CONFORMATIONAL MIMICRY - SYNTHESIS AND SOLUTION CONFORMATION OF A CYCLIC SOMATOSTATIN HEXAPEPTIDE CONTAINING A TETRAZOLE CIS AMIDE BOND SURROGATE

Potent, cyclic hexapeptide analogues of somatostatin are generally believed to adopt some common secondary structural features: alpha II'beta turn at one end of the cycle, and a type VI turn with a cis amide bond at the other. A proposed cis amide surrogate, the 1,5-disubstituted tetrazole, has been placed into a cyclic hexapeptide analog of somatostatin in order to constrain the putative cis amide bond. The final cyclization was done by either chemical or enzymatic means. The product, cycle (Ala(6)-Tyr(7)-D-Trp(8)-Lys(9)-Val(10)-Phe(11)-Psi[CN4]), was found to have 83% of the activity of somatostatin. Solution nmr analysis in DMSO/water revealed that the backbone as well as side chain chi(1) and chi(2) were well ordered. Relaxation matrix methods were rued to extract distance restraints from the nuclear Overhauser effect spectroscopy data set, and these were used in a systematic search of torsional space to identify structures consistent with the nmr data. Restrained minimizations of these structures using a number of different force fields produced structures having the expected beta II' turn at D-Trp(8)-Lys(9) and a beta VIa turn in the Phe(11)-Psi[CN4]-Ala(6) portion of the molecule. The similarity of the minimized structures to those previously reported for cyclic hexapeptide analogies of somatostatin confirms the similarity of the tetrazole geometry To that of the cis amide in solution. (C) 1995 John Wiley & Sons, Inc.