Design, synthesis & thermodynamic evaluation of conformationally-constrained pseudopeptides and synthetic approaches to sieboldine A

Teresk, Martin Gerald, 1981-
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A series of conformationally constrained and flexible pseudopeptides were prepared and their thermodynamic parameters on binding to the Grb2 SH2 domain were determined by isothermal titration calorimetry (ITC). Cyclopropane constrained analogs having hydrophobic amino acid residues at the pTyr+1 position exhibited, on average, a 2-5 fold improvement in binding affinities with the enhancement in affinities due to a more favorable enthalpy, not entropy, of binding. This serves as the first set of examples which demonstrate that favorable entropies of binding are not an inherent characteristic of ligand preorganization. Incorporation of polar amino acid residues at the pTyr+1 position eventuated in a slightly different thermodynamic effect than what was observed with the hydrophobic analogs. The constrained molecules exhibited greater binding affinities for the Grb2 SH2 domain and that increase in affinity was a consequence of a more favorable enthalpy, not entropy, of binding. However, the binding entropies for the polar set of constrained and flexible molecules were all negative. Structural information obtained from the co-crystallization of selected constrained and flexible ligand pairs with the Grb2 SH2 domain revealed an increase in conformational mobility of the BC loop in the complexes of the constrained derivatives and the presence of a greater number of direct polar contacts, but fewer water-mediated interactions between the phosphate group of the constrained molecules and the pTyr binding pocket of the domain. The construction of the cis-hydrindanone ring system in sieboldine A was accomplished utilizing either a Lewis acid-mediated silyl-directed Nazarov cyclization of a functionalized divinyl ketone or a sequential Ni(0)-catalyzed 1,4-addition/5-endo-dig cyclization. Propargylzinc bromide was shown to undergo conjugate addition to the [alpha]-aminopropyl substituted enone using Ni(acac)₂, thus providing a new, mild protocol for the conjugate propargylation reaction. Further efforts toward the formation of the α-epoxy ketone are described.