Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1999. / Includes bibliographical references. / by Evan T. Powers. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1991. / Includes bibliographical references. / by Andrew David Johnson. / Ph.D.

Thesis: Ph. D. in Biological Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Bacterial infections are a major cause of concern in healthcare because of a rise in antibiotic-resistant bacteria and an increase in hospital-acquired infections. In order to combat bacterial infections, we need fundamental understanding of the host-pathogen interaction. As a part of the innate immune response, various organisms, including humans, produce antimicrobial peptides. Human defensin 5 (HD5) is a 32-aa cysteine-rich peptide produced primarily in the small intestine that exhibits broad-spectrum activity against various bacteria, fungi and viruses. In this thesis, in order to study and understand the mechanism of action of HD5, we probed the antibacterial action of HD5 and the bacterial response. We synthesized a family of HD5 analogues with functional modifications including fluorophores. With this toolkit of HD5 derivatives, we examined the effect of HD5 on various bacteria. We demonstrated that HD5ox, the oxidized form of HD5, causes certain distinct morphological changes in Gram-negative bacteria, enters the bacterial cytoplasm and localizes near the cell poles and cell division sites. From these studies we propose that HD5ox overcomes the outer membrane permeability barrier and permeabilizes the inner membrane of Gram-negative bacteria, and it may interact with the cellular targets and interfere with the processes such as cell division. We extended these morphological studies of HD5 0x-treated bacteria and identified certain phenotypic responses in Gram-positive bacteria that further suggest that HD5ox interferes with cellular processes such as cell division. / by Haritha Reddy Chileveru. / Ph. D. in Biological Chemistry

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2018. / Cataloged from PDF version of thesis. / Includes bibliographical references. / The studies presented in this dissertation are aimed at the development and application of methodologies that enable carbon-nitrogen (C-N) bond formation catalyzed by late transition metals such as palladium and copper. The first part of this thesis focuses on the use of palladium catalysis for the construction of a carbon(sp²)-nitrogen bond in the context of a biphasic continuous-flow system (Chapter 1). The second part of this thesis describes the recent developments of copper-hydride (CuH) catalyzed asymmetric hydroamination for the formation of a-chiral carbon(sp³)-nitrogen bonds from olefins. This work includes the application of CuH catalysis to the synthesis of chiral N-alkyl aziridines (Chapter 2), and the discovery and development of novel electrophilic amines to enable CuH-catalyzed asymmetric hydroamination to directly access primary amines (Chapter 3). Part I. Chapter 1. Use of a "Catalytic" Cosolvent, N,N-Dimethyl Octanamide, Allows the Flow Synthesis of Imatinib with no Solvent Switch A general, efficient method for C-N cross-coupling has been developed using N,N-dimethyloctanamide as a cosolvent for biphasic continuous-flow applications. In addition to utilizing a proper co-solvent, the described method harnesses the superior mixing abilities of a stainless-steel powder packed tube reactor to efficiently couple a wide range of aryl/heteroaryl halides and aryl/heteroaryl/alkyl amines in a short period of time (< 15 min). The method was also integrated into a two-step sequence that converted phenols into biarylamines via the intermediate of either triflates or tosylates. Lastly, this method was applied to a telescoped three-step continuous-flow synthesis of imatinib, the API of Gleevec®, in good yield without the need of solvent switches, purification of intermediates, or aqueous extraction. Part II. Chapter 2. CuH-Catalyzed Regioselective Intramolecular Hydroamination for the Synthesis of Alkyl-Substituted Chiral Aziridines A general and enantioselective method for the synthesis of N-alkyl-substituted aziridines has been developed. This protocol offers a direct route for the synthesis of alkyl-substituted chiral aziridines from achiral starting materials. A convergent synthesis of allylic hydroxylamine esters has been developed from readily accessed allylic alcohols. The allylic hydroxylamine esters undergo copper hydride-catalyzed intramolecular hydroamination with a high degree of regio- and enantiocontrol to afford the aziridine products in good to excellent yields in highly enantioenriched form. The utility of the products derived from this method is further demonstrated through derivatization of the chiral aziridine products to obtain a diverse array of functionalized enantioenriched amines. Chapter 3. A Novel Electrophilic Nitrogen Source for Copper-Catalyzed Asymmetric Hydroamination for the Synthesis of Chiral Primary Amines A mild and practical method for the catalytic installation of the amino group across olefins has long been recognized as a significant challenge in synthetic chemistry. Despite substantial efforts in this area, to our knowledge, no effective strategy has been developed to directly access chiral primary amines from unsaturated hydrocarbons. While the direct hydroamination of olefins requires harsh conditions, the lack of suitable nitrogen sources has limited the development of potentially more practical formal hydroamination methods for the synthesis of primary amines. Here, we describe a mild and general protocol for the copper-catalyzed hydroamination of olefins to primary amines, utilizing commercially available isoxazole and its derivatives as novel nitrogen sources. This method provides a powerful means to access a broad range of a-chiral branched primary amines and linear primary amines, as demonstrated by the efficient synthesis of Maraviroc and the formal synthesis of other pharmaceutical agents including DMP 777, Rasagiline, Dapoxetine and Bifemelane. / by Jeffrey Chih-Yeh Yang. / Ph. D. in Organic Chemistry

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1995. / Includes bibliographical references. / by James J. Claus. / M.S.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2002. / Vita. / Includes bibliographical references (leaves 125-129). / by Jennifer Yvonne Jamieson. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 123-130). / Molecular sensors are powerful because they make it possible to adapt the measurement to the sample instead of a sample to an instrument. Many reporter are available for measuring the chemical properties of a sample, but no purpose-built molecular sensors exist to report a sample's mechanical properties. To address recent interest in the mechanical coordinate of molecular interactions, we developed a prototype molecular sensor, calibrated its force-fluorescence relationship, and adapted the sensor to a cell adhesion assay. This thesis focuses on the considerations for combining force measurement with the environmental and distance sensitivity offered by fluorescence to measure cell-surface adhesion. We showed that DNA can be used as a scaffold to build a sensor molecule, that fluorescence can be used as a reporter of a threshold force, and that introducing cells to the sensor molecules changes the fluorescence properties. Because Cy3 experiences an enhanced intensity sensitivity when conjugated to DNA, the reporter's FRET signal was occluded and we instead activated the sensor complex as a novel, all-fluorescent means of reporting cell-surface proximity. This method for reporting cell-surface separation is significant because it simplifies measurements in thicker and more complex materials interesting to cell-substrate interaction studies. / by Mariya Barch. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2010. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Vita. Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references. / The concentration of transition metals within the cell must be tightly regulated. If the concentration of a given transition metal is too low the cell may not be able to perform life-sustaining processes, while high levels of metals are poisonous to the cell and can cause cell death. In Escherichia coli, NikR regulates nickel uptake by blocking transcription of the genes encoding the nickel uptake transporter, NikABCDE. NikR is a homotetrameric transcription factor with a central metal binding domain (MBD) that includes the tetrameric interface and two flanking dimeric ribbon-helix-helix (RHH) DNA-binding domains. Early work revealed that NikR can bind a variety of transition metal ions and has two binding affinities for the nik operon: nM when stoichiometric Ni2+ binds NikR and pM when excess Ni2+ binds. The enhanced DNA affinity suggests the presence of low affinity nickel binding sites on the protein. Recently, it has been shown that NikR also requires K+ to bind DNA, suggesting yet another type of metal binding site on the protein. To understand NikR's ability to bind multiple transition metal ions and how Ni2+ specifically induces NikR-DNA binding, we solved the crystal structures of the apo- MBD and BMD bound to Zn2+ and Cu2+. Comparing these structures to the previously published Ni2+-MBD structure, we noted that when the proper metal binds to NikR it utilizes H76 of alpha helix 3 as a ligand. This, in turn, orders helix !3, and we propose this conformational stabilization is a key step in the NikR-DNA binding mechanism. Electrostatic free energy calculations and thermodynamic integration were used to study which metal prefers to bind at a site between the MBD and RHH domains that is formed when NikR is bound to DNA. Our studies illustrate that NikR-DNA binding was most favorable when this site contains a monovalent cation the size of K+. These studies support a physiological role of K+ in NikR-DNA binding. Structures from crystals of NikR and NikR-bound to DNA soaked with excess nickel ions indicate six types of potential low-affinity nickel binding sites on the protein surface. Binding of excess nickel ions to these sites does not induce any significant conformational change, suggesting that these sites have an electrostatic effect increasing ! 4 NikR's affinity for DNA. Using a combination of X-ray crystallography and molecular simulations we have identified and explored the metal binding sites on E. coli NikR and how they influence NikR:DNA binding. / by Christine M Phillips. / Ph.D.

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1995. / Includes bibliographical references (leaves 46-48). / by Xuedong Dai. / M.S.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1989. / Vita. / Includes bibliographical references. / by Lee Keem Hoong. / Ph.D.