Peptide nucleic acids (PNAs) are mimics of natural nucleic acids in which the sugar phosphate backbone present in oligonucleotides is replaced by a pseudopeptide backbone formed by N-(2-aminoethyl)glycine units, on which nucleobases are attached.1 PNAs are able to bind complementary DNA or RNA strands with high sequence specificity and affinity. Moreover, the high chemical and enzymatic stability towards nucleases make these systems excellent candidates in molecular biology, diagnostics and as therapeutics. However, unmodified PNAs often exhibit low cell penetration and this feature constitutes one of the most important drawbacks towards their effective use in therapy. One of the strategies to overcome this problem is the conjugation of PNA to metal complexes that can modify their intrinsic physico-chemical and spectroscopic properties.2 Currently, our group is working on the development of novel bioorganometallic iridium-PNA conjugates that can be employed as dual activity agents for the synergic treatment of cancer, combining antisense therapy based on PNAs and photodynamic therapy (PDT) related to the use of the Ir(III) complex as the photosensitizer3, which is able to generate cytotoxic singlet oxygen (1O2) under appropriate excitation light. This complex is also able to penetrate cell membrane, thus it could act as a carrier for the intracellular delivery of PNAs. In this communication we will report our studies on the synthesis of the Ir(III)-PNA conjugate (PNA-Ir, Figure 1), in which a PNA tetramer containing all the four nucleobases was selected as model PNA sequence. The PNA tetramers PNA-COOH and PNA-NH2 (Figure 1) were synthesized on solid phase using Fmoc/Bhoc strategy and their conjugation to Ir(III) complexes Ir-NH2 and Ir-COOH (Figure 1), respectively, was investigated through a coupling reaction on solid phase to form the amide bond. The acid-promoted cleavage of the oligomer from the resin followed by the reverse-phase HPLC purification allowed us to obtain the required conjugate PNA-Ir, which was characterized by HR-ESI mass spectrometry.
Conjugation of iridium(III) complexes to peptide nucleic acids through solid phase synthesis / R. Dell'Acqua, V. Schifano, M. Dozzi, M. Panigati, D. Maggioni, S. Cauteruccio. ((Intervento presentato al 14. convegno ISOC - International School of Organometallic Chemistry tenutosi a Camerino nel 2023.
Conjugation of iridium(III) complexes to peptide nucleic acids through solid phase synthesis
R. Dell'AcquaPrimo
;V. SchifanoSecondo
;M. Dozzi;M. Panigati;D. MaggioniPenultimo
;S. CauteruccioUltimo
2023
Abstract
Peptide nucleic acids (PNAs) are mimics of natural nucleic acids in which the sugar phosphate backbone present in oligonucleotides is replaced by a pseudopeptide backbone formed by N-(2-aminoethyl)glycine units, on which nucleobases are attached.1 PNAs are able to bind complementary DNA or RNA strands with high sequence specificity and affinity. Moreover, the high chemical and enzymatic stability towards nucleases make these systems excellent candidates in molecular biology, diagnostics and as therapeutics. However, unmodified PNAs often exhibit low cell penetration and this feature constitutes one of the most important drawbacks towards their effective use in therapy. One of the strategies to overcome this problem is the conjugation of PNA to metal complexes that can modify their intrinsic physico-chemical and spectroscopic properties.2 Currently, our group is working on the development of novel bioorganometallic iridium-PNA conjugates that can be employed as dual activity agents for the synergic treatment of cancer, combining antisense therapy based on PNAs and photodynamic therapy (PDT) related to the use of the Ir(III) complex as the photosensitizer3, which is able to generate cytotoxic singlet oxygen (1O2) under appropriate excitation light. This complex is also able to penetrate cell membrane, thus it could act as a carrier for the intracellular delivery of PNAs. In this communication we will report our studies on the synthesis of the Ir(III)-PNA conjugate (PNA-Ir, Figure 1), in which a PNA tetramer containing all the four nucleobases was selected as model PNA sequence. The PNA tetramers PNA-COOH and PNA-NH2 (Figure 1) were synthesized on solid phase using Fmoc/Bhoc strategy and their conjugation to Ir(III) complexes Ir-NH2 and Ir-COOH (Figure 1), respectively, was investigated through a coupling reaction on solid phase to form the amide bond. The acid-promoted cleavage of the oligomer from the resin followed by the reverse-phase HPLC purification allowed us to obtain the required conjugate PNA-Ir, which was characterized by HR-ESI mass spectrometry.Pubblicazioni consigliate
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