Internal Activation of Peptidyl Prolyl Thioesters in Native Chemical Ligation

Prolyl thioesters have shown significantly lower reactivities in native chemical ligation (NCL) in comparison to that of the alanyl thioester. This report describes a mild and efficient internal activation protocol of peptidyl prolyl thioesters in NCL without using any thiol-based additives, where the introduction of a 4-mercaptan substituent on the C-terminal proline significantly improves the reactivity of prolyl thioesters via the formation of a bicyclic thiolactone intermediate. The kinetic data indicate that the reaction rate is comparable to that of the reported data of alanyl thioesters, and the mechanistic studies suggest that the ligation of two peptide segments proceeds through an NCL-like pathway instead of a direct aminolysis, which ensures the chemoselectivity and compatibility of various amino acid side chains. This 4-mercaptoprolyl thioester-based protocol also allows an efficient one-pot ligation–desulfurization procedure. The utility of this method has been further demonstrated in the synthesis of a proline-rich region of Wilms tumor protein 1

Synthesis of Chamaecypanone C Analogues from <i>in Situ</i>-Generated Cyclopentadienones and Their Biological Evaluation

A rhodium-catalyzed dehydrogenation protocol for the conversion of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones has been developed. With this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized <i>via</i> Diels–Alder cycloaddition between the cyclopentadienones and <i>in situ</i>-generated <i>o</i>-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure

Synthesis of Chamaecypanone C Analogues from <i>in Situ</i>-Generated Cyclopentadienones and Their Biological Evaluation

A rhodium-catalyzed dehydrogenation protocol for the conversion of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones has been developed. With this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized <i>via</i> Diels–Alder cycloaddition between the cyclopentadienones and <i>in situ</i>-generated <i>o</i>-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure

Advances in Proline Ligation

Application of native chemical ligation logic to the case of an N-terminal proline is described. Two approaches were studied. One involved incorporation of a 3<i>R-</i>substituted thiyl-proline derivative. Improved results were obtained from a 3<i>R</i>-substituted selenol function, incorporated in the context of an oxidized dimer

Engineering of Therapeutic Polypeptides through Chemical Synthesis: Early Lessons from Human Parathyroid Hormone and Analogues

Application of chemical synthesis to gain access to high purity hPTH as well as more stable analogues was accomplished through a menu of extended NCL followed by metal free dethiylation

Microwave-Based Reaction Screening: Tandem Retro-Diels–Alder/Diels–Alder Cycloadditions of <i>o</i>-Quinol Dimers

We have accomplished a parallel screen of cycloaddition partners for <i>o</i>-quinols utilizing a plate-based microwave system. Microwave irradiation improves the efficiency of retro-Diels–Alder/Diels–Alder cascades of <i>o-</i>quinol dimers which generally proceed in a diastereoselective fashion. Computational studies indicate that asynchronous transition states are favored in Diels–Alder cycloadditions of <i>o</i>-quinols. Subsequent biological evaluation of a collection of cycloadducts has identified an inhibitor of activator protein-1 (AP-1), an oncogenic transcription factor