Chemoenzymatic parallel synthesis and high-throughput screening were employed to develop a multivalent aminoglycoside-polyamine library for use as high-affinity cation-exchange displacers and DNA-binding ligands. Regioselective lipase-catalyzed acylation, followed by chemical aminolysis, was used to generate vinyl carbonate and vinyl carbamate linkers, respectively, of the aminoglycosidic cores. These were further derivatized with polyamines, leading to library generation. A parallel batch-displacement assay was employed to identify the efficacy of the library candidates as potential displacers for protein purification. Using this approach, low-molecular-mass displacers with affinities higher than those previously observed have been identified. The aminoglycoside-polyamine library was also screened for DNA binding efficacy using an ethidium bromide displacement assay. These highly cationic molecules exhibited strong DNA-binding properties and may have potential for enhanced gene delivery.
We have recently developed a novel multivalent cationic library based on the derivatization of aminoglycosides by linear polyamines. In the current study, we describe the DNA-binding activity of this library. Screening results indicated that several candidates from the library showed high DNA-binding activities with some approaching those of cationic polymers. Quantitative Structure-Activity Relationship (QSAR) models of the screening data were employed to investigate the physicochemical effects governing polyamine-DNA binding. The utility of these models for the a priori prediction of polyamine-DNA-binding affinity was also demonstrated. Molecular descriptors selected in the QSAR modeling indicated that molecular size, basicity, methylene group spacing between amine centers, and hydrogen-bond donor groups of the polyamine ligands were important contributors to their DNA-binding efficacy. The research described in this paper has led to the development of new multivalent ligands with high DNA-binding activity and improved our understanding of structure-activity relationships involved in polyamine-DNA binding. These results have implications for the discovery of novel polyamine ligands for nonviral gene delivery, plasmid DNA purification, and anticancer therapeutics.
Chloroperoxidase (CPO) catalyzes the enantioselective oxidation of cyclopropylmethanols, such as 2-methylcyclopropylmethanol, to cyclopropyl aldehydes using tert-butyl hydroperoxide as the terminal oxidant. In all cases, CPO oxidation of cis-cyclopropanes shows much higher enantioselectivity than with the trans isomers, although CPO gives similar catalytic activity on both isomers. This presents the first example for a heme enzyme that catalyzes the enantioselective oxidation of cyclopropylmethanols. This finding enables a novel route to the synthesis of optically active cyclopropane derivatives, which occur widely in natural products and compounds of pharmaceutical interest. In addition, chiral cyclopropane molecules may be useful model substrates to investigate reaction mechanisms of CPO and the related cytochromes P450.
The selective oxidation and halogenation of nitroaromatics is a difficult task both chemically and enzymatically. We have discovered that vanadium chloro‐ and bromoperoxidases from Curvularia inaequalis and Corralina officinalis, respectively, are capable of catalyzing the hydroxylation, halogenation, and demethylation of 2,4,6‐trinitrotoluene (TNT) under alkaline conditions. At pH 8, the conversions for hydroxylation and demethylation reached 38 and 45%, respectively, while direct halogenation was minimal. Vanadium chloroperoxidase generated trinitrobenzyl alcohol with initial rates of 0.27 μM/h‐unit enzyme as compared with 0.11 μM/h‐unit enzyme for the vanadium bromoperoxidase. The products of the enzymatic reaction were easily separated and purified and the unreacted substrate recovered. In the presence of PCl5, the trinitrobenzyl alcohol produced by vanadium chloroperoxidase was readily converted to trinitrobenzyl chloride (TNBCl). This chemoenzymatic synthesis may be useful in the environmentally benign synthesis of hexanitrostilbene, a key component of heat‐resistant explosive materials.
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