Synthesis, SAR, and preliminary mechanistic evaluation of novel antiproliferative N 6,5′-bis-ureido- and 5′-carbamoyl- N 6-ureidoadenosine derivatives

摘要

We have developed efficient methods for the preparation of N 6,5′-bis-ureidoadenosine derivatives and their 5′-carbamoyl-N 6-ureido congeners. Treatment of 5′-azido-5′-deoxy-N 6-(N-alkyl or -arylurea)adenosine derivatives (6a-d) with H 2/Pd-C or Ph 3P/H 2O, followed by N-methyl-p-nitrophenylcarbamate gave N 6,5′-bis- ureido products 7a-d in 49-78% yield. Analogous derivatives in the 5′-carbamoyl-N 6-ureido series were prepared by treatment of 2′,3′-bis-O-TBS-adenosine (11) with N-methyl-p-nitrophenylcarbamate followed by acylation with appropriate isocyanates which gave 13a-d in 45-69% yield. A more versatile route for obtaining potentially vast libraries of compounds from both series was achieved by treatment of 5′-N-methylureido- or 5′-N-methylcarbamoyladenosine derivatives with ethylchlorformate to give N 6-ethoxycarbonyl derivatives (9 and 14) in 55-63% yields, respectively. Simple heating of 9 or 14 in the presence of primary alkyl- or arylamines gave the corresponding N 6,5′-bis-ureido- or 5′-carbamoyl-N 6-ureidoadenosine derivatives in good yields (33-72% and 39-83%; 10a-e and 15a-e, respectively). Significant antiproliferative activities (IC 50 ≈ 4-10 μg/mL) were observed for a majority of the N 6,5′-bis-ureido derivatives, whereas the 5′-carbamoyl-N 6-ureido derivatives were generally less active (IC 50 100 μg/mL). A 2′,3′-O-desilylated derivative (5′-amino-5′-deoxy-5′-N-methylureido-N 6-(N- phenylcarbamoyl)adenosine, 16) was shown to inhibit binding of 16 of 441 protein kinases to immobilized ATP-binding site ligands by 30-40% in a competitive binding assay at 10 μM. Compound 16 was also shown to bind to bone morphogenetic protein receptor 1b (BMPR1b) with a Kd = 11.5 ± 0.7 μM.