Synthesis, SAR, and preliminary mechanistic evaluation of novel antiproliferative N⁶,5'-bis-ureido- and 5'-carbamoyl-N⁶-ureidoadenosine derivatives.

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(3)P/H(2)O, 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.

Antiproliferative and protein kinase binding activities of Some N6, 5'-bis-ureido 5'-amino-5'-deoxyadenosine derivatives.

Two novel N(6),5'-bis-ureido 5'-amino-5'-deoxyadenosine derivatives are shown to inhibit tumor cell growth in the NCI 60 human tumor cell panel. Compounds 2c and 2d exhibited GI(50) values of 1-6 microM in 35 and 14 cell lines, respectively. Compound 2c was shown to selectively inhibit binding of protein kinases to immobilized ATP-binding site ligands via a competitive binding assay (11 of 353 protein kinases inhibited by > or =30% at 10 microM compound concentration).

Preliminary SAR analysis of novel antiproliferative N(6),5'-bis-ureidoadenosine derivatives.

A preliminary library of novel N(6),5'-bis-ureidoadenosine analogs and related derivatives was prepared and tested for activity against the NCI 60 panel of human cancers. A 2'-O-TBS group was found to be necessary, but not sufficient, for optimal antiproliferative activity. Neither the N(6)- nor 5'-ureido substituents were sufficient to achieve significant antiproliferative effects when present in the absence of the other.