Convergent synthesis of phosphorodiamidate morpholino oligonucleotides (PMOs) by the H-phosphonate approach.

Phosphorodiamidate morpholino oligonucleotides (PMOs) are a promising type of antisense oligonucleotides, but their challenging synthesis makes them difficult to access. This research presents an efficient synthetic approach for PMOs using the H-phosphonate approach. The use of phosphonium-type condensing reagents significantly reduced coupling times compared with the current synthetic approach. Furthermore, phosphonium-type condensing reagents facilitated the fragment condensation of PMO, synthesizing up to 8-mer containing all four nucleobases with remarkable coupling efficacy. This is the first report on the convergent synthesis of PMOs. This approach would facilitate the large-scale synthesis of PMOs and accelerate their popularity and accessibility as a next-generation therapy.

Properties of 5- and/or 2-modified 2'-O-cyanoethyl uridine residue: 2'-O-cyanoethyl-5-propynyl-2-thiouridine as an efficient duplex stabilizing component.

We systematically synthesized eight types of 5- and/or 2-modified uridine derivatives and evaluated their effect on duplex stability. The incorporation of 2'-O-cyanoethyl-2-thio-5-propynyluridine (p(5)s(2)UOCE) into RNA was significantly effective for stabilization of RNA/RNA (+8.5 °C) and DNA/RNA (+10.4 °C) duplexes. These striking effects were maintained in oligonucleotides with different sequences or multiple incorporations. In addition, p(5)s(2)UOCE increased selectivity toward the correct AU Watson-Crick base pair over the most stable mismatched base pair in both RNA/RNA and DNA/RNA duplexes. Hence, p(5)s(2)UOCE could be useful for various applications of modified oligonucleotides that need high duplex stability and base pairing selectivity.

Prediction of the stability of modified RNA duplexes based on deformability analysis: oligoribonucleotide derivatives modified with 2'-O-cyanoethyl-5-propynyl-2-thiouridine as a promising component.

We describe a method to predict the stability of a modified RNA duplex. Ten unique modified RNA duplexes showed a linear relationship between the calculated and experimentally determined duplex stabilities.

Total syntheses of (+)-1893B and its three diastereomers and evaluation of their biological activities.

The total syntheses of natural (+)-1893B (2) and three other diastereomers 14, 18, and 21 were accomplished. Starting from the sequential metathesis product 5 prepared in turn from a 7-oxanorbornene derivative (+)-4, 2 was synthesized by means of an epoxy-ring opening of 9a with trimethylsilylacetylide followed by Wacker-type oxidation of the resulting alkyne 10 for the construction of the gamma-lactone moiety. By applying the same synthetic sequence, three additional diastereomers of 2, 14, 18, and 21 were also synthesized. The biological activities of previously synthesized 1893A (1), 1893B (2), and the diastereomers of 1893B 14, 18, and 21 were investigated.