(-)-sandramycin and analogs: Syntheses and characterization of DNA binding properties
Abstract
The first total synthesis of the potent antitumor antibiotic ($-$)-sandramycin (3), a member of a growing class of natural products now including the luzopeptins and quinaldopeptins, is described. Members of this class of agents have been shown to exhibit sequence selective DNA bifunctional intercalation and possess potent antitumor, antimicrobial, and antiviral properties. Structure characteristics common to this class of natural products, include a two fold axis of symmetry and two pendant heteroaromatic quinoline chromophores. Key strategic elements of the approach to ($-$)-sandramycin which confirmed its structure and unambiguously established the absolute stereochemistry include the late stage introduction of the heteroaromatic chromophore, thereby providing a simple access to structural analogs possessing altered intercalation capabilities, symmetrical pentadepsipeptide coupling and 32-membered macrocyclization conducted at the single secondary amide site in excellent conversion, and a convergent assemblage of the precursor pentadepsipeptide in which the potentially labile ester linkage was introduced in the final key coupling reaction. This approach also provided the cyclic decadepsipeptides 58 possessing a single chromophore and was extended to the preparations of analogs 84-102. A single-crystal X-ray structure determination of 52 and its comparisons with that of luzopeptin A in addition to the $\sp1$H NMR solution conformations of sandramycin, 51 and 52 are detailed and reveal that the same characteristic rigid conformation is inherent in both the solid and solution structure of the cyclic decadepsipeptide. Characterizations of the DNA binding properties of sandramycin employing fluorescence and absorption quenching, agarose gel electrophoresis, and DNase I footprinting techniques are detailed. Sandramycin was found to exhibit an exceptionally high affinity for duplex calf thymus DNA and proved to be slightly better than luzopeptin A, substantially more effective than 58 possessing a single chromophore, and much more effective than 52 lacking both intercalation chromophores.
Degree
Ph.D.
Advisors
Boger, Purdue University.
Subject Area
Organic chemistry
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