Synthesis and Evaluation of the Antiproliferative Properties of a Tethered Tubercidin–Platinum(II) Complex

Abstract

Herein, the synthesis of a nucleoside platinum(II) complex in which a cisplatin-like unit is joined to 7-deazaadenosine through an amino alkyl chain installed at the C6 position of purine was explored. The capability of the new complex to react with DNA purine bases was confirmed by a model reaction with deoxyguanosine monophosphate, whereas its antiproliferative activity against A549 and Cal27 human cancer cell lines was studied by sulforhodamine B assay in comparison with its unplatinated precursor and cisplatin

Synthesis and Evaluation of the Antitumor Properties of a Small Collection of PtII Complexes with 7‐Deazaadenosine as Scaffold

“…In detail, all the platinum complexes 15a – e ‐( R ) and 15a – e ‐( S ) were less active than cisplatin in the induction of cell‐growth inhibition with IC 50 values 45 to 100 times higher than those of cisplatin. These results parallel those reported for the mixture of diastereomers 4 on the same cancer cell lines . In particular, the results evidence that neither the variation of the absolute configuration of the chiral center introduced with the DAPA moiety nor the modulation of the length of the alkyl chain separating the 7‐deazaadenosine scaffold from the platinum moiety was advantageous for improving the antineoplastic potency of the compounds 15 with respect to platinum complexes 4 .…”

“…Despite this potential, only a few examples of molecules containing platinum and nucleoside moieties have been described in the literature . We have recently reported on the synthesis of a diastereoisomeric mixture of Pt II complexes ( 4 , Scheme ) in which a cisplatin‐like unit is joined to 7‐deazaadenosine (a natural nucleoside analogue endowed with potent antibiotic and antitumor properties), through the chelation of a diaminopropanoic group installed at the purine C6 position through a three‐carbon‐atoms linker . The mixture of the two compounds, subjected to preliminary biological tests, revealed a capability to inhibit the proliferation of the A549 and Cal27 human cell lines in a dose‐dependent manner.…”

Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

“…Conjugation of tubercidin ( 3 ) and cisplatin, a clinically used cytostatic, through N6‐nitrogen of tubercidin furnished derivative 38 . Although compound 38 was able to react with purine residues in a similar way as cisplatin, its cytotoxic activity against cancer cell lines was only weak (micromolar) and dropped by one order of magnitude compared to cisplatin . Based on these two examples, it could seem that attachment of larger substituents to the N6‐amino group is not suitable for improvement of cytotoxic effect of 7‐deazapurine nucleosides but such conclusion would be too simplistic.…”

“…Although compound 38 was able to react with purine residues in a similar way as cisplatin, its cytotoxic activity against cancer cell lines was only weak (micromolar) and dropped by one order of magnitude compared to cisplatin. 79 Based on these two examples, it could seem that attachment of larger substituents to the N6-amino group is not suitable for improvement of cytotoxic effect of 7-deazapurine nucleosides but such conclusion would be too simplistic. Pevonedistat (39, MLN4924) is N6-substituted carbocyclic 7-deazapurine nucleoside analogue which shows mode of action distinct from those of other 7-deazapurine nucleosides.…”

Probing the DNA Reactivity and the Anticancer Properties of a Novel Tubercidin-Pt(II) Complex

“…For the potential biological implications, the presence of two adjacent amine functions on the same alkyl chain is more appealing, as the nucleophilicity of the two nitrogen atoms may be exploited to chelate important bio-metals [ 33 ]. Accordingly, we probed the anticancer potential of some platinum(II) complexes carrying the cisplatin-like moiety linked to tubercidin through a N -alkyl-amide diamino spacer installed at the C6 purine position ( 5a–e-( R ) and 5a–e-( S ) , Figure 2 ) [ 34 , 35 ].…”