Alexander Goldberg

Highlights:
• Designed covalent p97 ATPase inhibitors to target the D2 active site.

• Identified PPA as a selective p97 covalent inhibitor.

• PPA can block growth of CB-5083 and NMS-873 resistant cancer cells.

• Proteomic analysis revealed PPA-induced protein level changes.

**GZ is lead author on this publication

Process analytical technology (PAT; Raman spectroscopy and FBRM) was used to monitor the salt formation step of a development compound in real time. The data obtained were used to understand the crystallization kinetics and behavior. A mechanistic model was proposed on the basis of the sequence of events, and the mechanism was verified by the Raman profiles. Several operational parameters were studied in a matrix setting in order to identify the factors that affect the quality attributes of the… Show more

Process analytical technology (PAT; Raman spectroscopy and FBRM) was used to monitor the salt formation step of a development compound in real time. The data obtained were used to understand the crystallization kinetics and behavior. A mechanistic model was proposed on the basis of the sequence of events, and the mechanism was verified by the Raman profiles. Several operational parameters were studied in a matrix setting in order to identify the factors that affect the quality attributes of the final product such as particle size and morphology. The kinetic characterization through PAT revealed that the process is primarily influenced by temperature and solvent composition and that the acid addition rate and agitation speed were found to have a marginal effect. A regression model on API particle size was extracted from the data set, and its accuracy was verified at various set points of the parameter range covered in the investigation. The workflow adopted by this study illustrates how process knowledge generated by a combination of PAT and modeling, as well as a multistaged experimental plan executed on the basis of learning from technical insight, can efficiently lead to the process control as required under the current regulatory frameworks.

** Peter Fung is lead author on this publication. Show less

"... This scalable approach features a broadly-applicable method for accessing complex bioactive natural products, and adheres closely to the principles of green chemistry. For instance, our approach to strychnine was solvent-free and atom-economical, and all raw materials were obtained from renewable sources, which were fully incorporated into the final product..."

An oxidative sequence for the conversion of oxindoles to structurally distinct heterocyclic scaffolds and aniline derivatives is disclosed by the combination of a copper-catalyzed C–H peroxidation and subsequent base-mediated fragmentation reaction. In contrast to classic enzymatic (i.e., kynurenine pathway) and biomimetic methods (i.e., Witkop–Winterfeldt oxidation) for oxidative indole cleavage, this protocol allows for the incorporation of external nucleophiles. The new transformation… Show more

An oxidative sequence for the conversion of oxindoles to structurally distinct heterocyclic scaffolds and aniline derivatives is disclosed by the combination of a copper-catalyzed C–H peroxidation and subsequent base-mediated fragmentation reaction. In contrast to classic enzymatic (i.e., kynurenine pathway) and biomimetic methods (i.e., Witkop–Winterfeldt oxidation) for oxidative indole cleavage, this protocol allows for the incorporation of external nucleophiles. The new transformation displays broad functional group tolerance and is applicable to tryptophan derivatives, opening potential new avenues for postsynthetic modification of polypeptides, bioconjugation, and unnatural amino acid synthesis.
*HFTK is the lead author on this publication Show less

Wir haben die Kennzeichnungen einer großen Anzahl von Haushaltsprodukten in Hinblick auf Ihre “Chemiefreiheit” überprüft, wobei neben Kosmetikprodukten und Haushaltsreinigern, auch Kräuterzusätze, verarbeitete Nahrungsmittel und Getränke eingeschlossen waren. Als Ergebnis konnten wir eine vollständige Liste aller tatsächlich “chemiefreien” Haushaltsprodukte erstellen.

(Translation/Reprint of 2014 Sceptical Chymist blog post)

Single-molecule detection is one of the fundamental challenges of modern biology. Such experiments often use labels that can be expensive, difficult to produce, and for small analytes, might perturb the molecular events being studied. Analyte size plays an important role in determining detectability. Here we use laser-frequency locking in the context of sensing to improve the signal-to-noise ratio of microtoroid optical resonators to the extent that single nanoparticles 2.5 nm in radius, and… Show more

Single-molecule detection is one of the fundamental challenges of modern biology. Such experiments often use labels that can be expensive, difficult to produce, and for small analytes, might perturb the molecular events being studied. Analyte size plays an important role in determining detectability. Here we use laser-frequency locking in the context of sensing to improve the signal-to-noise ratio of microtoroid optical resonators to the extent that single nanoparticles 2.5 nm in radius, and 15.5 kDa molecules are detected in aqueous solution, thereby bringing these detectors to the size limits needed for detecting the key macromolecules of the cell. Our results, covering several orders of magnitude of particle radius (100 nm to 2 nm), agree with the ‘reactive’ model prediction for the frequency shift of the resonator upon particle binding. This confirms that the main contribution of the frequency shift for the resonator upon particle binding is an increase in the effective path length due to part of the evanescent field coupling into the adsorbed particle. We anticipate that our results will enable many applications, including more sensitive medical diagnostics and fundamental studies of single receptor–ligand and protein–protein interactions in real time.

* Judith Su is the lead author of this publication Show less

The atom-efficient and environmentally benign catalytic hydrogenation of carboxylic acid esters to alcohols has been accomplished in recent years with precious-metal-based catalysts. Presented here is the first cobalt-catalyzed hydrogenation of esters to alcohols. The evidence indicates the unprecedented involvement of ester enolate intermediates.

A series of highly substituted vinylcyclopropanes were prepared and examined as reaction partners in a palladium-catalyzed (3+2) cycloaddition with nitrostyrenes. Described herein are our efforts to synthesize an elusive 1,1-divinylcyclopropane by several distinct approaches, and to apply surrogates of this fragment toward the synthesis of the Melodinus alkaloids.

Manufacturers of consumer products, in particular edibles and cosmetics, have broadly employed the term ‘Chemical free’ in marketing campaigns and on product labels. Such characterization is often incorrectly used to imply — and interpreted to mean — that the product in question is healthy, derived from natural sources, or otherwise free from synthetic components. We have examined and subjected to rudimentary analysis an exhaustive number of such products, including but not limited to lotions… Show more

Manufacturers of consumer products, in particular edibles and cosmetics, have broadly employed the term ‘Chemical free’ in marketing campaigns and on product labels. Such characterization is often incorrectly used to imply — and interpreted to mean — that the product in question is healthy, derived from natural sources, or otherwise free from synthetic components. We have examined and subjected to rudimentary analysis an exhaustive number of such products, including but not limited to lotions and cosmetics, herbal supplements, household cleaners, food items, and beverages. Herein are described all those consumer products, to our knowledge, that are appropriately labelled as ‘Chemical free’. Show less

Alkyl and aryl isothiocyanates and carbodiimides are effective substrates in (3+2) cycloadditions with N-sulfonyl-2-substituted aziridines and 2-phenylaziridine for the synthesis of iminothiazolidines and iminoimidazolidines. Additionally, the stereoselective (3+2) cycloaddition of N-H- and N-sulfonylaziridines with isothiocyanates can be accomplished, allowing for the synthesis of highly enantioenriched iminothiazolidines. Evidence for an intimate ion-pair mechanism is presented herein in the… Show more

Alkyl and aryl isothiocyanates and carbodiimides are effective substrates in (3+2) cycloadditions with N-sulfonyl-2-substituted aziridines and 2-phenylaziridine for the synthesis of iminothiazolidines and iminoimidazolidines. Additionally, the stereoselective (3+2) cycloaddition of N-H- and N-sulfonylaziridines with isothiocyanates can be accomplished, allowing for the synthesis of highly enantioenriched iminothiazolidines. Evidence for an intimate ion-pair mechanism is presented herein in the context of these chemo-, regio-, and diastereoselective transformations. The demonstrated ability to remove the sulfonyl group from the heterocyclic products displays the utility of these compounds for further derivatization and application. Show less

This chapter discusses the C-alkylation of enolates and enols and deals with all aspects of this venerable transformation, from early examples of bond formation, to more stereochemically rich reactions, to the most modern catalytic enantioselective processes. Although not exhaustively comprehensive, it is our intuition that readers of this chapter will emerge with a deep understanding of enol/enolate alkylation technologies from both fundamental and practical vantage points.

This chapter discusses the C-alkylation of enolates and enols and deals with all aspects of this venerable transformation, from early examples of bond formation, to more stereochemically rich reactions, to the most modern catalytic enantioselective processes.

Isocyanates, isothiocyanates, and carbodiimides are effective substrates in (3 + 2) cycloadditions with donor–acceptor cyclopropanes for the synthesis of five-membered heterocycles. These reactions exhibit a broad substrate scope, high yields, and well-defined chemoselectivity. Discussed herein are the implications of Lewis acid choice on the stereochemical outcome and the reaction mechanism.

* Checker

A palladium-catalyzed (3 + 2) cycloaddition of a vinylcyclopropane and a β-nitrostyrene is employed to rapidly assemble the cyclopentane core of the Melodinus alkaloids. The ABCD ring system of the natural product family is prepared in six steps from commercially available materials.

A selective metal-catalyzed ring opening of alkylidenecyclopropane derivatives leads to various functionalized acyclic derivatives possessing challenging quaternary stereocenters. The key feature of this transformation is that the ring opening is faster than the reductive elimination and is highly regioselective; a single ring-opened product was always observed and the stereointegrity of the quaternary stereogenic center remains unaffected in the process.
*Second Author

Background: Therapeutic interchange is a means of decreasing drug costs within a hospital formulary system. Little is known about the substitutions made by hospitals that use this approach.

Objectives: To determine, for Ontario, which agents are used within selected classes of cardiovascular medications and proton pump inhibitors and to determine whether medications available in generic formulations are used.

Methods: A questionnaire was sent to pharmacy directors at all 177 acute… Show more

Background: Therapeutic interchange is a means of decreasing drug costs within a hospital formulary system. Little is known about the substitutions made by hospitals that use this approach.

Objectives: To determine, for Ontario, which agents are used within selected classes of cardiovascular medications and proton pump inhibitors and to determine whether medications available in generic formulations are used.

Methods: A questionnaire was sent to pharmacy directors at all 177 acute care hospitals in Ontario, Canada.

Results: Among the 166 hospitals that responded to the survey (response rate 94%), 141 (85%) reported therapeutic interchange programs. Of the hospitals reporting such programs, 76 (54%) included therapeutic interchange of cardiovascular medications. Most frequently included were HMG (3-hydroxy-3-methylglutaryl) CoA reductase inhibitors (statins) (63/141 or 45%), followed by angiotensin converting-enzyme inhibitors (47/141 or 33%) and angiotensin II receptor blockers (20/141 or 14%). Atorvastatin, ramipril, and losartan were the most commonly used in their respective classes. Proton pump inhibitors were included in 116 (82%) of the therapeutic interchange programs. Lansoprazole, pantoprazole, and omeprazole were used almost equally. Medications available in generic formulations were never the most commonly substituted in any class.

Conclusions: Therapeutic interchange is practised by most hospital formulary systems, and there is considerable variation in the specific agents used. The observed lack of use of medications that are available in generic formulations may extend to the outpatient setting. Show less