Project Details


In order to understand such important processes as enzyme-substrate binding and antibody-antigen recognition, numerous investigators have synthesized and studied artificial hosts like water soluble cyclophanes. Some of these hosts have bound guests with high affinity constants but many improvements are needed. We intend to synthesize and study a particularly rigid "molecular tweezer" which will "sandwich" aromatic guests between two DNA intercalators. The complexation is expected to be very efficient and with a predictable geometry. We also believe that the approximate binding constant can be predicted using a simple cooperative model. Molecular tweezers with functional groups converging on the binding site will be investigated. These will be the first hosts which include their guests using both hydrogen bonding and hydrophobic forces resulting in improved guest discrimination. The specificity in binding mono-nucleotides will be investigated. In addition to host-guest chemistry these molecular tweezers are expected to be novel probes of DNA structure. A tremendous array of medicinals, including the clinically useful anticancer agent adriamycin, contain flat aromatic chromophores which bind to DNA by intercalation. Many aspects of the intercalation processes are not well understood including the important neighbor exclusion principle. Our molecular tweezers are the first bis-intercalators to force chromophores into adjacent sites. We will investigate chromophores of different "widths" to determine the origin of the neighbor exclusion principle. Those molecular tweezers which obey the principle will be unable to act as mono-intercalators and therefore unable to bind the internal sites of the DNA helix. We will demonstrate that these molecules are able to selectively bind to the ends of DNA helices which are not constrained by neighbor exclusion. This type of selective binding has not been seen before and should have a number of important applications.
Effective start/end date1/04/8731/03/92


  • National Institute of General Medical Sciences


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