CC-1065 CBI analogs: an example of enhancement of DNA alkylation efficiency through introduction of stabilizing electrostatic interactions

• Published in: Bioorganic & medicinal chemistry 1995-06, Vol.3 (6), p.611-621
• Main Authors: Boger, Dale L., Yun, Weiya, Han, Nianhe, Johnson, Douglas S.
• Format: Article
• Language: English
• Subjects: Alkylation; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Base Sequence; Binding Sites; DNA - drug effects; Electrochemistry; Indoles; Leucomycins - chemistry; Leucomycins - pharmacology; Models, Molecular; Molecular Sequence Data; Quaternary Ammonium Compounds - chemistry; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(95)00048-L

The three trimethylammonium salts 3–5 proved to be 100 times more efficient at alkylating DNA than 2 and exhibited DNA alkylation efficiencies identical to that of (+)-CC-1065 ( 1). In addition, the agents 3 and 4 exhibited DNA alkylation selectivities identical to that of 2. This may be attributed to spatially well-defined stabilizing electrostatic interactions between the positively charged trimethylammonium salt lying on the peripheral face of the agents and the bracketing, negatively charged phosphates located in the DNA backbone that enhance the DNA noncovalent binding affinity without affecting DNA binding or alkylation selectivity. The agent 5 exhibited an altered and more discriminating AT-rich adenine N3 alkylation selectivity than 2–4 that may be attributed to the groove placement of the large trimethylammonium salt. The three trimethylammonium salts 3–5 proved to be 100x more efficient at alkylating DNA than 2 and exhibited DNA alkylation efficiencies identical to that (+)-CC-1065 ( 1).