The main aims of our research program involve the synthesis of target bioactive hormones selected from results of conformational analysis and bioassays. The synthesis will be carried out in solution and by solid phase peptide methodologies. Our synthetic projects include somatostatin and oxytocin analogs emphasizing lanthionine containing structures. We will incorporate peptidomimetics such as cyclic structures, chiral methylated amino acids and peptoid structures. Specifically, the sandostatin {D-Phe-c(Cys-Phe-D-Trp-Lys-Thr-Ser-Cys]-Thr-ol} and the somatostatin related cyclohexapeptide [Pro-Phe-D-Trp-Lys-Thr-Phe] will be modified in the bridging region using lanthionine derivatives and multiple chiral methylations on the alpha-carbons and in the side chains. We will incorporate diastereomeric cyclolanthionine building units as conformationally constrained residues with cis amide bonds. We gain crucial information on the structure/bioactivity relationships using 2-D1H-NMR experiments, including 2-D total correlation spectroscopy (TOCSY) and rotating frame Overhauser enhancement spectroscopy (ROESY), in conjunction with molecular modeling techniques such as distance geometry, energy minimization, cluster analysis and molecular dynamics. We are also exploring 2-D 13C-1H heteronuclear techniques, such as the omega1 hetero half filtered TOCSY (HETLOC) and the multiple quantum coherence spectroscopy (HNQC) in order to define the backbone conformation of our analogs and measure at the rotamer populations of the side chains of the target molecules. The structural results together with bioassays carried out in the laboratories of our collaborators enable us to refine our selections of target molecules for synthesis. Currently, five different somatostatin receptors are available. Since these are genetically expressed in different organs, each receptor can be an important target for our program. Our somatostatin related ligands will be tested to determine potency and selectivity for each specific receptor type. In addition, novel lanthionine analogs of the antineoplastic somatostatin TT-232 [D-Phe-c(Cys-Trp-Lys-Cys)-Thr-NH2] will be prepared and tested for antitumor bioactivity. We intend to develop novel molecules with strong antitumor activity with low affinity to other somatostatin related receptors (SSTR1-3 and SSTR5). The results will provide crucial information to define structure requirements for recognition of each somatostatin receptor. Since there is a strong need of enzymatically stable and highly active oxytocin agonists and antagonists, we plan to synthesize and study molecules incorporating beta-methylated lanthionine building blocks. Some of our designed oxytocin analogs are expected to possess high antagonistic potency such as Atosiban {[1-deamino,Tyr2(OEt), Thr4, Orn8]vasotocin} but with higher selectivity. These compounds could be useful e.g., for the prevention of pre-term births. From this integrated approach, we hope to design and synthesize new candidate drug molecules.
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