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

Abstract

Compounds condensing DNA and RNA molecules can essentially affect important biological processes including DNA replication and transcription. Here, this work shows with the aid of total intensity light scattering, gel electrophoresis, and atomicf orce microscopy (AFM) that the substitution-inert polynuclearp latinum complexes (SI-PPCs), particularly [{trans-Pt(NH 3 ) 2 (NH 2 (CH 2 ) 6 -NH 3 + )} 2 -m-{trans-Pt(NH 3 ) 2 (NH 2 (CH 2 ) 6 NH 2 ) 2 }] 8 + (Triplatin NC), exhibit an unprecedented high potency to condense/aggregatef ragments of DNA and RNA as shorta s2 0b ase pairs. SI-PPCsc ondensates are distinctive from those generated by the naturally occurring polyamines (commonly used DNA compacting/condensing agents). Collectively, the results further confirm that SI-PPCs are very efficient inducers of condensation of DNA and RNA, including their short fragments that might have potentiali ng ene therapy,b iotechnology,a nd bionanotechnology.M oreover,t he data confirm the structural advantages of the phosphate clamp,w ith aw ell-defined rigid DNA recognition motif in initiating condensationa nd aggregation phenomena on oligonucleotides.[a] Dr.

Conformational Modulation of Iduronic Acid‐Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs

“…[31] Tr iPtNC is an especially effective condensing agent on DNAand RNAand by analogy is likely to be equally effective on the GAGp olyelectrolyte. [32,33] TheC Ds pectrum of FPX is very similar to that of heparin [34] and preliminary results show an unusual decrease in this band in the presence of Tr iPtNC (Supporting Information, Figure S8). We suggest that the related conformational selection and condensation may contribute to modulation of GAGb iological function.…”

“…Counterion condensation modifies the negative charge of GAGs and counterion release may play a role in GAG‐protein binding [31] . TriPtNC is an especially effective condensing agent on DNA and RNA and by analogy is likely to be equally effective on the GAG polyelectrolyte [32, 33] . The CD spectrum of FPX is very similar to that of heparin [34] and preliminary results show an unusual decrease in this band in the presence of TriPtNC (Supporting Information, Figure S8).…”

“…[47] In both solution and gas-phase DNAb inding studies,c omplexes such as Tr iPtNC have significantly higher affinity than the simple polyamines and are significantly more effective DNA-condensing agents. [32,33,35,48] We would predict that these differences will also be observed for comparative GAG-binding studies due to the unique nature of the PPC-GAGs ulfate cluster interaction. Metalloshielding, especially where the GlcNS(3S)(6S) trisulfated cluster may be considered a"hot spot" for Tr iPtNC binding,could find applicability in sequencing of longer heterogeneously substituted oligosaccharides.…”

“…Spermine itself binds to and modifies the structure of HS with effects on polyamine pathways [47] . In both solution and gas‐phase DNA binding studies, complexes such as TriPtNC have significantly higher affinity than the simple polyamines and are significantly more effective DNA‐condensing agents [32, 33, 35, 48] . We would predict that these differences will also be observed for comparative GAG‐binding studies due to the unique nature of the PPC‐GAG sulfate cluster interaction.…”

Exploring the Potential of Metallodrugs as Chemotherapeutics for Triple Negative Breast Cancer

“…In this report, the authors clearly demonstrated for the first time that a small molecule may affect conformational changes on a HS oligosaccharide (TriPtNC drives the conformation of Iodo(2S) in FPX to the 1 C 4 chair). This in turn (and coupled with results from previous studies on the interaction of TriPtNC with DNA) [32] allowed the authors to propose a dual role for this type of Pt complexes (cytotoxicity through DNA targeting and potential antimetastatic action through the above-mentioned interference with HS function). [31] Moreover, the authors reported on the effects of TriPtNC on bovine heparinase (bHPSE) in the TNBC cell line MDA-MB-231.…”