Search

A synthesis is presented of the cyclic trimeric d-oligonucleotide 3′-isopropylphosphate I, comprising one formacetal and two (3′ → 5′)-internucleosidic phosphodiester bonds. The ester linkages connect d-guanosine with the 3′ and 5′ ends of thymidine and 5-hydroxymethyl-2′-deoxyuridine-3′-isopropylphosphate (HMDUpiPr), respectively. The 5′-end of the thymidine unit is anchored via the formacetal bond to the allylic hydroxyl group of HMDUpiPr. The cyclic arrangement of the three d-nucleosides in I mimics, as based on molecular modeling, the key structural features of the conformationally constrained T7pG8pT9p-domain of the thrombin-binding DNA aptamer d(G1G2T3T4G5G6 T 7 G 8 T 9 G10G11T12T13G14G15). Biological evaluation showed that compound I did not exhibit anti-thrombin activity.

Trisubstrate UGT transition state analogue 2 is readily accessible by nucleophilic ring-opening of 1,2-anhydroglucose precursor 5 with diethylmalonate anion followed by reduction of the ethyl ester moieties ( 6→7 ). Subsequent C 6 oxidation ( 8→9 ), NIS/ cat . TfOH-mediated introduction of the androsterylmethylene unit ( 12→15 ) and phosphitylation with 5′-uridine phosphoramidite 16 furnished, after oxidation and deprotection, target derivative 2 , the two individual diastereomers of which ( 2a and 2b ) were separated by HPLC. Trisubstrate analogues 2a,b show a different inhibition pattern for several UGT isoforms, indicating isoenzyme selectivity. Moreover, C 7″ -epimers 2a and 2b exert a different inhibitory effect on UGT2B15.