Targeting the Minor Groove of DNA:  Crystal Structures of Two Complexes between Furan Derivatives of Berenil and the DNA Dodecamer d(CGCGAATTCGCG)2

• Published in: Journal of medicinal chemistry Vol. 39; no. 23; pp. 4554 - 4562
• Main Authors: Trent, John O, Clark, George R, Kumar, Arvind, Wilson, W. David, Boykin, David W, Hall, James Edwin, Tidwell, Richard R, Blagburn, Byron L, Neidle, Stephen
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08-11-1996
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Crystallography, X-Ray; Diminazene - analogs & derivatives; Diminazene - chemistry; DNA - chemistry; Furans - chemistry; Medical sciences; Models, Molecular; Nucleic Acid Conformation; Oligodeoxyribonucleotides - chemistry; Pharmacology. Drug treatments; Furan derivatives; Molecular interaction; Pneumocystis carinii; Modeling; Antiprotozoal agent; Double stranded DNA; Cryptosporidium parvum; Structure activity relation; Parasiticid; Molecular model; Mechanism of action; Oligodeoxyribonucleotide; Chemical synthesis; Protozoa; Minor groove; Rodentia; Benzene derivatives; X ray diffraction; In vitro; Diminazene; In vivo; Vertebrata; Biological fixation; Mammalia; Mouse; Animal; Sporozoa; Organic dication; Hydrogen bond
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9604484

Crystal structures are reported of complexes of two novel furan derivatives of berenil with alkyl benzamidine groups bound to the DNA sequence d(CGCGAATTCGCG)2. They have both been determined to 2.2 Å resolution and refined to R factors of 16.9% and 18.6%. In both structures the alkyl substituents, cyclopropyl and isopropyl, are found to be orientated away from the floor of the minor groove. The drugs are located in the minor groove by two strong amidinium hydrogen bonds, to the O2 of the thymines situated at the 5‘ and 3‘ ends of the AT-rich region. The isopropyl-substituted derivative has a tight hydrogen-bonded water network in the minor groove at one amidine site, which alters the orientation of the isopropyl substituent. This compound has superior DNA-binding properties and activity against Pneumocystis carinii and Cryptosporidium parvum infections in vivo compared to the cyclopropyl derivative, which in turn is superior to the parent furan compound. We suggest that the nature and extent of the interactions of these compounds in the DNA minor groove play an important role in these activities, possibly in conjunction with a DNA-binding protein. The overall effect of these alkyl benzamidine substitutions is to increase the binding of the drugs to the minor groove.