Sodium triacetoxyborohydride is presented as a general reducing agent for the reductive amination of aldehydes and ketones. Procedures for using this mild and selective reagent have been developed for a wide variety of substrates. The scope of the reaction includes aliphatic acyclic and cyclic ketones, aliphatic and aromatic aldehydes, and primary and secondary amines including a variety of weakly basic and nonbasic amines. Limitations include reactions with aromatic and unsaturated ketones and some sterically hindered ketones and amines. 1,2-Dichloroethane (DCE) is the preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran (THF) and occasionally in acetonitrile. Acetic acid may be used as catalyst with ketone reactions, but it is generally not needed with aldehydes. The procedure is carried out effectively in the presence of acid sensitive functional groups such as acetals and ketals; it can also be carried out in the presence of reducible functional groups such as C-C multiple bonds and cyano and nitro groups. Reactions are generally faster in DCE than in THF, and in both solvents, reactions are faster in the presence of AcOH. In comparison with other reductive amination procedures such as NaBH(3)CN/MeOH, borane-pyridine, and catalytic hydrogenation, NaBH(OAc)(3) gave consistently higher yields and fewer side products. In the reductive amination of some aldehydes with primary amines where dialkylation is a problem we adopted a stepwise procedure involving imine formation in MeOH followed by reduction with NaBH(4).

IntroductionLiver-directed gene transfer using adeno-associated virus (AAV) vectors has the potential to serve as therapy for several inherited hematologic diseases. One such disease is the bleeding disorder hemophilia B, caused by a deficiency in coagulation factor IX (FIX). Currently, there are 2 clinical trials for hemophilia B that use liver-directed AAV-mediated gene transfer of the F9 gene (www. clinicaltrials.gov; identifiers NCT00515710 and NCT00979238). One of these trials reported transient efficacious circulating FIX levels (ϳ 10%) with the use of the vector AAV2-hFIX16. 1 Although AAV vectors are predominantly nonintegrating, with most of the transgene expression from stable episomes, 2 it has been shown through direct sequencing that integration can occur. 3,4 When integration takes place, there is a preference for integrating in regions where DNA breaks occur. These can be regions of endonuclease cleavage, 5 active transcription, 6-8 cytosine-phosphateguanosine (CpG) islands, 7,8 and palindromes. 9 All of these studies describing AAV vector genome integration identified vector integration sites through plasmid rescue of vectors containing bacterial origins of replication (ori). 4 Amplification of these plasmids in bacterial culture allows for sequencing of the integration junction between vector and host genome. Because of the bacterial selection involved in this method, bias may occur against recovering integrants whose size or sequence negatively affect bacterial growth, resulting in incomplete mapping of the full spectrum of integrants.Vector genome integration has been associated with adverse events; integrating ␥-retroviral vectors were implicated in the clonal expansion of transduced cells in 3 clinical studies, 2 for X-linked severe combined immunodeficiency 10,11 and the other for chronic granulomatous disease. 12,13 Although AAV vectors integrate at a much lower frequency than retroviral vectors, low-level AAV vector integration in transduced cells may still be a concern. A compelling argument supporting low genotoxic risk of AAV vectors comes from long-term follow-up of liver-directed AAVmediated gene transfer in canine and murine models. Of 77 dogs receiving AAV vector at doses up to 3.4 ϫ 10 12 vector genomes(vg)/kg and followed for Յ 10 years, none developed liver tumors as assayed by ultrasound, computed tomographic (CT) scan, and magnetic resonance imaging (MRI) 14,15 (K.A.H., V.R.A., and Timothy C. Nichols, unpublished data, October 15, 2010). Similarly, Ͼ 300 mice receiving AAV vectors with a therapeutic transgene at doses up to 4 ϫ 10 13 vg/kg and followed Յ 14 months have not shown a difference in tumor incidence compared with control mice. 16,17 However, a study by one group reported an increase in tumor incidence that was attributed to AAV vectors. 18 These investigators reported that administration of an AAV serotype 2 (AAV2) vector encoding ␤-glucuronidase in neonatal mice resulted in a significant increase in incidence of hepatocellular carcinoma (HCC), a tumor commonly fou...

IMPORTANCE A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis.OBJECTIVE To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy. DESIGN, SETTING, AND PARTICIPANTSIn this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed.

Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride.Studies on Direct and Indirect Reductive Amination Procedures.-NaBH(O-Ac) is found to be a synthetically useful reagent for reductive amination of aldehydes and ketones. With aliphatic acyclic and cyclic ketones, aliphatic and aromatic aldehydes, and primary and secondary amines including weakly basic and nonbasic amines the reaction proceeds effectively. In some cases of reductive amination of aldehydes with primary amines considerable amounts of dialkylated or other side products are obtained. A stepwise (indirect) procedure involving imine formation followed by NaBH4-mediated reduction is a convenient alternative for such cases. -(ABDEL-MAGID, A. F.; CARSON, K. G.; HARRIS, B. D.; MARYANOFF, C. A.; SHAH, R. D.; J.

The first use of Fourier transform vibrational circular dichroism (FT-VCD) to follow changes in the percent enantiomeric excess (% EE) of chiral molecules in time using a flow cell sampling apparatus is reported. FT-VCD, as opposed to dispersive scanning VCD, eliminates the need to scan the VCD spectrum in time to monitor the % EE at more than one spectral location. The first use of partial least-squares chemometric analysis to determine % EE values from kinetic sets of VCD spectral data is also reported. These two advances have been used to monitor simultaneously changes in the fractional composition and the % EE of a mixture of two different chiral molecules. This simulates the progress of the chemical reaction from a chiral reactant to a chiral product where the % EE of both molecules can change with time. For the molecules studied, alpha-pinene, camphor, and borneol, the accuracy of following % EE changes for one species alone is approximately 1%, while for simultaneously following % EE changes in two species is approximately 2% for 10-20-min sampling periods at 4 cm(-)(1) spectral resolution. This accuracy can be increased for the same collection times or maintained for shorter periods of collection by lowering the spectral resolution. These findings demonstrate the potential for VCD to be used for real-time monitoring of the composition and % EE of chemical reactions involving the synthesis chiral molecules.

Early detection may help improve survival from lung cancer. In this study our goal was to derive and validate a signature from the proteomic analysis of bronchial lesions that could predict the diagnosis of lung cancer. Using previously published studies of bronchial tissues we selected a signature of 9 matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) mass to charge ratio features to build a prediction model diagnostic of lung cancer. The model was based on MALDI MS signal intensity (MALDI score) from bronchial tissue specimens from our 2005 published cohort of 51 patients. The performance of the prediction model in identifying lung cancer was tested in an independent cohort of bronchial specimens from 60 patients. The probability of having lung cancer based on the proteomic analysis of the bronchial specimens was characterized by an area under the receiver operating characteristic curve of 0.77 (95% CI 0.66 to 0.88) in this validation cohort. Eight of the 9 features were identified and validated by Western blotting and immunohistochemistry. These results demonstrate that proteomic analysis of endobronchial lesions may facilitate the diagnosis of lung cancer and the monitoring of high risk individuals for lung cancer in surveillance and chemoprevention trials.

2018 report linked long-term use of pentosan polysulfate sodium (PPS) to a vision-threatening macular disease. 1 Subsequent larger studies have corroborated this finding, demonstrating a strong drug-disease association. [2][3][4] Affected patients typically report difficulty with reading and problems with dark adaptation. Retinal imaging demonstrates characteristic changes within the retinal pigment epithelium (RPE) and at the RPE-photoreceptor interface, with some patients exhibiting fovea-involving RPE atrophy. 3,5 Because PPS has been widely prescribed since its approval by the US Food and Drug Administration in 1996, thousands of patients are at risk. 4 Although affected patients are typically advised to discontinue PPS therapy, little is known about the evolution of this newly described retinopathy after drug cessation. The present study is a retrospective evaluation of outcomes after drug cessation in a group of affected individuals across 2 institutions. MethodsThis retrospective study was approved by each participating institution's institutional review board and was conducted at Emory University. Data collection was performed systemati-IMPORTANCE Recent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS).OBJECTIVE To evaluate the disease course in PPS-associated maculopathy after drug cessation.

Although intravenously administered antiplatelet fibrinogen receptor (GPIIb/IIIa) antagonists have become established in the acute-care clinical setting for the prevention of thrombosis, orally administered drugs for chronic use are still under development. Herein, we present details from our exploration of structure-activity surrounding the prototype fibrinogen receptor antagonist RWJ-50042 (racemate of 1), which was derived from a unique approach involving the gamma-chain of fibrinogen (Hoekstra et al. J. Med. Chem. 1995, 38, 1582). Our analogue studies culminated in the discovery of RWJ-53308 (2), a potent, orally active GPIIb/IIIa antagonist. To progress from RWJ-50042 to a suitable candidate for clinical development, we conducted a series of optimization cycles that employed solid-phase parallel synthesis for the rapid, efficient preparation of nearly 250 analogues, which were assayed for fibrinogen receptor affinity and inhibition of platelet aggregation induced by four different activators. This strategy produced several promising analogues for advanced study, including 3-(3,4-methylenedioxybenzene)-beta-amino acid analogue 3 (significant improved in vivo potency) and 3-(3-pyridyl)-beta-amino acid 2 (significantly improved potency, oral absorption, and duration of action). In dogs, 2 displayed significant ex vivo antiplatelet activity on oral administration at 1.0 mg/kg, 16% systemic oral bioavailability, minimal metabolic transformation, and an excellent safety profile. Additionally, 2 was found to be efficacious in three in vivo thrombosis models: canine arteriovenous (AV) shunt (0.01-0.1 mg/kg, iv), guinea pig photoactivation-induced injury (0.3-3 mg/kg, iv), and guinea pig ferric chloride-induced injury (0.3-1 mg/kg, iv). On the basis of its noteworthy preclinical data, RWJ-53308 (2) was selected for clinical evaluation.