WestCHEM Research School, Department of Pure & Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, Scotland, United Kingdom.
Eur J Med Chem. 2011 Nov;46(11):5343-55. doi: 10.1016/j.ejmech.2011.08.035. Epub 2011 Aug 30.
Antibacterial minor groove binders related to the natural product, distamycin, are development candidates for novel antibiotics. Alkenes have been found to be effective substitutes for the isosteric amide links in some positions and alkyl groups larger than methyl have been found to increase binding to DNA in both selectivity and affinity. However the impact of other isosteres such as diazenes and the position of an alkyl group with respect to DNA binding and antibacterial activity are not known. The effects of some systematic variations in the structure of polyamide minor groove binders are investigated. Isosteres of the amide link (alkenes and diazenes) are compared: it is shown that all three are competent for binding to DNA but that alkene links give the tightest binding and highest antibacterial activity; no significant antibacterial activity was found for compounds with a diazene link. Within a series of alkene linked compounds, the effect of branched N-alkyl substituents on binding to DNA and antibacterial activity is investigated: it was found that C3 and C4 branched chains are acceptable at the central pyrrole residue but that at the pyrrole ring adjacent to the basic tail group, a C4 branched chain was too large both for DNA binding and for antibacterial activity. The active branched alkyl chain compounds were found to be especially active against Mycobacterium aurum, a bacterium related to the causative agent of tuberculosis.
与天然产物放线菌素相关的具有抗菌作用的小沟结合物是新型抗生素的候选药物。已经发现烯烃在某些位置是酰胺键的有效替代品，并且发现烷基大于甲基可以增加 DNA 结合的选择性和亲和力。然而，其他等排体（如重氮）以及烷基在 DNA 结合和抗菌活性方面的位置的影响尚不清楚。本文研究了聚酰胺小沟结合物结构的一些系统变化的影响。对酰胺键的等排体（烯烃和重氮）进行了比较：结果表明，这三种都能够与 DNA 结合，但烯烃键的结合最紧密，抗菌活性最高；具有重氮键的化合物没有表现出显著的抗菌活性。在一系列烯键连接的化合物中，研究了 N-烷基取代基在 DNA 结合和抗菌活性方面的影响：结果发现，在中央吡咯残基上，C3 和 C4 支链是可以接受的，但在与碱性尾部相邻的吡咯环上，C4 支链对于 DNA 结合和抗菌活性来说太大了。具有活性支链烷基的化合物被发现对金黄色葡萄球菌（一种与结核病病原体有关的细菌）特别有效。
