Michael Joseph Luzzio

Fmoc mediated synthesis of Peptide Nucleic Acids

Abstract The syntheses of the Fmoc-protected Peptide Nucleic Acid (PNA) monomer pentafluorophenyl esters of adenine (26), cytosine (23), guanine (29) and thymine (20), and their oligomerization are described. The Fmoc PNA backbone 1 is prepared as a stable hydrochloride salt. The base acetic acids of adenine (4) and cytosine (3) were prepared by Cbz protection of the exocyclic amino groups followed by alkylation with t-butylbromoacetate and subsequent acid hydrolysis of the t-butyl ester. Allylation of 6-chloro-2-aminopurine followed by acid hydrolysis, Cbz protection with N-(benzyloxycarbonyl)imidazole, ozonolytic cleavage, and oxidation afforded the Cbz-protected guanine acetic acid (5). The base acetic acids (2, 3, 4 and 5) were coupled to the backbone (1) with either EDC (2 and 3) or BOP reagent (4 and 5). Acid hydrolysis of the resulting t-butyl esters and transesterification afforded the corresponding pentafluorophenyl esters (20, 23, 26 and 29). Oligomerization is conducted on a 0.05 mmol scale with a mere 2 fold excess of monomer in each coupling cycle. The N-terminal Fmoc group is retained on the final oligomer, following HF cleavage and deprotection, providing a convenient lipophilic handle for HPLC purification.

Design of selective, ATP-competitive inhibitors of Akt.

This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.