Theses/Dissertations - Chemistry & Biochemistry
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Browsing Theses/Dissertations - Chemistry & Biochemistry by Subject "Antineoplastic agents -- Development."
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Item 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.Item 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.Item 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.Item 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.