Substitution‐Inert Polynuclear Platinum Complexes That Inhibit the Activity of DNA Polymerase in Triplex‐Forming Templates

Abstract

The formation of triple-helical DNA is implicated in the regulation of gene expression. The triplexes are, however, unstable under physiological conditions so that effective stabilizers for the triplex formation are needed. Herein, we describe a new strategy for the stabilization of such triplexes that is based on antitumor substitution-inert polynuclear platinum complexes (SI-PPCs). These compounds were previously shown to bind to DNA through the phosphate clamp-a discrete mode of DNA-ligand recognition distinct from the canonical intercalation and minor-groove binding. We have found that SI-PPCs efficiently inhibit DNA synthesis by DNA polymerase in sequences prone to the formation of pyrimidine- and purine-motif triplex DNAs. Moreover, the results suggest that SI-PPCs are able to induce the formation of triple-helical DNA between duplexes and strands that are not completely complementary to each other. Collectively, these data provide evidence that SI-PPCs are very efficient stabilizers of triple-stranded DNA that might exert their action by stabilizing higher-order structures such as triple-helical DNA.

Substitution‐Inert Polynuclear Platinum Complexes Act as Potent Inducers of Condensation/Aggregation of Short Single‐ and Double‐Stranded DNA and RNA Oligonucleotides

“…Recently, we showed that SI‐PPCs disrupt DNA‐related enzymatic activities by stabilizing higher‐order DNA structures such as triplexes even at concentrations lower than required for the condensation/aggregation of nucleic acids . SI‐PPCs were able to efficiently inhibit DNA synthesis by DNA polymerase in sequences prone to the formation of triplex DNAs.…”

“…[8] Recently,w es howed thatS I-PPCsd isrupt DNA-relatede nzymatic activities by stabilizing higher-order DNA structures such as triplexes even at concentrationsl ower than requiredf or the condensation/aggregation of nucleic acids. [9] SI-PPCs were able to efficientlyi nhibit DNA synthesis by DNA polymerase in sequencesp rone to the formation of triplex DNAs. The effectiveness of individual complexesc orrelated with their biological activity and the highest stabilizing activity was observed for TriplatinN C. This compound,u nlike other SI-PPCs, was at elevated concentrations even able to inhibitD NA elongation on templates incompatible with the triplex formation.…”

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

“…However, analogous to cisplatin mechanism of action hampers elimination of all problems associated with Pt(II) therapy. Therefore "trans" geometries [6][7][8][9], polynuclear [10][11][12][13][14], or platinum (IV) prodrugs [15,16] have been Importantly, high efficacy of platinum paved the way for the development of other transition metal complexes, many with outstanding cytotoxic properties against cancer cells.…”

An Antitumor Bis(N‐Heterocyclic Carbene)Platinum(II) Complex That Engages Asparagine Synthetase as an Anticancer Target

“…[7] Nonetheless, the molecular targets of these clinically used platinum complexes are conceived to be DNA. [9] PPCs were also found to interact with non-DNAt argets such as glycans to elicit anti-angiogenic properties. [9] PPCs were also found to interact with non-DNAt argets such as glycans to elicit anti-angiogenic properties.…”