John P. Mayer

SOLID PHASE SYNTHESIS OF 1,4-BENZODIAZEPINE-2,5-DIONES

Abstract 1,4-benzodiazepine-2,5-diones were synthesized by a simple procedure utilizing polymer supported amino acids and o-nitrobenzoic acids or protected anthranilic acids. Cyclization of the common aminoamide intermediate with concomitant release from the support furnished the desired 1,4-benzodiazepine-2,5-diones. The products were recovered in high yields and exhibited excellent purities.

Solid phase synthesis of quinazolinones

Abstract Substituted 4(3H)-quinazolinones were synthesized under acidic conditions from polymer supported anthranilamide precursors and aldehyde inputs. Dehydrogenation using potassium permanganate followed by trifluoroacetic acid cleavage afforded the desired compounds in acceptable yields and purities. Additional diversity at the 3 position was realized by employing amino acid derivatized polymer support.

In Vitro Assay and Characterization of the Farnesylation-dependent Prelamin A Endoprotease

The 72-kDa nuclear lamina protein lamin A is synthesized as a 74-kDa farnesylated precursor. Conversion of this precursor to mature lamin A appears to be mediated by a specific endoprotease. Prior studies of overexpressed wild-type and mutant lamin A proteins in cultured cells have indicated that the precursor possesses the typical carboxyl-terminal S-farnesylated, cysteine methyl ester and that farnesylation is required for endoproteolysis to occur. In this report, we describe the synthesis of an S-farnesyl, cysteinyl methyl ester peptide corresponding to the carboxyl-terminal 18 amino acid residues of human prelamin A. This peptide acts as a substrate for the prelamin A endoprotease in vitro, with cleavage of the synthetic peptide at the expected site between Tyr657 and Leu658. Endoproteolytic cleavage requires the S-prenylated cysteine methyl ester and, in agreement with transfection studies, is more active with the farnesylated than geranylgeranylated cysteinyl substrate. N-Acetyl farnesyl methyl cysteine is shown to be a noncompetitive inhibitor of the enzyme. Taken together, these observations suggest that there is a specific farnesyl binding site on the enzyme which is not at the active site.

Application of the Pictet-Spengler reaction in combinatorial chemistry

Abstract Reaction of polymer bound tryptophan with a variety of aldehydes and ketones under Pictet-Spengler like conditions was found to produce 1,2,3,4-tetrahydro-β-carbolines in excellent yield. The straightforward, easily automated chemistry and the availability of numerous commercial aldehydes and ketones makes this approach ideal for combinatorial chemistry application.

SOLID-PHASE SYNTHESIS OF BENZIMIDAZOLES

Abstract A readily automated solid-phase approach to the synthesis of diverse benzimidazoles is described. The procedure utilizes polymer supported 4-fluoro-3-nitrobenzoic acid and a wide range of commercially available amines and aldehydes. The key heterocyclization step is achieved under mild conditions and was found to be general for a large number of diverse inputs.

An alternative solid-phase approach to C1-oxytocin

Abstract A general, solid-phase method based on in situ formation of a cystathionine residue is described. The procedure allows for the introduction of a thioether moiety in place of a native disulfide bond and is illustrated here by the synthesis of C 1 -oxytocin 1 .

Solid phase synthesis of peptidomimetics

The characteristic peptide properties of low bioavailability and short half life present significant problems in their development as therapeutic agents. One approach to overcoming these problems has been the identification of non-peptide structures whose topological features enable them to mimic binding of the native peptide at the receptor level. These compounds are collectively known as peptidomimetics and have been the subject of several extensive reviews [1, 2, 3]. Recent advances in solid phase organic synthesis have the potential to accelerate the discovery and lead optimization phases of medicinal chemistry, including the area of peptidomimetic research. While much peptidomimetic chemistry has traditionally been performed by solution phase methods, the application of solid phase methodology can offer many of the same inherent advantages with respect to speed and ease of automation which have been realized in solid phase peptide synthesis. Our initial efforts have centered around the development of solid phase methods for two well established peptidomimetic scaffolds shown in Fig.l, the l,4-benzodiazepine-2,5-diones 1 [4], and the 4-(3H)-quinazolinones 2 [5].