Caspases and cancer: Connections through circular dichroism spectroscopy

While excessive cell death inevitably leads to negative effects, the endurance of damaged cells in the presence of death signals can be equally detrimental to health. Apoptosis, or programmed cell death, is a highly regulated process in which cues from within or from outside a cell can trigger an irreversible sequence of signals that carry out cell destruction known as the apoptotic cascade. A group of enzymes called caspases play a vital role in this cascade with some participating as initiators and others acting as effectors of protein cleavage and intracellular breakdown. Although it is normal for the activity of caspases to be suppressed during a cell’s lifetime, continued suppression of apoptotic enzymes even in the presence of pro-apoptotic signals is one of the hallmarks of cancer cells. There is evidence that certain metal ions can bind and inhibit caspases, and fluctuations in intracellular Fe3+ concentrations during apoptosis raise the question whether this ion has a similar effect. In this study, plasmid DNA encoding caspase-7 was expressed in E. coli, and the resulting protein was purified using nickel affinity chromatography. The protein’s structure will be analyzed both on its own and in the presence of Fe3+ in order to determine whether interactions are present that may lead to caspase-7 inhibition. Structural changes will be monitored using circular dichroism spectroscopy. Further understanding of cationic interactions with caspases could answer many existing questions about apoptotic resistance in cells and perhaps even lead to the development of treatments for such conditions

Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives through Iridium-Catalyzed Allylic Alkylation

The first highly enantioselective iridium-catalyzed allylic alkylation providing access to products bearing an allylic all-carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one-pot preparation of α-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored via a series of diverse product transformations

The Effects of Long-Term Benzodiazepine Use and Withdrawal in the Elderly

Benzodiazepines remain a commonly prescribed medication in the United States, and the high usage of this drug class is especially a concern in the elderly population for several reasons. First, elderly patients metabolize drugs differently, leading to varying responses. Age-related changes also have a significant impact on the effects of benzodiazepines. Second, elderly patients are more likely to be taking multiple centrally-acting drugs, which can further exacerbate negative effects. In regard to long-term benzodiazepine use, elderly patients experience an increased risk of cognitive impairment, motor vehicle accidents, decline in physical performance, falls and subsequent fractures, and sleep disturbances. Withdrawal is also a significant concern with long-term benzodiazepine treatment, which can lead to rebound symptoms in addition to mood swings, tremor, headache and loss of appetite. A taper of less than six months is recommended when discontinuing benzodiazepines after use longer than the recommended three month duration of treatment. Pharmacists can have a substantial impact in reducing the detrimental effects of long-term use of benzodiazepines by aiding in the tapering process, as well as identifying inappropriate prescribing and use of benzodiazepines in the elderly population. Overall, pharmacists should be knowledgeable on the appropriate use of benzodiazepines, associated side effects and withdrawal concerns to reduce the negative effects elderly patients may experience with long-term use

Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents

The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has been developed. The transformation allows for the use of an umpoled synthon, which serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives

Total synthesis of (–)-dihydroprotolichesterinic acid via a diastereoselective conjugate addition, development of enantioselective halocyclization reactions, and progress towards the total synthesis of jiadifenolide

In an effort to develop a unified route to functionalized succinic acid derivatives, a new diastereoselective conjugate addition of monoorganocuprates, Li[RCuI], to a chiral fumarate was developed. The conjugate addition proceeded with good yields and a high degree of diastereoselectivity for a variety of alkyl and aryl nucleophiles. Application of this new methodology culminated in the shortest total synthesis of (–)-dihydroprotolichisterenic acid to date. The novel organocatalyst developed by the Martin group was applied to enantioselective iodolactonization reactions. Reaction conditions were optimized and the resulting halolactones were obtained in high yields and enantioselectivities for a number of olefinic acids. Of particular note is the disclosure of the first iodolactonization reactions forming a C–I bond at a stereogenic center. The utility of this catalyst was further extended to kinetic resolution reactions. Additionally, this catalyst was found to promote the first enantioselective halolactamization reaction with moderate enantioselectivity. Finally, the catalyst was modified in an effort to enhance the enantioselectivity and verify the proposed bifunctional nature of the catalyst. Lastly, an enantiospecific total synthesis of the neurotrophic sesquiterpenoid natural product (–)-jiadifenolide was progressed. The stereochemistry was introduced by the use of commercially available (+)-pulegone as the starting material. The first diastereoselective decarboxylative allylation on a cyclopentanone was developed A samarium diiodide mediated radical annulation was planned to forge two of the rings, and late stage oxidation manipulation could then lead to the completion of the synthesis.Chemistr

Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via a Catalytic Enantioselective Allylic Alkylation Strategy

Rapid access to enantioenriched spirocycles possessing a 1,4-dicarbonyl moiety spanning an all-carbon quaternary stereogenic spirocenter was achieved using a masked bromomethyl vinyl ketone reagent. The developed protocol entails an enantioselective palladium-catalyzed allylic alkylation reaction followed by a one-pot unmasking/RCM sequence that provides access to the spirocyclic compounds in good yields and selectivities

Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account

Our lab has long been interested in the development of methods for the creation of enantioenriched all-carbon quaternary stereocenters. Historically, our interest has centered on palladium-catalyzed allylic alkylation, though recent efforts have moved to include the study of iridium catalysts. Whereas palladium catalysts enable the preparation of isolated stereocenters, the use of iridium catalysts allows for the direct construction of vicinal stereocenters via an enantio-, diastereo-, and regioselective allylic alkylation. This Account details the evolution of our research program from inception, which focused on the first iridium-catalyzed allylic alkylation to prepare stereodyads containing a single quaternary stereocenter, to our most recent discovery that allows for the synthesis of vicinal quaternary centers

Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation

The development of the first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers is disclosed. The iridium‐catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo‐ and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all‐carbon quaternary stereocenters