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

Abstract

Herein we report on the synthesis and evaluation of the preliminary antitumor properties of a small collection of platinum(II) complexes in which a cisplatin‐like unit is tethered to 7‐deazaadenosine through linear alkyl chains (from two to six carbon atoms) installed at the purine C6 position. The complexation was performed by exploiting the reactivity of the bidentate amino ligands (R)‐ and (S)‐2,3‐diaminopropanoic acids (DAPA) attached to the end of the alkyl chain spacer. By varying the length of the alkyl chain and the chirality of the DAPA moiety we obtained 10 novel nucleoside–platinum complexes, the anticancer properties of which have been evaluated against the A549 and Cal27 human cancer cell lines.

Synthesis, Antiproliferative Activity, and DNA Binding Studies of Nucleoamino Acid-Containing Pt(II) Complexes

“…In particular, in the 1 H NMR spectra of T1 and T2 complexes, two signals, i.e., broad multiplets at 5.68 and 6.29 ppm (for T1 , Figure S6, up ) and 5.63 and 6.25 ppm (for T2 , Figure S7 ), were diagnostic of protons belonging to a nitrogen bound to platinum(II) center, in accordance with other complexes reported in the literature [ 32 ]. The two amino protons, equivalent and easily exchangeable in the starting compound, became not equivalent and not easily exchangeable when the α-amino group coordinated the Pt ion.…”

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

“…Compound 8 was then reacted with the nucleoside 7 in ethanolic solution under reflux; differently from our previous reports on similar reactions [ 34 , 35 ], compound 11 did not precipitate after cooling, and the product was isolated only after column chromatography (76% yield). Next, the C7-Br bond in 11 was hydrogenated in the presence of H 2 /Pd/C and the crude was directly subjected to the sugar deprotection (Zemplen conditions, NaOMe/MeOH), yielding compound 13 (60% over two steps).…”

“…In detail, cells were incubated for 72 h in the presence of complexes at increasing concentrations ranging from 5 to 100 µM for 6 and 14 , and from 0.3 to 20 µM for cisplatin and from 0.075 to 20 µM for tubercidin. Complex 6 and cisplatin were dissolved in 100% DMSO and immediately diluted with 0.9% NaCl aqueous solution to obtain the 2 mM stock solutions, which were diluted with the growth medium at the final concentrations containing less than 0.5% DMSO [ 34 , 35 , 50 ]. The small amount of DMSO, necessary to completely solubilize the Pt(II) complex, should not affect its biological activity, in accordance with the recent findings on the combination studies of cisplatin and DMSO on KB-3-1 or DLD-1 tumor cells lines [ 55 ].…”

“…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 ].…”

Fluorinated Cycloplatinated(II) Complexes Bearing Bisphosphine Ligands as Potent Anticancer Agents

“…In spite of numerous investigations on Pt-based chemotherapeutic agents, several unsolved questions remain on the toxicity, ototoxicity, low selectivity, and drug resistance of cells . To remove such limitations, many strategies have been employed, such as using chelating ligands instead of Cl ligands, , encapsulating agents to enhance drug delivery, ,, replacing Pt­(II) centers with the Pt­(IV) counterparts, − and using ligands which are able to selectively interact with biological targets. − Additionally, in order to achieve the best formulation for such drugs, their size, shape, and favorable balance between lipophilicity and hydrophilicity should be considered. Thus, to facilitate the administration and cell uptake for the drugs, the existence of lipophilic and hydrophilic functional groups seems to be necessary …”