Novel reagents and reactions for drug design

Abstract

In this presentation, we cover new results from two of our synthetic endeavors: guanidinylation reagents and novel bridged opioids. In the first part, we describe the applications of the diurethane-triflylguanidines to prepare target bioactive structures including peptides, heterocyclic drugs, and aminoglycoside derivatives. The formation of novel guanidinoglycosides led to a family of effective binders to the RNA recognition element of the HIV-1 Rev protein. In the second part, the syntheses of sulfur and amine-bridged cyclic opioids is described. These analogs exhibit enhanced binding, both in vitro and in vivo. Specifically, H-Tyr-c[d-Val_l-Gly-Phe-d/l-Ala_l]-OH (Val_l and Ala_l denote the lanthionine amino acid ends linked by a monosulfide bridge) is potent and highly δ -receptor selective while Tyr-c[(Nγ CH₃ )-d-A₂ bu-Gly-Phe-NHCH₂CH₂ -] though nonselective is one of the most potent opioids prepared to date. These molecules are representative of our design of novel peptidomimetic opioids.