65361-29-7Relevant academic research and scientific papers
A new DNA minor groove binding motif: Cross-linked lexitropsins
Chen,Lown
, p. 6995 - 7005 (1994)
The nitrogen atoms of central pyrrole rings on two separate tripyrrolecarboxamide strands were covalently linked through poly(methylene) chains to provide a novel class of lexitropsins potentially capable of B-DNA double-strand reading via the minor groove. CD titration experiments revealed increasingly enhanced binding of 1:1 stoichiometry to the poly(dA-dT)- poly(dA-dT) DNA from the tetrakis(methylene) linkage to the heptakis(methylene) linkage, suggesting gradually growing importance of the bidentate antiparallel side by side binding. Ethidium bromide fluorescence displacement experiments on both poly(dA-dT)-poly(dA-dT) and poly(dA)- poly(dT) DNA's supported this analysis by providing quantitative measurement of intrinsic binding constants. The heptakis(methylene) linkage offered a binding enhancement of approximately 1000 times compared with that of the monomer.
Distamycin Analogues with Enhanced Lipophilicity: Synthesis and Antimicrobial Activity
Khalaf, Abedawn I.,Waigh, Roger D.,Drummond, Allan J.,Pringle, Breffni,McGroarty, Ian,Skellern, Graham G.,Suckling, Colin J.
, p. 2133 - 2156 (2007/10/03)
Forty-eight heterocyclic amino acid trimers, analogues of distamycin, with a number of features that enhance lipophilicity are described. They contain alkyl or cycloalkyl groups larger than methyl; some are N-terminated by acetamide or methoxybenzamide an
Total synthesis of distamycin A and 2640 analogues: 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
Boger, Dale L.,Fink, Brian E.,Hedrick, Michael P.
, p. 6382 - 6394 (2007/10/03)
The development of a solution-phase synthesis of distamycin A and its extension to the preparation of 2640 analogues 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 analogues 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 oligionucleotides 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 (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 106 M-1) maintained the high affinity binding (K = 4.5 x 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.
