Boger, Dale L.; Fink, Brian E.; Hedrick, Michael P. published the artcile< Total Synthesis of Distamycin A and 2640 Analogs: A Solution-Phase Combinatorial Approach to the Discovery of New, Bioactive DNA Binding Agents and Development of a Rapid, High-Throughput Screen for Determining Relative DNA Binding Affinity or DNA Binding Sequence Selectivity>, Recommanded Product: (9Z,12Z)-Methyl octadeca-9,12-dienoate, the main research area is combinatorial library distamycin A analog binding DNA.
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. The complementary development of a simple, rapid, and high-throughput screen for DNA binding affinity based on the loss of fluorescence derived from displacement of prebound ethidium bromide is disclosed which is applicable for assessing relative or absolute binding affinity to DNA homopolymers or specific sequences (hairpin oligonucleotides). Using hairpin oligonucleotides, this method permits the screening of a library of compounds against a single predefined sequence to identify high affinity binders, or the screening of a single compound against a full library of individual hairpin oligonucleotides to define its sequence selectivity. The combination permits the establishment of the complete DNA binding profile of each member of a library of compounds Screening the prototypical library provided compounds that are 1000 times more potent than distamycin A in cytotoxic assays (I, Boc = tert-butoxycarbonyl; 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 (II, R = 4-dimethylaminobutyryl; K = 3.2 × 106 M-1) maintained the high affinity binding (K = 4.5 × 106 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.
Journal of the American Chemical Society published new progress about Combinatorial library. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Recommanded Product: (9Z,12Z)-Methyl octadeca-9,12-dienoate.
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