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Zawartość zarchiwizowana w dniu 2022-12-23

Antisense oligonucleotides as anticancer agents

Cel



Among several analogues of oligonucleotides synthesized as potential antisense therapeutics the most extensively studled are phosphorothioate analogues of DNA (oligo-S). Favorable features of oligo-S include extensive biodistribution in vivo with relatively slow excretion, adequate potency, and low toxicity. Efficacy of oligo-Sin gene-directed antisense based therapy has been proved in initial studies in animal models and phase I clinical investigations. So far performed studies utilized diastereomeric mixtures of Oligo-S, since existing methodologies of their chemical synthesis are not meaningfully stereoselective. The synthetic Oligo-S bearing n internucleotide phosphorothioate functions consists of the mixture of 2n diastereomers. Each diastereomer represents a distinct entity characterized bY its own chirality. Besides fundamental problem of stereodifferentiated interaction with cellular biopolymers the polydiastereomeric nature of Oligo-Sis notwithstanding legalistic requirements for new potential drugs, structure and/or composition of which should be well defined. In Lodz Laboratory we obtained first promising results on the stereocontrolled synthesis of oligo-S starting from diastereomerically pure nucleoside 3'-0-(2-thiono-1,3,2- oxathiaphospholanes). Although this novel method still suffers from several limitations (unsatisfactory yield of step condensation, limited scale of preparation, and difficulties with efficient separation of diastereomeric substrates), the heptadecamer 5'-d(CCA CAC CGA CGG CGC cC)- 3'(selected earlier as the optimal antisense Oligo-S for inhibition of the expression of oncogene Ha Ras in vitro and in vivo) can be prepared as stereoregular (all-Rp) and (all-sp) phosphorothioate constructs. These constructs can be further evaluated (professor T. Saison-Behmoaras) for their physicochemical and biological properties. The research project includes: 1) Improvement of the efficiency of the coupling step via structural modification of the starting oxathiaphospholane substrates or search for new catalysts of condensation; 2) Search for oxathiaphospholane substrates of improved "separability" into diastereomerically pure species; 3) The synthesis of (all-Rp) and (all-Sp)-Oligo-Sof anti-Ha-ras-mRNA sequence in quantities of several A260 o.d.units.

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System finansowania

CSC - Cost-sharing contracts

Koordynator

KATHOLIEKE UNIVERSITEIT LEUVEN
Wkład UE
Brak danych
Adres
10,Minderbroedersstraat 10
3000 LOUVAIN / LEUVEN
Belgia

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