Design, Syntheses, and Bioactivities of Conformationally Locked Pin1 Ground State Inhibitors
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In order to assist the understanding of the biological function of Pin1 using molecular probes, two amide isosteres of Ser-trans-Pro and Ser-cis-Pro dipeptides were designed and stereoselectively synthesized. The conformationally locked Serâ transâ Pro mimic, Bocâ SerY[(E)CH=C]Proâ OH, was synthesized through the use of an Ireland-Claisen [3,3]-sigmatropic rearrangement in nine steps with 13% overall yield from a serine derivative. The Ser-cis-Pro mimic, Bocâ SerY[(Z)CH=C]Proâ OH, was synthesized through the use of a Still-Wittig [2,3]-sigmatropic rearrangement in 11 steps with an overall yield of 20% from the same starting material.
Conformationally locked peptidomimetics, including two exactly matched peptidomimetics, Acâ Pheâ Pheâ pSerΨ(E)CH=C]Proâ Argâ NH2 and Acâ Pheâ Pheâ pSerΨ[(Z)CH=C]Proâ Argâ NH2, were synthesized from these Ser-Pro isosteres using Fmoc SPPS. A protocol for in vitro Pin1 inhibition assay was established for measuring the inhibition constant for these peptidomimetics. A conformationally locked cis peptidomimetic inhibits Pin1 with a Ki of 1.7 mM, 23-fold more potent than its trans counterpart, illustrating the preference of Pin1 for a cis amide bond in its PPIase domain. The A2780 ovarian cancer cell antiproliferation activity of these peptidomimetics parallels their respective Pin1 inhibition data. This research provides a start toward more drug-like Pin1 inhibitor design. Glyâ transâ Pro isosteres were synthesized using the Ireland-Claisen route. The construction of a non-peptidic (Z)-alkene library for Pin1 inhibition was attempted using the Ser-cis-Pro mimic, Boc—SerΨ[(Z)CH=C]Proâ OH as the core.
- Doctoral Dissertations