Cynthia A. Maryanoff

Reductive amination of aldehydes and ketones by using sodium triacetoxyborohydride

Abstract Sodium triacetoxyborohydride is a reagent of choice in the reductive amination of aldehydes and saturated aliphatic ketones with primary and secondary amines. Sodium triacetoxyborohydride was successfully used in the reductive amination of variety of aldehydes and ketones with primary and secondary amines.

Thrombogenic collagen-mimetic peptides: Self-assembly of triple helix-based fibrils driven by hydrophobic interactions

Collagens are integral structural proteins in animal tissues and play key functional roles in cellular modulation. We sought to discover collagen model peptides (CMPs) that would form triple helices and self-assemble into supramolecular fibrils exhibiting collagen-like biological activity without preorganizing the peptide chains by covalent linkages. This challenging objective was accomplished by placing aromatic groups on the ends of a representative 30-mer CMP, (GPO)10, as with l-phenylalanine and l-pentafluorophenylalanine in 32-mer 1a. Computational studies on homologous 29-mers 1a′–d′ (one less GPO), as pairs of triple helices interacting head-to-tail, yielded stabilization energies in the order 1a′ > 1b′ > 1c′ > 1d′, supporting the hypothesis that hydrophobic aromatic groups can drive CMP self-assembly. Peptides 1a–d were studied comparatively relative to structural properties and ability to stimulate human platelets. Although each 32-mer formed stable triple helices (CD) spectroscopy, only 1a and 1b self-assembled into micrometer-scale fibrils. Light microscopy images for 1a depicted long collagen-like fibrils, whereas images for 1d did not. Atomic force microscopy topographical images indicated that 1a and 1b self-organize into microfibrillar species, whereas 1c and 1d do not. Peptides 1a and 1b induced the aggregation of human blood platelets with a potency similar to type I collagen, whereas 1c was much less effective, and 1d was inactive (EC50 potency: 1a/1b ≫ 1c > 1d). Thus, 1a and 1b spontaneously self-assemble into thrombogenic collagen-mimetic materials because of hydrophobic aromatic interactions provided by the special end-groups. These findings have important implications for the design of biofunctional CMPs.

An investigation of adhesion in drug-eluting stent layers

An atomic force microscopy (AFM) method was developed to quantify the adhesion forces between and cohesive forces within the layers of a drug-eluting stent (DES). Surface pairs representing both the individual components and the complete chemistry of each layer within the DES were prepared. As a model, the CYPHER Sirolimus-eluting Coronary Stent was studied. This DES consists of a stainless steel stent substrate, a parylene C primer layer, and a drug-eluting layer that contains poly(ethylene-co-vinyl acetate), poly(n-butyl methacrylate), and sirolimus (rapamycin). Coated AFM tips and two-dimensional substrates or coupons, which act as surrogates to the CYPHER Stent, were prepared and characterized. The force-displacement measurements were conducted to evaluate the adhesion between the middle parylene C layer and the 316L stainless steel substrate, the adhesion between the parylene C layer and the outer drug-eluting layer, and the cohesion between the three constituents of the drug-eluting layer. The average adhesion forces between the parylene C to drug layer varied from 88 to 167 nN, and the drug layer-to-drug layer interactions were between 194 and 486 nN within the model CYPHER Stent coating. All the adhesion forces measured were larger than those observed for gold-gold interactions, which yielded a pull of force of 19 nN (Zong et al., J Appl Phys 2006;100:104313-104323).

Hydrolysis of polypeptide esters with tetrabutylammonium hydroxide

Abstract Tetrabutylammonium hydroxide is effective in hydrolysis of polypeptide esters to the corresponding acids with minimum racemization of the stereogenic centers at the α-positions. It is especially effective in hydrolysis of non-polar polypeptide esters that are insoluble in most common solvents.

Adhesion and interfacial fracture toughness between hard and soft materials

This paper presents the results of a combined experimental and theoretical study of adhesion between hard and soft layers that are relevant to medical devices such as drug-eluting stents and semiconductor applications. Brazil disk specimens were used to measure the interfacial fracture energies between model parylene C and 316L stainless steel over a wide range of mode mixities. The trends in the overall fracture energies are predicted using a combination of adhesion theories and fracture mechanics concepts. The measured interfacial fracture energies are shown to be in good agreement with the predictions.

Adhesion and interfacial fracture in drug-eluting stents

This paper presents experimental and theoretical studies of the adhesion between the drug-eluting layer and a Parylene C primer layer in coatings present on a model drug-eluting stent. To quantify adhesion, Brazil nut sandwich specimens were prepared mimicking the layers of this coating. These samples were stressed to fracture, and the resulting initial cracks at the Parylene C/drug interface were used to measure the dependence of interfacial fracture energy of mode mixity. The mating fracture surfaces were then analyzed using scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy (EDX). The interfacial energy release rates were obtained over a wide variety of mode mixities. Adhesion and fracture mechanics models were then used to estimate the mode mixity dependency of interfacial fracture toughness. Fracture toughness was found to be larger under higher mode mixity than that under lower mixity and the analytical model showed close agreement with experimental results.

Multivariate analysis applied to the study of spatial distributions found in drug-eluting stent coatings by confocal Raman microscopy.

Multivariate data analysis was applied to confocal Raman measurements on stents coated with the polymers and drug used in the CYPHER Sirolimus-eluting Coronary Stents. Partial least-squares (PLS) regression was used to establish three independent calibration curves for the coating constituents: sirolimus, poly(n-butyl methacrylate) [PBMA], and poly(ethylene-co-vinyl acetate) [PEVA]. The PLS calibrations were based on average spectra generated from each spatial location profiled. The PLS models were tested on six unknown stent samples to assess accuracy and precision. The wt % difference between PLS predictions and laboratory assay values for sirolimus was less than 1 wt % for the composite of the six unknowns, while the polymer models were estimated to be less than 0.5 wt % difference for the combined samples. The linearity and specificity of the three PLS models were also demonstrated with the three PLS models. In contrast to earlier univariate models, the PLS models achieved mass balance with better accuracy. This analysis was extended to evaluate the spatial distribution of the three constituents. Quantitative bitmap images of drug-eluting stent coatings are presented for the first time to assess the local distribution of components.

An efficient stereoselective synthesis of methyl (S)-3-amino-3-(3-pyridyl)propanoate

Methyl (S)-3-amino-3-(3-pyridyl)propanoate (2) is a key starting material in the synthesis of RWJ-53308 (1), an orally active antagonist of the platelet fibrinogen receptor (GP IIb/IIIa antagonist). Herein, we describe an efficient stereoselective synthesis of 2 by the hydrogenation of enantiomeric enamine 8 with Pd(OH)2C, followed by the removal of the chiral auxiliary under mild conditions, a novel procedure that employs the combination of formic acid and triethylsilane.

A Practocal Prepraration of D1-2-Substituted and D1-2,3-Disubstituted Pyrrolines

Addition of N-vinylpyrrolidinone and an ester to NaH in THF effects acylation and affords keto lactams (1) in high yields. Hydrolysis of 1 in strong acid generates Δ 1 -2-substituted pyrrolines (2) in good yield. Keto lactams (1) can be further alkylated and hydrolyzed to produce Δ 1 -2,3-disubstituted pyrrolines (4) in good isolated yield

Pore Networks and Polymer Rearrangement on a Drug-Eluting Stent as Revealed by Correlated Confocal Raman and Atomic Force Microscopy

Drug release from and coating morphology on a CYPHER sirolimus-eluting coronary stent (SES) during in vitro elution were studied by correlated confocal Raman and atomic force microscopy (CRM and AFM, respectively). Chemical surface and subsurface maps of the SES were generated in the same region of interest by CRM and were correlated with surface topography measured by AFM at different elution times. For the first time, a direct correlation between drug-rich regions and the coating morphology was made on a drug-eluting medical device, linking drug release with pore formation, pore throats, and pore networks. Drug release was studied on a drug-eluting stent (DES) system with a multicomponent carrier matrix (poly(n-butyl methacrylate) [PBMA] and poly(ethylene-co-vinyl acetate) [PEVA]). The polymer was found to rearrange postelution because confluence of the carrier polymer matrix reconstituted the voids created by drug release.