Glycosylated natural products are reliable platforms for the development of many front-line drugs, yet our understanding of the relationship between attached sugars and biological activity is limited by the availability of convenient glycosylation methods. When a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation is used, the glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycosideinduced cytotoxicity and Na ؉ ͞K ؉ -ATPase inhibition. This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery.carbohydrate ͉ natural product ͉ sugar
The use of a simple fluorescent nucleoside analogue in detection of point mutations by hybridization in solution is described. Pyrene is placed at 3' and 5' ends of a pair of oligodeoxynucleotide probes via a phosphoramidite derivative of deoxyribose with this fluorophore attached at the 1' position, replacing a DNA base. Adjacent binding of dual probes containing this fluorophore to a complementary target sequence results in a pronounced spectral change from blue pyrene monomer emission (lambdamax= 381 398 nm) to green-white excimer emission (lambdamax= 490 nm). Optimization of the relative binding positions of the two probes shows that the greatest spectral change occurs when they bind with partial end overlap. In optimum orientation, the monomer emission band for the probes decreases intensity by as much as a factor of seven and the excimer band increases up to 40-fold on binding a complementary target. Application to the detection of a single-base point mutation in solution is described.
The asymmetric synthesis of the potent immunosuppressive agent (−)-pateamine A isolated from
the marine sponge Mycale sp. is described. A key strategy employed in the synthesis was a β-lactam-based
macrocyclization to form the 19-membered dilactone macrolide. The synthesis confirms the relative and absolute
stereochemistry as 3R,5S,10S,24S and sets the stage for studies into the mechanism of action of pateamine A.
Other studies and findings made in the course of the synthesis and described herein include the following: (1)
a Stille coupling can be competitive with π-allyl formation, (2) SmI2 effects a mild N−O cleavage of
N-benzyloxy-β-lactams, (3) the synthesis of a pateamine A-dexamethasone hybrid molecule for use in a yeast
three-hybrid assay was accomplished, and (4) IC50 values were determined for synthetic and natural pateamine
A and related compounds in the interleukin 2 reporter gene assay.
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