| 摘要 |
The development of a solution-phase synthesis of distamycin A and its extension to the preparation of 2640 analogs are described. Thus, solution-phase synthesis techniques with reaction workup and purification employing acid/base liquid-liquid extractions were used in the multistep preparation of distamycin A (8 steps, 40 % overall yield) and a prototypical library of 2640 analogs providing intermediates and final products that are ≥ 95 % pure on conventional reaction scales. Screening the prototypical library provided compounds that are 1000 times more potent than distamycin A in cytotoxic assays (67, IC50 = 29 nM, L1210), that bind to poly[dA]-poly[dT] with comparable affinity, and that exhibit an altered DNA binding sequence selectivity. Several candidates were identified which bound the five base-pair AT-rich site of the PSA-ARE-3 sequence, and one (128, K = 3.2 x 10<6> M<-1>) maintained the high affinity binding (K = 4.5 x 10<6> M<-1>) to the ARE-consensus sequence containing a GC base-pair interrupted five base-pair AT-rich site suitable for inhibition of gene transcription initiated by hormone insensitive androgen receptor dimerization and DNA binding characteristic of therapeutic resistant prostate cancer.
|
