Heterobiaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part II.

C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18 g and 9 c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).

Biaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part I.

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).

Preparation of 8-Amido-2-dimethylamino-1,2,3,4-tetrahydro-2-dibenzofurans and several fluorinated derivatives via [3,3]-sigmatropic rearrangement of O-aryloximes.

Methodology to prepare 8-amido-2-amino-1,2,3,4-tetrahydro-2-dibenzofurans, analogues with a fluorine substituent incorporated in the 6-, 7-, and 9-positions, and a difluorinated analogue with fluorines in the 6- and 9-positions is described. The tetrahydrodibenzofuran ring systems are prepared by acid-catalyzed [3,3]-sigmatropic rearrangement of O-aryloximes. Regioselective reactions to prepare the requisite O-aryloxime intermediates from commercially available fluorobenzene derivatives are discussed.