The purine derivative fludarabine is part of frontline therapy for chronic lymphocytic leukaemia (CLL). It has shown positive effects on solid tumours such as melanoma, breast, and colon carcinoma in clinical phase I studies. As the treatment of CLL cells with combinations of fludarabine and metal complexes of antitumoural natural products, e.g., illudin M ferrocene, has led to synergistically enhanced apoptosis, in this research study different complexes of fludarabine itself. Four complexes bearing a trans-[Br(PPh3)2]Pt/Pd fragment attached to atom C-8 via formal η1-sigma or η2-carbene bonds were synthesised in two or three steps without protecting polar groups on the arabinose or adenine. The platinum complexes were more cytotoxic than their palladium analogues, with low single-digit micromolar IC50 values against cells of various solid tumour entities, including cisplatin-resistant ones and certain B-cell lymphoma and CLL, presumably due to the ten-fold higher cellular uptake of the platinum complexes. However, the palladium complexes interacted more readily with isolated Calf thymus DNA. Interestingly, the platinum complexes showed vastly greater selectivity for cancer over non-malignant cells when compared with fludarabine.

Department of Biophysics Faculty of Science Palacky University Slechtitelu 27 783 71 Olomouc Czech Republic

Organic Chemistry Laboratory University Bayreuth Universitaetsstrasse 30 95447 Bayreuth Germany

University Clinic for Internal Medicine 4 Hematology Oncology Medical Faculty Martin Luther University Halle Wittenberg Ernst Grube Str 40 06120 Halle Germany

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Ferlay J., Colombet M., Soerjomataram I., Parkin D.M., Pineros M., Znaor A., Bray F. Cancer statistics for the year 2020: An overview. Int. J. Cancer. 2021;149:778–789. doi: 10.1002/ijc.33588. PubMed DOI

El-Zine M.A.Y., Alhadi A.M., Ishak A.A., Al-Shamahy H.A. Prevalence of different types of leukemia and associated factors among children with leukemia in children’s cancer units at Al-Kuwait Hospital, Sana’a City: A cross-sectional study. Glob. J. Ped. Neonatol. Car. 2021;3:000569. doi: 10.33552/GJPNC.2021.03.000569. DOI

Burger J.A. Treatment of chronic lymphocytic leukemia. N. Engl. J. Med. 2020;383:460–473. doi: 10.1056/NEJMra1908213. PubMed DOI

Eichhorst B., Robak T., Montserrat E., Ghia P., Niemann C.U., Kater A.P., Gregor M., Cymbalista F., Buske C., on behalf of the ESMO Guidelines Committee et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2021;32:23–33. doi: 10.1016/j.annonc.2020.09.019. PubMed DOI

Huang C., Tu Y., Freter C.E. Fludarabine-resistance associates with ceramide metabolism and leukemia stem cell development in chronic lymphocytic leukemia. Oncotarget. 2018;9:33124–33137. doi: 10.18632/oncotarget.26043. PubMed DOI PMC

Hallek M., Fischer K., Fingerle-Rowson G., Fink A.M., Busch R., Mayer J., Hensel M., Hopfinger G., Hess G., Von Grünhagen U., et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: A randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–1174. doi: 10.1016/S0140-6736(10)61381-5. PubMed DOI

Hanauske A.-R., von Hoff D.D. Clinical development of fludarabine. In: Cheson B.D., Keating M.J., Plunkett W., editors. Nucleoside Analogs in Cancer Therapy. CRC Press; Boca Raton, FL, USA: 2021.

Gandhi V., Plunkett W. Cellular and clinical pharmacology of fludarabine. Clin. Pharmacokinet. 2002;41:93–103. doi: 10.2165/00003088-200241020-00002. PubMed DOI

Huang P., Chubb S., Plunkett W. Termination of DNA synthesis by 9-beta-d-arabinosyl-2-fluoroadenine. A mechanism for cytotoxicity. J. Biol. Chem. 1990;265:16617–16625. doi: 10.1016/S0021-9258(17)46267-3. PubMed DOI

Plunkett W., Huang P., Gandhi V. Metabolism and action of fludarabine phosphate. Semin. Oncol. 1990;17:3–17. PubMed

Huang P., Sandoval A., Van Den Neste E., Keating M.J., Plunkett W. Inhibition of RNA transcription: A biochemical mechanism of action against chrocic lymphocytic leukemia cells by fludarabine. Leukemia. 2000;14:1405–1413. doi: 10.1038/sj.leu.2401845. PubMed DOI

Christopherson R.I., Mactier S., Almazi J.G., Kohnke P.L., Best O.G., Mulligan S.P. Mechanism of action of fludarabine nucleoside against human Raji lymphoma cells. Nucleos. Nucleot Nucl. 2014;33:375–383. doi: 10.1080/15257770.2013.863334. PubMed DOI

Takagi K., Kawai Y., Yamauchi T., Iwasaki H., Ueda T. Synergistic effects of combination with fludarabine and carboplatin depend on fludarabine-mediated inhibition of enhanced nucleotide excision repair in leukemia. Int. J. Hematol. 2011;94:378–389. doi: 10.1007/s12185-011-0930-8. PubMed DOI

Zecevic A., Sampath D., Ewald B., Chen R., Wierda W., Plunkett W. Killing of chronic lymphocytic leukemia by the combination of fludarabine and oxaliplatin is dependent on the activity of XPF endonuclease. Clin. Cancer Res. 2011;17:4731–4741. doi: 10.1158/1078-0432.CCR-10-2561. PubMed DOI PMC

Moufarij M.A., Sampath D., Keating M.J., Plunkett W. Fludarabine increases oxaliplatin cytotoxicity in normal and chronic lymphocytic leukemia lymphocytes by suppressing interstrand DNA crosslink removal. Blood. 2006;108:4187–4193. doi: 10.1182/blood-2006-05-023259. PubMed DOI PMC

Lohmann G., Vasyutina E., Bloehdorn J., Reinart N., Schneider J., Babu V., Knittel G., Mayer P., Prinz C., Biersack B., et al. Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia. Leukemia. 2017;31:1177–1186. doi: 10.1038/leu.2016.294. PubMed DOI

Gianferrara T., Bratsos I., Alessio E. A categorization of metal anticancer compounds based on their mode of action. Dalton Trans. 2009;37:7588–7598. doi: 10.1039/b905798f. PubMed DOI

Bär S.I., Gold M., Schleser S.W., Rehm T., Bär A., Köhler L., Carnell L.R., Biersack B., Schobert R. Guided antitumoral drugs: (imidazol-2-ylidene)(L)gold(I) complexes seeking cellular targets controlled by the nature of ligand L. Chem. Eur. J. 2021;27:5003–5010. doi: 10.1002/chem.202005451. PubMed DOI PMC

Nguyen A., Vessieres A., Hillard E.A., Top S., Pigeon P., Jaouen G. Ferrocifens and ferrocifenols as new potential weapons against breast cancer. Chimia. 2007;61:716–724. doi: 10.2533/chimia.2007.716. DOI

Knauer S., Biersack B., Zoldakova M., Effenberger K., Milius W., Schobert R. Melanoma specific ferrocene esters of the fungal cytotoxin illudin M. Anticancer Drugs. 2009;20:676–681. doi: 10.1097/CAD.0b013e32832e056a. PubMed DOI

Kober L., Schleser S.W., Bär S.I., Schobert R. Revisiting the anticancer properties of phosphane(9-ribosylpurine-6-thiolato)gold(I) complexes and their 9H-purine precursors. J. Biol. Inorg. Chem. 2022;27:731–745. doi: 10.1007/s00775-022-01968-x. PubMed DOI PMC

Leitão M.I.P.S., Herrera F., Petronilho A. N-heterocyclic carbenes derived from guanosine: Synthesis and evidences of their antiproliferative activity. ACS Omega. 2018;3:15653–15656. doi: 10.1021/acsomega.8b02387. PubMed DOI PMC

Kampert F., Brackemeyer D., Tan T.T.Y., Hahn F.E. Selective C8-metalation of purine nucleosides via oxidative addition. Organometallics. 2018;37:4181–4185. doi: 10.1021/acs.organomet.8b00685. DOI

Goossen L.J., Koley D., Hermann H.L., Thiel W. Mechanistic pathways for oxidative addition of aryl halides to palladium(0) complexes: A DFT study. Organometallics. 2005;24:2398–2410. doi: 10.1021/om0500220. DOI

Casado A.L., Espinet P. A novel reversible aryl exchange involving two organometallics: mechanism of the gold(I)-catalyzed isomerization of trans-[PdR2L2] complexes (R = aryl, L = SC4H8) Organometallics. 1998;17:3677–3683. doi: 10.1021/om980283s. DOI

Leitão M.I.P.S., Francescato G., Gomes C.S.B., Petronilho A. Synthesis of platinum(II) N-heterocyclic carbenes based on adenosine. Molecules. 2021;26:5384. doi: 10.3390/molecules26175384. PubMed DOI PMC

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. doi: 10.17344/acsi.2019.5196. PubMed DOI

Kapdi A.R., Fairlamb I.J.S. Anti-cancer palladium complexes: A focus on PdX2L2, palladacycles and related complexes. Chem. Soc. Rev. 2014;43:4751–4777. doi: 10.1039/C4CS00063C. PubMed DOI

Heinrich A.-K., Lucas H., Schindler L., Chytil P., Etrych T., Mäder K., Mueller T. Improved tumor-specific drug accumulation by polymer therapeutics with pH-sensitive drug release overcomes chemotherapy resistance. Mol. Cancer Ther. 2016;15:998–1007. doi: 10.1158/1535-7163.MCT-15-0824. PubMed DOI

Purine Scaffold in Agents for Cancer Treatment