• Design & Synthesis of Pyrazinamide Hybrid Conjugates as Potential Anti-tubercular Agents

      Torkian,Behrad; Panda, Siva S.; Department of Chemistry & Physics (2017-03)
      Tuberculosis (TB) is a bacterial pathogen caused by Mycobacterium tuberculosis, which generally causes pulmonary infection and is extremely pervasive within the lungs and between subjects. Pyrazinamide (PZA) is a first-line prodrug used synergistically with two or more chemotherapies to eradicate TB. PZA is hydrolyzed to its active constituent, pyrazinoic acid, intracellularly in M. tuberculosis via pyrazinamidase. With prolonged administration of the recommended dose, harmful side effects have been reported: hepatitis, acute hypertension, thrombocytopenia, and gastrointestinal discomfort Drug-amino acid conjugates are used because of increased tissue delivery, in which the amino acids act as effective carriers of these agents while maintaining, and even amplifying, their bioactive integrity. Amino acid conjugates can increase bioavailability and quantitatively decrease the required amount of active drug thus preventing toxic side effects. We have synthesized several pyrazinamide conjugates with secondary amines via amino acid linkers with retention of chiral integrity of the desired products. Secondary amines are known for enhancing biological properties of various potential molecules. All the synthesized compounds were characterized by NMR and X-ray studies. The synthesized conjugates are expected to have better anti-tubercular properties with less side effects.
    • Investigation of the Properties of Stem-Loop DNA

      Spencer, Angela; Benny, Reshma; Department of Chemistry & Physics (2017-03)
      Deoxyribonucleic acid (DNA) is the genetic material of almost all living organisms and a polymer of deoxynucleotide monomers. Stem-loop DNA (slDNA) is a type of secondary structure formed when a single strand of DNA folds over on itself and contains complementary deoxynucleotides that form base pairs in the stem while the deoxynucleotides that are not complementary to each other forms the loop. SlDNA sizes in this study varied in the stem to loop ratios with ranges from 10 to 20 base pairs in the stem and from 3 to 60 nucleotides in the loop. The behavior of these slDNAs in native polyacrylamide gel electrophoresis (PAGE) and denaturing PAGE with different urea and formamide concentrations, common denaturing agents used to destabilize DNA, were studied to determine that slDNAs with higher stem-loop ratios did not denature while the ones with lower stem-loop ratios successfully denatured at an optimal condition of 12% PAGE 9.0 M Urea and 10% PAGE 16 M formamide. Polymerase chain reactions (PCR) using slDNA molecules were studied to determine if the slDNAs of similar stem to loop ratios will have a similar response to PCR as gel electrophoresis, but the analysis of the products on PAGE conveyed obscure results.
    • Phytochemical Investigation and Anticancer Evaluation of Pimenta dioica (Allspice) Berries

      Capito, Jason E.; Lokeshwar, Bal L.; Panda, Siva S.; Department of Chemistry & Physics (2017-03)
      Cancer of the prostate (CaP) is the most common non-skin cancer in American men. As the disease recurs over several years in a significant fraction of patients, it is a good target for chemoprevention. If began early, preventive agents may enhance the survival and quality of the patients’ life profoundly such that the disease, even if not completely eliminated, may pose little threat to life. Recurrent CaP following radiation therapy, surgery or both is incurable at present. All studies reported to date state that conventional chemotherapy is used with limited effect, prolonging life between 2 and 4 months. Many aromatic tropical plants contain a rich assortment of secondary metabolites that are evolved to protect and preserve the nutrients from bacterial, fungal and insect infestations. These include alkaloids, glycosides, polyphenols, terpenes and terpenoids. Several compounds with pharmacological activities have been isolated from fresh leaves of Pimenta dioica (Family: Myrtaceae; alternate name: Jamaican pepper) and the dried, unripe berries, known as allspice, are marketed as an edible spice. Allspice, which tastes like a blend of cloves, nutmeg, cinnamon and pepper, is a common flavoring compound in Asian, Middle Eastern and Jamaican cuisines. In this study, the bioassay, isolation and phytochemical investigation of active component from the aromatic berries of Pimenta dioica (allspice) were carried out. Potential antitumor activities of allspice extract and a compound purified from the extract were tested against prostate and breast cancer cell lines.
    • Purification of Recombinant Human Histone Methyltransferases for Inhibition Studies

      Jahan, Asmat; Shaikh, Zahid; Department of Chemistry & Physics (2017-03)
      Resistance to cellular apoptotic pathways is a major contributing factor in the metastasis of cancer. One such cell-intrinsic pathway which induces programmed cell death is ligand cell surface death receptors, including Fas protein. In primary colorectal cancer, Fas expression is often diminished. The silencing of Fas expression is perhaps a mechanism by which human colorectal cancer cells evade apoptosis. The decrease in Fas expression levels is associated with hypermethylation of histone 3 lysine 9 catalyzed by histone methyltransferases (HMTases) such as SUV39H1 and SUV39H2. Because of the role of methylation in silencing Fas expression, HMTase inhibitors represent potential anti-cancer agents. Verticillin A, a natural compound extracted from wild mushroom, is a broad-based HMTase inhibitor and has been shown to cause toxicity in mice. Our goal in this study is to identify specific SUV39H1 and SUV39H2 inhibitors that are less toxic than Verticillin A. To investigate this, human SUV39H1 was sub-cloned into an expression vector, transformed into an E.coli expression strain and purified using affinity chromatography. Gel electrophoresis and Western blot analysis confirmed the presence of partially purified human SUV39H1. The next phase of the project will involve testing the activity of the purified protein in an in vitro assay.
    • Synthesis, Antibacterial Properties and Molecular Modeling Studies of Quinolone-triazole Hybrids

      Honkanadavar, Hitesh; Panda, Siva S.; Department of Chemistry & Physics (2017-03)
      Quinolones are one of the most important synthetic antibacterial agents and have been widely used in the treatment of diverse infections including urinary tract, respiratory and bone joint infections as well as sexually transmitted diseases, prostatitis, pneumonia and acute bronchitis. However, quinolone resistance increases in almost all Gram-negative and Gram-positive species as well as tuberculosis. The continued increase in resistance has put enormous pressure on public health systems worldwide, mainly due to the high level of use and to some degree of abuse. The current study deals with bio-conjugation of quinolone antibiotics, including ciprofloxacin, norfloxacin, and pipemidic acid (considering that the pyridopyrimidinyl nucleus is the bio-isosteric form of the quinoline ring), with triazole rings. Interest in the 1,2,3-triazol scaffold for developing novel bio-conjugates is attributed to the pharmacological properties exhibited by 1,2,3-triazole containing-compounds as anti-inflammatory, anti-tumor, and antibacterial agents. Additionally, 1,2,3-triazole possesses favorable properties in the medicinal chemistry field. It has a moderate dipole character, hydrogen bonding capability, rigidity and remarkable metabolic stability. In a previous study, it was found that antibiotic conjugates with amino acids enhance the lipophilic properties of quinolone antibiotics with a retention or increase in antibacterial activity. In the current study, a 1,2,3-triazole nucleus is being introduced into amino acid and antibiotic conjugates to alter their biological properties. Computational chemistry studies including 3D-pharmacophore and 2D-QSAR (quantitative structure-activity relationship) are being used to assist in the understanding of observed biological properties as well as determining the most important structural parameters controlling bio-activity. These studies are also being used to validate observed biological data.