Department of Chemistry & Biochemistry

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Characterization of the metallo-ß-lactamase from Pseudomonas aeruginosa, IMP-1.
(2014-06-11) Solida, Nicole R.; Kim, Sung-Kun, 1968-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The rate at which pathogenic bacteria are gaining antibiotic resistance has become increasingly alarming. Major contributors of this antibiotic resistance in microbes are a class of enzymes known as β-lactamases. These enzymes are effective in breaking down the most commonly prescribed antibiotics at present. This work investigates two separate metallo-β-lactamase enzymes, first IMP-1, which provides antibiotic resistance to Pseudomonas aeruginosa, and second Bla2, which grants antibiotic resistance to Bacillus anthracis. The main focus of this work was to investigate and characterize IMP-1 according to its activity and stability in temperature and pH. This was done in an effort to increase the general knowledge for potential inhibitors to be designed. The secondary focus of this work was to examine the ability of novel hydroxamate compounds to inhibit the growth of bacterial cells expressing Bla2. In addition to this work, aptamers were investigated as a potential means of future inhibitor design.
Chemistry, electrochemistry and electron transfer induced reactions of cobalt complexes with fluorinated ligands.
(2008-03-03T17:20:55Z) Gunawardhana, Kihanduwage N.; Gipson, Stephen L. (Stephen Lloyd); Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
The chemical or electrochemical reduction of the trifluoroacetyl complex CF3COCo(CO)3PPh3 involves a single electron transfer yielding trifluoromethyl radical and an anionic cobalt carbonyl complex. The mechanism is proposed to involve electron transfer followed by initial dissociation of either a carbonyl or phosphine ligand from the 19-electron [CF3COCo(CO)3PPh3 ]- anion. The resulting 17-electron intermediate undergoes subsequent one-electron reductive elimination of trifluoromethyl radical by homolytic cleavage of the carbon-carbon bond of the trifluoroacetyl group. The CF3· radical can be trapped by either benzophenone anion, forming the anion of [a]-(trifluoromethyl)benzhydrol, or Bu3SnH, yielding CF3H. The final organometallic product is an 18-electron anion, either [Co(CO)4]- or [Co(CO)3(PPh3)]-, depending upon which ligand is initially lost. The chemical or electrochemical reduction CF3Co(CO)3PPh3 is a two-electron process involving heterolytic cobalt-carbon bond cleavage to yield trifluoromethyl anion and cobalt carbonyl anions. The trifluoromethyl anion rapidly decomposes to fluoride and difluorocarbene. This carbene may dimerize to form C2F4. The unstable fluoro carbene can also be trapped by cyclohexene. The mechanism proposed for the reduction of C6F5Co(CO)3PPh3 involves a homolytic cobalt-carbon bond cleavage to form C6F5[bullet] radical. The resultant C6F5[bullet] radical abstracts hydrogen or deuterium from the solvent or trace amounts of water to produce C6F5H or C6F5D. With an excess of reducing agent this C6F5[bullet] radical can be further reduced to C6F5- anion before forming pentafluorobenzene by protonation. The inorganic fragment, the 18-electron [Co(CO)3PPh3]- anion, may participate in a ligand exchange reaction to form [Co(CO)4]-. In addition, interesting reactivity was observed between C6F5Co(CO)3PPh3 and tin hydrides, deuterides and chlorides without any reducing agents. We have demonstrated that ligand replacement reactions can be used for the synthesis of new cobalt-NHC complexes with fluorinated alkyl, acyl and aryl ligands. In addition, the X-ray crystal structure of CF3COCo(CO)3PPh3 was obtained to compare the bond lengths and bond angles with other related compounds. An unusual Co-C(acyl) bond length was observed for CF3COCo(CO)3PPh3. Considering the bond lengths of other alkyl and acyl complexes, it can generally be argued that the position of the alkyl/acyl equilibrium varies with the Co-C(alkyl/acyl) bond length.
Chemometric modeling of UV-visible and LC-UV data for prediction of hydrolysate fermentability and identification of inhibitory degradation products.
(2011-12-19) Hedayatifar, Negar.; Chambliss, C. Kevin.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Production of ethanol from lignocellulosic biomass requires a pretreatment step to liberate fermentable sugars trapped within the plant. During pretreatment, lignin and some sugars undergo degradation to form compounds which have shown inhibitory effects to fermentative microorganisms. Accordingly, development of a rapid and accurate method for assessment of microbial inhibition and identification of inhibitory compounds is essential for gaining a better understanding of pretreatment and its downstream effects on fermentation processes. Traditional methods for identification of inhibitory compounds involve a “bottom-up” approach. Using this approach, one or more known degradation compounds are added to fermentation media and their effects on batch fermentation of ethanol are observed. These methods are extremely time-consuming and labor-intensive which makes them unattractive to researchers. Furthermore, they are carried out on degradation compounds that have already been identified. Given that biomass hydrolysates contain many unidentified constituents, identification of inhibitory compounds by traditional means is unlikely to occur on a timescale that is consistent with current mandates for commercial production of cellulosic ethanol. To address these limitations, we have developed a chemometric model that correlates ultraviolet (UV)-visible spectroscopic data of 21 different biomass hydrolysates with their fermentability (percent inhibition of ethanol production). This novel approach enables rapid prediction of hydrolysate fermentability using UV-visible spectroscopic data alone and offers significant improvements in throughput and labor when compared to traditional batch fermentation methods. The model was subsequently used to predict percent inhibition for five hydrolysate samples, with a root-mean-square error of prediction of 6%. To evaluate the use of chemometric modeling for identification of inhibitory compounds in biomass hydrolysate, a second model was developed to correlate HPLC-UV chromatographic data of the 21 hydrolysates with their percent inhibition. Detection was monitored at four specific wavelengths identified by the UV-visible model as significant spectral regions. Once constructed, the HPLC-UV model was used to identify retention times that had the highest correlation with inhibition. To determine whether better resolution or more universal detectability of sample constituents may lead to identification of additional retention times, a third chemometric model was developed with chromatographic data of hydrolysates obtained via ion chromatography with conductivity detection.
Construction and calibration of a custom time-of-flight mass spectrometer and its use in measuring the reaction kinetics of transition metal ion-organic interactions.
(2009-09-03) Castleberry, Vanessa A.; Bellert, Darrin Joseph, 1968-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
A unique instrument was constructed and used to generate and interrogate jet cooled neutrals, ions and their respective clusters. The instrument is a result of the artful marriage of supersonic expansions combined with time of flight spectroscopy. Ionization occurs in a large main chamber. The ions are separated via a kinetic energy pulse from a custom built linear particle accelerator. The revelatory hardware for our instrument is a microchannel plate detector (MCP). The MCP is mounted on the exit of a custom designed and built hemispherical energy analyzer (sector), which acts as an energy filter. This filtering characteristic of the sector permits study of selected ionized fragments. To test the instrument, the 2-photon resonant, 3-photon ionization spectrum of gaseous atomic copper was measured. The (n = 9 – 21) Rydberg series was observed in 2-photon excitation. The term energies of this series converged to copper's lowest ionization threshold with an apparent quantum defect of 0.92. The state which couples the ground state of copper to the Rydberg series is a non-stationary state composed primarily of the spin-orbit components of the lowest 2P° atomic states. Additionally, the time dependence of the gaseous unimolecular decomposition of the jet-cooled adduct ion, Ni⁺•Acetone was monitored by selective detection of the daughter fragment, Ni⁺CO. Various photon energies were supplied to initiate dissociation of the adduction. The energies employed in this reaction were well below that required to fragment C-C ς-bonds. First-order unimolecular decomposition rate constants, k(E) ranged from 55000 – 113000 s⁻¹. The rate constants decreased with decreasing amounts of internal excitation. Ni⁺ cation is implicated as a catalytic necessity to activate the bond and cause molecular fragmentation. These experiments represent the first direct kinetic study of such catalytic type reactions.
Copper ionophores induce autophagy in melanoma cells.
(2013-09-16) Dao, Long, 1988-; Farmer, Patrick Joseph, 1957-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Malignant melanoma is a particularly aggressive form of skin cancer, for which the only current treatment option is excision. As melanoma is an inherently antiapoptotic model of cancer, other avenues of cell death were pursued, namely autophagy, a mechanism in which a cell devours itself in times of stress. In this study, two copper ionophores, disulfiram and thiomaltol, were investigated against melanoma. By using immunocytochemistry, Western Blotting and supravital staining, it was confirmed that both ionophores induce autophagy, and furthermore, drive the process to completion. In addition, when tested for viability with the autophagy inhibitor hydroxychloroquine, both ionophores showed evidence of synergism. To further study the migration of copper, STEM-EDX was used on thiomaltol treated melanoma cells.
Decarbonylation, reductive electrochemistry and x-ray crystal structures of some rhodium diphosphine acyl complexes.
(2011-01-05T19:43:44Z) Panthi, Basu Dev.; Gipson, Stephen L. (Stephen Lloyd); Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Acyl complexes of rhodium(III) with chelating diphosphine ligands (P-P = 1,3- bis(diphenylphosphino)propane and others) are well known for their stability toward decarbonylation. Various rhodium diphosphine acyl complexes were synthesized and characterized by IR, NMR (¹H, ¹⁹F, and ³¹P), cyclic voltammetry, elemental analysis and X-ray crystallography. The chemical and electrochemical reduction of the rhodium diphosphine acyl complexes Rh(P-P)(COR)I₂ involves a net two-electron transfer yielding Rh(P-P)(CO)I, alkyl anion and iodide. The mechanism involves an initial one-electron transfer followed by the liberation of one of the iodides. Then a second electron transfer with the migration of alkyl group takes place yielding the 18-electron complex [Rh(P-P)(CO)(R)I]⁻. This 18-electron complex loses the alkyl group as the anion, producing Rh(P-P)(CO)I as the final product. We observed a difference in thermal stability between the acetyl and trifluoroacetyl complexes. Others have found that the acetyl complex is very stable in terms of alkyl migration while the monodentate phosphine analog of this complex undergo alkyl migration followed by the loss of alkyl halide. We discovered that when the acetyl group is replaced by a trifluoroacetyl group the resulting complex is unstable in terms of alkyl migration. It slowly changes from the acyl complex to the alkyl complex in solution at room temperature. If the resulting solution is allowed to stand for a long period of time, ca. 20 days or more, it gives the decarbonylated product Rh(P-P)(CF₃)I₂. When the trifluoroacetyl group is replaced by a difluoroacetyl group the complex does not undergo alkyl migration while replacing it with a chlorodifluoroacetyl group increases the rate of alkyl migration. The pentafluoropropionyl complex also undergoes alkyl migration. X-ray crystal structures of 19 rhodium diphosphine complexes were measured and their geometric parameters are compared with related structures. All five-coordinate complexes have square pyramidal geometries with the acyl group occupying the apical position.
Design and synthesis of combretastatin A-1 analogs, small molecule vascular disrupting agents, and bioreductive triggers as potential therapeutic agents for the treatment of cancer.
(2011-01-05T19:43:27Z) Nguyen, Benson Lee.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Cancer is the second leading cause of death in the United States with over 550,000 deaths in 2009 and a devastating 7.9 million deaths worldwide in 2007. Vascular disrupting agents (VDAs) represent a novel method developed for the treatment of cancer. VDAs, such as combretastatin A1 phosphate (CA1P, Oxi4503) and combretastatin A4 phosphate (CA4P, ZybrestatTM, fosbretabulin), after undergoing phosphate cleavage by non-specific phosphatase enzymes, selectively bind to the colchicine site on tubulin, disrupting tubulin polymerization. The integrity of the microtubules that form the cytoskeleton of the endothelial cells that line the tumor vasculature is altered, causing tumor vasculature occlusion and collapse, thus preventing nutrients and oxygen from reaching the tumor. This leads to severe tumor hypoxia, tumor perfusion regression and tumor necrosis. A series of anticancer agents were designed to incorporate a VDA or cytotoxic agent linked to a bioreductive drug to form a bioreductive prodrug conjugate. When the bioreductive portion of the molecular conjugate is reduced, the linkage between the VDA and the bioreductive drug is broken, releasing the VDA in its active form to act upon the tumor vasculature. The reduced bioreductive drug becomes a chemotherapeutic agent that can damage the tumor cells. CA1 is a potent inhibitor of tubulin polymerization and it has been shown that CA1 undergoes a second mechanism of action against tumors. CA1 incorporates an ortho diphenolic moiety that can be oxidized to form an ortho quinone that can damage DNA. To further elucidate the biological mechanism of action of CA1, a synthetic methodology was developed to incorporate a radioisotope at a metabolically stable position. In addition, a total synthesis was designed to prepare each of the combretastatin A1 monophosphates in regioisomeric pure form.
Design and synthesis of dihydronaphthalene vascular disrupting agents and indolequinone-based bioreductives.
(2007-03-08T15:41:24Z) Dogra, Abhishek.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Cancer remains a deadly affliction for millions across the United States, and the number of new cases is only expected to rise in the years to come. In the field of anticancer research, vascular disrupting agents (VDAs) that preferentially target the tumor vasculature show great promise. The naturally occurring combretastatins, especially combretastatin A-4 (CA4) and combretastatin A-1 (CA1), in suitable prodrug form, have proven to be highly effective VDAs. In this study, efforts were directed towards the synthesis of two combretastatin analogs bearing key features of CA4 on a dihydronaphthalene framework: Oxi 6196 and a beta-dihydronaphthalene analog. In addition to VDAs, another class of exciting anticancer drugs is bioreductive agents that are selectively targeted towards the hypoxic region of tumors. These compounds are chemically reduced selectively and intracellularly to form active cytotoxic compounds. This study also presents the design and synthesis of two analogs of indolequinone-based prodrugs, which can be triggered to release an attached VDA upon bioreductive activation from the 3- or the 2-position, as well as the attempted synthesis of a CA4-tirapazamine bioconjugate drug.
Design and synthesis of functionalized small-molecule inhibitors of cathepsins L and K.
(2012-08-08) Jones, Lindsay M.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Inhibition of a class of cysteine proteases known as the cathepsins has received increasing attention in recent years, since these enzymes play key roles in cancer metastasis. Cathepsins B, K, and L have been of particular interest to this research study. These proteases have also been implicated in various disease states, including Alzheimer’s disease, osteoporosis, and the severe acute respiratory syndrome (SARS). Cathepsin L is a ubiquitous cysteine protease found primarily within the lysosomes of most tissues; it is involved in normal protein turnover. The increased expression of this enzyme in cancer cells and increased secretion into the extracellular matrix aids in cancer growth and invasion. Within this study, a small library of inhibitors containing the thiosemicarbazone moiety was designed, synthesized, and evaluated for inhibition against these cathepsin proteases. The thiosemicarbazone moiety was contained on the thiochromanone, tetralone, chromanone, and 2,3-dihydroquinolinone molecular frameworks. Several of these analogues demonstrated potent inhibition of cathepsin L or cathepsin K. For example, 6-bromo- 2,3-dihydroquinolinone thiosemicarbazone strongly inhibited cathepsin L (IC50 = 164 nM), while 6-isopropylthiochromanone thiosemicarbazone proved to be a potent inhibitor of cathepsin K (IC50 = 21 nM). Each of the thiosemicarbazone analogues in this study was inactive against cathepsin B (IC50 >10,000 nM). This study further elucidates the structure activity relationship between these small molecules and the active sites of these enzymes.
Design and synthesis of non-peptidic thiosemicarbazone derivatives as inhibitors of cathepsins L and K.
(2012-11-29) Song, Jiangli.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Cathepsin L, a member of the lysosome cysteine proteases, is ubiquitously expressed in tissue and is responsible for protein turnover. An overexpression of cathepsin L by certain tumor types is associated with enhanced tumor expansion through degradation of the extracellular matrix and the invasion and migration of cancer cells. Therefore, the inhibition of cathepsin L has emerged as a therapeutic strategy against metastatic cancer. Cathepsin K is involved in osteoclastic bone resorption because it is selectively expressed in osteoclasts and is capable of degrading bone matrix. In this project, a small library of thiosemicarbazone derivatives containing thiochromanone, 2,3-dihydroquinoline-4-one, and dibenzoylbenzene scaffolds has been successfully designed and synthesized as potential inhibitors of cathepsin L and other homologous cathepsins (B and K). Through a collaborative study, ten compounds from this library were found to be potent inhibitors (IC50 < 300 nM) of cathepsin L, and nine compounds were potent inhibitors of cathepsin K. None of these inhibitors showed activity against cathepsin B. For example, 6,7-difluorothiochromanone thiosemicarbazone 4 (IC50 = 46 nM) was the most potent inhibitor against cathepsin L from this group, while the 6-trifluoromethyl derivative 28 (IC50 = 21 nM) was the most potent inhibitor against cathepsin K. Structure activity relationship (SAR) studies centered on the thiochromanone thiosemicarbazone scaffold demonstrated that electron-withdrawing functionalities, incorporated primarily at the 6-position of the thiochromanone scaffold, showed good inhibition against cathepsin L in comparison to related analogues bearing electron-donating groups. Collectively, these results expand the known SAR regarding molecular structures and their inhibitory activity against cathepsins L and K.
Design and synthesis of novel β-cyclodextrins and their application as chiral stationary phases for gas chromatography.
(2011-01-05T19:46:00Z) Hayden, Tiffany Renee Turner.; Garner, Charles M. (Charles Manley), 1957-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Enantiomers can be directly separated only with use of systems containing a chiral selector. Cyclodextrins (CDs) and modified cyclodextrins have been used as chiral selectors for their ability to form host-guest complexes with various analytes. The scaffold of the CD allows for assembly of functional groups with controlled geometry. CDs can be readily modified through substitution of the hydroxyl groups, giving rise to derivatives with significantly different properties, especially increased solubility and controlling the hydrophobicity of the cavity. Even though CDs can be readily modified, the syntheses can be tedious and complicated with various protecting group strategies to control the reactivity of the various alcohols. The preparation of modified cyclodextrins for use as chiral stationary phases (CSP) for gas chromatography (GC) is the focal point of this research. Our effort to identify useful new β-CD derivatives involved attempts to make bridged (annulated) derivatives, could increase the thermal stability of the derivatives, and change the length, width and polarity of the CD cavity. To date, there are no reports of annulated CD derivatives in the chemical literature. In the process of evaluating a wide range of electrophiles that could accomplish annulation, several new β-CD derivatives, i.e., per(6-O-TBS-2,3-O-cyclodimethylsilyl)- β-CD, per(6-O-TBS-2,3-O-cyclodiphenylsilyl)- β-CD, per(6-O-Pivaloyl-2,3-O-cyclodimethylsilyl)-β-CD, per(6-deoxy-2,3-O-methyl)- β-CD, and per(6-deoxy-2,3-O-allyl)- β-CD, were synthesized. Two of the new derivatives were evaluated as components of stationary phases for GC, per(6-O-TBS-2,3-Ocyclodimethylsilyl)-β-CD and per(6-deoxy-2,3-O-methyl)-β-CD. Overall, this work resulted in five new CD derivatives.
Design and synthesis of potential serotonin-selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for the treatment of depression.
(2010-10-08T16:17:26Z) Elguézabal-Torralba, Gerardo Arturo.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Depression is a common disease characterized by feelings of deep sadness, guiltiness, loss of interest in once pleasurable activities, and thoughts of self-harm among others. Affecting an estimated 121 million people worldwide, depression does not discriminate on the basis of gender, age, culture or social status. Research shows a diminished concentration of the neurotransmitters serotonin and norepinephrine in the synapses between neurons of depressed patients. For this reason, and with the advent of new and more powerful computational tools, two families of compounds called Serotonin-Selective Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) have been developed. These compounds block the reuptake process of serotonin and norepinephrine into the presynaptic neuron in order to increase the amount of these neurotransmitters in the synapses. Although these drugs have been successful in the treatment of depression, the side effects that accompany them are the major reason for patients to abandon treatment before completion. One of these side effects is sexual dysfunction, which has been associated with the serotonin receptor 2A (5-HT2A). In this project, a series of compounds based on the molecular structures of fluoxetine (Prozac ®) and 4-[(3-fluorophenoxy)phenylmethyl)piperidine were coupled with chemical entities that are known to possess activity against the 5-HT2A receptor by chemical synthesis. It is anticipated that hybrid molecules will reduce the sexual dysfunction side effect without significantly affecting the antidepressant activity. Since serotonin is known to act as a growth factor, the synthesized compounds were tested for activity against several human cancer cell lines. A second project involved progress towards the synthesis of a new compound designed to selectively target the tumor microenvironment. This compound incorporates structural features of both combretastatin A4 and the bioreductive agent tirapazamine. Certain members of the combretastatin series of natural products demonstrate tumor cytotoxicity and damage tumor vasculature. Since many solid tumors are hypoxic, bioreductive entities such as tirapazamine are viable treatment agents.
Design, synthesis and biological evaluation of new anti-Cancer nitrogen-containing combretastatins and novel cysteine protease inhibitors for the treatment of Chagas.
(2006-05-29T01:54:54Z) Siles, Rogelio.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
In an effort to combat cancer, the development of a relatively new type of anti-cancer drugs known as vascular disrupting agents (VDAs) seems to be a promising clinical approach. VDAs selectively interfere with blood flow in the microvessels that carry nutrients and oxygen to the tumor. Blockage of these vessels will stop tumor growth, produce necrosis, and hence prevent proliferation of cancer cells through the body. The discovery of a group of VDAs known as combretastatins (CA) has sparked an exciting area of anti-cancer drug discovery due to their robust biological activity as evidenced through clinical success, particularly for combretastatin A-4 phosphate (CA-4P) and one nitrogen-based combretastatin CA-4 analogue, AVE8062 which are currently in clinical development. Herein, a small library of seventeen new synthetic oxygen and nitrogen-bearing CA-1 and CA-4 analogues is described. Three of these analogues showed significant inhibition of tubulin assembly (IC50= 2-3 μM) as well as in vitro cytotoxicity against selected human cancer cell lines and in vivo blood flow reduction in SCID mice (23-25% at 10 mg/Kg) suggesting that they have potential for further prodrug modification and development as vascular disrupting agents for the treatment of solid tumor cancers. A separate research project has concentrated on the development of cysteine protease inhibitors, primarily focused toward the inhibition of cruzain, the major cysteine protease of Trypanosoma cruzi which is the agent of the parasitic disease called Chagas’ disease. Currently there is no satisfactory treatment for this disease, and the two accepted drugs, nifurtimox and benznidazole, are associated with significant clinical toxicity. A library of fourteen small non-peptidic thiosemicarbazones has been successfully designed, synthesized and tested against cruzain and cathepsin L from which five compounds showed significant cruzain inhibition in the low namolar range. Although the most active compound synthesized, which is a bromotetrahydronaphthalene thiosemicarbazone, exhibited an IC50=12 nM against cruzain, it also showed activity against cathepsin L (IC50=134 nM). This new pharmacophore introduced may prove useful as a lead compound for further optimization. In addition, this research revealed further insights into the complex structure-activity relationship parameters which may lead to the further development of more selective cruzain inhibitors.
Design, synthesis and biological evaluation of novel serotonin reuptake inhibitors and novel derivatives of a nitrogen-containing combretastatin analog.
(2006-10-13T16:13:02Z) Miranda, Maria Graciela.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Depression is a common and serious illness that affects one out of every ten Americans each year. Since the 1980's, selective serotonin reuptake inhibitors (SSRIs) have been the pharmaceuticals of choice for the treatment of depression and related disorders. Despite their indisputable efficacy, there is still room for improvement in SSRIs, especially in regard to their onset of action and adverse reaction profile. The research presented herein focused on the design and synthesis of a library of thirty-three novel bivalent molecules that could combine into one molecular entity an enhanced antagonism towards the 5-HT2A receptors while keeping a highly selective inhibition of the serotonin transporter (SERT). These bivalent molecules were constructed by covalently coupling two types of fluoxetine hydrochloride structural homologues (for SERT affinity) with a series of nine functionalized piperazines and piperidines (for 5-HT2A antagonism). Preliminary biological evaluation shows that two of the synthesized molecules, 16b and 17b, exhibit the desired dual activity (Ki = 237 and 195 nM respectively for the 5-HT2A receptor and Ki = 1.2 and 1.8 microM respectively for SERT). The complete set of biological data will outline the potential of the synthesized molecules as a new generation of improved antidepressants. Although remarkable advances have been made in cancer pharmacotherapy, the American Cancer Society declared this disease as the top killer of Americans in January, 2005. Therefore, a second research project presented herein focused on the development of a bivalent drug candidate for the treatment of cancer, which could combine into one molecular entity two distinct forms of cancer treatment, vascular disruption and bioreduction. Although the desired target molecule was not achieved, two unexpected and structurally unique products were obtained, which were fully characterized in regards to their structure. Preliminary biological evaluation indicates that compound 73 shows significant inhibition of tubulin assembly (IC50 = 3.3 microM), while compound 74 shows potent and selective in vitro cytotoxicity towards three human cancer cell lines. Therefore, the continuation of this line of research aimed at an improved treatment option for cancer patients is strongly encouraged.
Design, synthesis and evaluation of di-nitrogen derivatives of combretastatin and novel cruzain inhibiting compounds for the treatment of Chagas disease.
(2008-03-03T17:32:22Z) Ackley, J. Freeland.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Over the past years cancer statistics have continued to rise to the point that the World Health Organization said that in 2005 cancer was leading cause of death worldwide. Years of research have resulted in many new promising therapies and treatment agents and very recently the field of vascular targeting therapies has grown in a strong proportion. One especially promising technique focuses on the use of vascular disrupting agents (VDAs). This clinical approach targets the endothelial cells partially composed of the tubulin-microtubule protein system in microvessels in the tumor microenvironment. The vascular damage caused by these drugs has seen to be highly selective due, in part, to the chaotic nature of the vessels created by these rapidly proliferating endothelial cells in the tumor microenvironment. The continued success of combretastatin A4 and combretastatin A1 in human clinical development indicate the importance of preparing new synthetic analogs to further understand the role of these anti-mitotic agents. Accordingly, a small library of eleven functionalized Z-stilbenes was created containing various nitro and amine moieties substituted in a 2,3, 3,5, and 2,3 pattern. These compounds have showed impressive biological results with the leading compound 18 demonstrating an IC50 value of 2.8 [mu]M for the inhibition of tubulin assembly and in vitro GI50 values in selected human cancer cell lines that are sub-nanomolar. A separate research project has recently been focused on the design and synthesis of new cruzain inhibitors modeled around an initial small library of molecules previously prepared by the Pinney Research Group at Baylor University. These thiosemicarbazone bearing molecules were designed to target the major cysteine protease of Trypanosoma cruzi also known as cruzain. Selected compounds were successfully designed and synthesized and are awaiting biochemical and biological evaluation.
The design, synthesis, and biological evaluation of indole-based anticancer agents.
(2014-01-28) MacDonough, Matthew T.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Solid tumors depend on a vascular network that delivers nutrients and oxygen, thus selectively targeting the developed tumor vasculature represents a feasible strategy for the treatment of cancer. Both small-molecules and biologics that function in this manner are referred to as vascular disrupting agents (VDAs). Two benchmark VDAs, combretastatin A-1 (CA1) and combretastatin A-4 (CA4), that are both natural products inhibit the dynamic tubulin-microtubule protein system responsible, in part, for the cellular shape of endothelial cells lining tumor blood vessels. This inhibition ultimately results in morphological changes of endothelial cells, from flat to round, and leads to vessel collapse precluding blood flow to the tumor. The success of CA1P and CA4P (corresponding phosphate salts of CA1 and CA4) as VDAs has inspired the development of inhibitors of tubulin that bear structural similarities and incorporate the indole molecular template. 2-(3ʹ′-Hydroxy-4ʹ′-methoxyphenyl)-3-(3ʹ′ʹ′, 4ʹ′ʹ′, 5ʹ′ʹ′-trimethoxybenzoyl)-6- methoxyindole (OXi8006), prepared as its water-soluble phosphate prodrug salt (OXi8007), is a lead VDA discovered by the Pinney Research Group. Scale-up syntheses were necessary to facilitate planned biological studies. To investigate structure activity relationship considerations, analogues of OXi8006 were prepared which incorporate functional group modifications of the 3-aroyl ring, the 2-aryl ring, and the indole fused-ring. These derivatives were evaluated for their ability to inhibit tubulin assembly and for their cytotoxicity against three human cancer cell lines (NCI-H460, SKOV- 3, and DU-145) through collaborative studies with the Trawick Research Group. Bioreductively activatable prodrug conjugates (BAPCs) of OXi8006 that incorporate nitro-thiophenyl bioreductive triggers were synthesized to target tumor hypoxia. The mechanistic pathway for 2-aryl indole formation via the Bischler-Mohlau indole reaction was explored through isotopic labeling of key intermediates. This strategy was also applied to benzo[b]furan and benzo[b]thiophene analogues. Results suggest formation of an imine intermediate for 2-aryl indoles as evidenced by key ¹³C NMR signatures. Similar studies suggest the formation of 3-aryl benzo[b]furans and benzo[b]thiophenes via a pathway in which no aryl shift (2- to 3-position) was observed when hydroxyl substitution is present on the bromoacetophenone starting material. In summary, OXi8006 and OXi8007, a focused library of analogues including BAPCs, as well as isotopically labeled indoles, benzo[b]thiophenes, and benzo[b]furans were prepared.
Design, synthesis, biochemical and biological evaluation of benzocyclic and enediyne analogs of combretastatins as potential tubulin binding ligands in the treatment of cancer.
(2008-03-03T17:33:50Z) Sriram, Madhavi.; Pinney, Kevin G.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
One out of four deaths per day in the United States will be caused by cancer in the year 2007. Cancer still remains the second major cause of mortality both in developed as well as developing countries. Small molecule vascular disrupting agents (VDAs) selectively damage the rapidly proliferating tumor vasculature resulting in hypoxia and eventual necrosis. Examples of VDAs currently in clinical development include CA4P, Oxi4503, and AVE8062. Certain VDAs such as CA4P bind to tubulin (following the conversion of CA4P to CA4) at the colchicine binding site, and cause cytoskeletal disruption of the endothelial cells lining the vasculature in the tumor microenvironment. Based on SAR studies, we have designed a series of novel molecules that bear structural resemblance to certain of the combretastatins, displaying the 1, 2-diarylethene and biaryl scaffold respectively. The synthetic ligands designed also include structural features bearing benzocyclic moieties such as indanes, dihydronapthalenes, benzosuberenes and benzocyclo-octanes. The benzocyclic analogs were synthesized and analyzed for their ability to inhibit microtubule polymerization as well as inhibition of growth in selected human cancer cell lines in vitro. Anti-tumor antibiotics such as calicheamycins, comprise enediyne as one of the pharrmacophores which undergoes Bergman cyclization to generate bi-radicals that damage DNA and cause apoptosis. A series of enediyne and ketodiyne analogs bearing combretastatin structural scaffolds were also designed. The enediyne and ketodiyne analogs were designed from the speculation of their dual activity in both DNA intercalation and vascular disruption. Only one such analog was synthesized and analyzed for it ability to inhibit tubulin polymerization. Protocol for the synthesis of radiolabelled prodrug of CA1 (OX16C) was also carried out successfully as a team effort. The trans-analog of OX16C was also synthesized for the purpose of comparative biological studies between the cis- and trans-isomers of CA1 prodrug. The synthesis of both cis- and trans-OX16C were performed following previously established procedures.
Determination of pharmaceuticals and personal care products in fish using high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry.
(Washington, DC : American Chemical Society Publications., 2007) Ramirez, Alejandro Javier.; Chambliss, C. Kevin.; Brooks, Bryan W.; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
Labeled as emerging organic contaminants, pharmaceuticals and personal care products (PPCPs) have been the focus of global environmental research for over a decade. PPCPs have caused widespread concern due to their extensive use. As PPCPs were designed to correct, enhance, or protect a specific physiological or endocrine condition, their target effects in humans and/or farm stocks are relatively well understood and documented. However, there is limited knowledge about their unintended effects in the environment. To address the occurrence, distribution and fate of PPCPs in the environment, efficient and reliable analytical methods are needed. The relatively low concentration, high polarity, and thermal lability of some PPCPs, together with their interaction with complex environmental matrices, makes their analysis challenging. Sample preparation followed by GC or HPLC separation and mass spectrometry (MS) detection has become the standard approach for evaluating PPCPs in environmental samples. PPCPs have been widely reported in water, sediment and biosolids, but reports of their occurrence in aquatic organisms have been limited by the difficulty of analysis. Herein, we report the first HPLC-MS/MS screening method for the analysis of 23 pharmaceuticals and 2 metabolites representing multiple therapeutic classes in fish tissues. The developed methodology was successfully applied to assess the occurrence of target analytes in fish collected from 8 locations throughout the United States (6 effluent-dominated rivers and two reference sites). A complementary GC-MS method was developed for the analysis of 12 additional compounds belonging to either personal care product or industrial use compound classes in fish muscle. This approach was also applied to screen for target analytes in fish collected from a regional effluent-dominated stream.
Discovery and development of unique small molecule chromene based ligands and combretastatin analogs as potential second generation vascular disrupting agents towards cancer chemotherapy.
(2006-05-29T02:07:12Z) Arthasery, Phyllis.; Pinney, Kevin G.; Chemistry and Biochemistry.; Center for Drug Discovery.; Baylor University. Dept. of Chemistry and Biochemistry.; Baylor University. Center for Drug Discovery.
Cancer is a devastating disease, which remains one of the leading causes of death worldwide. In our continuing quest to help find a cure for cancer, we have discovered and developed new small molecule vascular disrupting agents also known as VDAs for the treatment of cancer. Vascular disrupting agents, by definition, cause a rapid collapse in tumor blood flow, and an effective agent will cause a prolonged period of vascular shutdown, culminating in extensive tumor cell necrosis. The possibility of targeting a tumor's vasculature using small molecule VDAs is currently under active investigation and lead compounds, like combretastatin-A4P, combretastatin-A1P, AC7700 and ZD6126 are in clinical trials for the treatment of cancer, here in the US and in the UK. In this study, a small library of thirteen unique chromenes have been synthesized and evaluated for their anti-cancer efficacy against a panel of human cancer cell lines, and against the P388 mouse leukemia cell line. The inhibition of tubulin assembly data has also been obtained for some of the compounds. Two of the chromenes synthesized show remarkable cytotoxicity (GI50 values) against prostate, lung, CNS-Giobl, and breast adenocarcinoma cancer cell lines. Their ED50 values against the P388 cancer cell line are better than one of the lead compounds combretastatin-A1 (CA-1). In addition, one of these compounds has an IC50 value of 2-4 µM which is comparable to that of bench lead compounds. This compound, therefore, has the potential for further development as a clinical candidate for the treatment of cancer. Further, combretastatin-A4 (CA-4) and CA-1 analogs have been synthesized and their biological activity has been evaluated. Collaborative research efforts (as a member of a research team of the Pinney laboratory) for the synthesis of a dihydronaphthalene analog, trouble shooting in a project centered on the synthesis of a precursor of CA-1 which would ultimately be suitable for radiolabeling, and a scaling up project of OXi8007 were also undertaken. OXi8007 is now in advanced preclinical development for the treatment of cancer and ophthalmology studies. A significant attempt has also been undertaken for the total synthesis of ZD6126 phenol whose phosphate prodrug was recently evaluated in clinical trials for the treatment of cancer. ZD6126 is currently prepared by semi-synthesis starting from colchicine.
Discovery of a novel adenosine 5'-phosphosulfate (APS) reductase from the methanarcheon Methanocaldococcus jannaschii.
(Elsevier, 2010-12) Lee, Jong-Sun, 1979-; Kim, Sung-Kun, 1968-; Chemistry and Biochemistry.; Baylor University. Dept. of Chemistry and Biochemistry.
This thesis presents the first discovery of adenosine 5'-phosphosulfate reductase (APR), a key enzyme of the sulfate reduction pathway, in the methanarchaeon Methanocaldococcus jannaschii. While the sulfate reduction pathway is present in other organisms, it is not expected to exist in methanarchaea because their habitats often already possess an abundance of reduced sulfur, particularly H₂S. However, the gene product of open reading frame (ORF) Mj0973 in M. jannaschii possesses sequence similarities with known APRs and 3'-phosphoadenosine-5'-phosphosulfate reductases (PAPRs) from various organisms. In order to further investigate this ORF, the gene Mj0973 from M. jannaschii was expressed and the resulting protein was purified. Kinetic studies revealed that the purified protein is able to reduce APS with E. coli thioredoxin (Trx) supplied as the electron donor, but is unable to reduce PAPS. The apparent Km, Vmax, and kcat/Km values at pH 8.0 and 30°C were 0.29 µM, 0.079µMmg⁻¹min⁻¹, and 299,655 M⁻¹s⁻¹, respectively. This observation of APR activity strongly indicates the presence of an APS-utilizing sulfate reduction pathway in the methanarchaeon M. jannaschii.

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