2)8 (M = Ca, Sr, Ba). Nat. Commun. 2019, 10, 3375.10.1038/s41467-019-11323-5. PubMed DOI PMC

Islam S.; Asaduzzaman; Simol H. A.; Bakshi P. K. Synthesis, characterization, and evaluation of the antimicrobial, cytotoxic properties of alkaline earth metal complexes containing the nucleobase guanine. Chem. Papers 2024, 78, 5545–5561. 10.1007/s11696-024-03494-3. DOI

Bildziukevich U.; Özdemir Z.; Šaman D.; Vlk M.; Šlouf M.; Rárová L.; Wimmer Z. Novel cytotoxic 1,10-phenanthroline-triterpenoid amphiphiles with supramolecular characteristics capable of coordinating 64Cu(II) labels. Org. Biomol. Chem. 2022, 20, 8157–8163. 10.1039/D2OB01172G. PubMed DOI

Alanazi A. S.; Mirgany T. O.; Alsfouk A. A.; Alsaif N. A.; Alanazi M. M. Antiproliferative activity, multikinase inhibition, apoptosis-inducing effects and molecular docking of novel isatin-purine hybrids. Medicina 2023, 59, 610.10.3390/medicina59030610. PubMed DOI PMC

Yang M.; Özdemir Z.; Kim H.; Nah S.; Andris E.; Li X.; Wimmer Z.; Yoon J. Acid-responsive nanoporphyrin evolution for near-infrared fluorescence-guided photo-ablation of biofilm. Adv. Healthcare Mater. 2022, 11, 2200529.10.1002/adhm.202200529. PubMed DOI

Özdemir Z.; Wimmer Z. Selected plant triterpenoids and their amide derivatives in cancer treatment: A review. Phytochem. 2022, 203, 113340.10.1016/j.phytochem.2022.113340. PubMed DOI

Özdemir Z.; Nonappa; Wimmer Z. Triterpenoid building blocks for functional nanoscale assemblies: A review. ACS Appl. Nano Mater. 2022, 5, 16264–16277. 10.1021/acsanm.2c03304. DOI

de O Torres N. M. P.; Cardoso G. d. A.; Silva H.; de Freitas R. P.; Alves R. B. New purine-triazole hybrids as potential anti-breast cancer agents: synthesis, antiproliferative activity, and ADMET in silico study. Med. Chem. Res. 2023, 32, 1816–1831. 10.1007/s00044-023-03115-w. DOI

Rečnik L.-M.; Kandioller W.; Mindt T. L. 1,4-Disubstituted 1,2,3-triazoles as amide bond surrogates for the stabilization of linear peptides with biological activity. Molecules 2020, 25, 3576.10.3390/molecules25163576. PubMed DOI PMC

Burcevs A.; Sebris A.; Traskovskis K.; Chu H.-W.; Chang H.-T.; Jovaisaite J.; Jursenas S.; Turks M.; Novosjolova I. Synthesis of fluorescent C-C bonded triazole-purine conjugates. J. Fluoresc. 2024, 34, 1091–1097. 10.1007/s10895-023-03337-6. PubMed DOI

Özdemir Z.; Rybková M.; Vlk M.; Šaman D.; Rárová L.; Wimmer Z. Synthesis and pharmacological effects of diosgenin-betulinic acid conjugates. Molecules 2020, 25, 3546.10.3390/molecules25153546. PubMed DOI PMC

Özdemir Z.; Šaman D.; Bednárová L.; Pazderková M.; Janovská L.; Nonappa; Wimmer Z. Aging-induced structural transition of nanoscale oleanolic acid amphiphiles and selectivity against Gram-positive bacteria. ACS Appl. Nano Mater. 2022, 5, 3799–3810. 10.1021/acsanm.1c04374. DOI

Bildziukevich U.; Šlouf M.; Rárová L.; Šaman D.; Wimmer Z. Nano-assembly of cytotoxic amides of moronic and morolic acid. Soft Matter 2023, 19, 7625–7634. 10.1039/D3SM01035J. PubMed DOI

Liu X.; Zhang Y.; Wang Y.; Yang M.; Hong F.; Yang S. Protein phosphorylation in cancer: role of nitric oxide signaling pathway. Biomolecules 2021, 11, 1009.10.3390/biom11071009. PubMed DOI PMC

Ridnour L. A.; Thomas D. D.; Switzer C.; Flores-Santana W.; Isenberg J. S.; Ambs S.; Roberts D. D.; Wink D. A. Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric Oxide 2008, 19, 73–76. 10.1016/j.niox.2008.04.006. PubMed DOI PMC

Bormon R.; Srivastava E.; Ali R.; Singh P.; Kumar A.; Verma S. Anti-proliferative, -migratory and -clonogenic effects of long-lasting nitric oxide release in HepG2 cells. Chem. Commun. 2024, 60, 3527–3530. 10.1039/D4CC00232F. PubMed DOI

Yeo C. T.; Stancill J. S.; Oleson B. J.; Schnuck J. K.; Stafford J. D.; Naatz A.; Hansen P. A.; Corbett J. A. Regulation of ATR-dependent DNA damage response by nitric oxide. J. Biol. Chem. 2021, 296, 100388.10.1016/j.jbc.2021.100388. PubMed DOI PMC

Bonfili L.; Gong C.; Lombardi F.; Cifone M. G.; Eleuteri A. M. Strategic modification of gut microbiota through oral bacteriotherapy influences hypoxia inducible factor-1α: Therapeutic implication in Alzheimer’s disease. Int. J. Mol. Sci. 2022, 23, 357.10.3390/ijms23010357. PubMed DOI PMC

Srivastava A.; Srivastava P.; Mathur S.; Abbas S.; Rai N.; Tiwari S.; Tiwari M.; Sharma L. Lipid metabolism and mitochondria: Cross talk in cancer. Curr. Drug Targets 2022, 23, 606–627. 10.2174/1389450122666210824144907. PubMed DOI

Sflakidou E.; Adhikari B.; Siokatas C.; Wolf E.; Sarli V. Development of 2-aminoadenine-based proteolysis-targeting chimeras (PROTACs) as novel potent degraders of monopolar spindle 1 and Aurora kinases. ACS Pharmacol. Transl. Sci. 2024, 7, 3488–3501. 10.1021/acsptsci.4c00405. PubMed DOI PMC

Gomez-Romero P.; Pokhriyal A.; Rueda-Garcia D.; Bengoa L. N.; Gonzalez-Gil R. M. Hybrid materials: A metareview. Chem. Mater. 2024, 36, 8–27. 10.1021/acs.chemmater.3c01878. PubMed DOI PMC