The Groebke-Blackburn-Bienayme Reaction

Imidazo[1,2a]pyridine is a well‐known scaffold in many marketed drugs, such as Zolpidem, Minodronic acid, Miroprofen and DS‐1 and it also serves as a broadly applied pharmacophore in drug discovery. The scaffold revoked a wave of interest when Groebke, Blackburn and Bienaymé reported independently a new three component reaction resulting in compounds with the imidazo[1,2‐a]‐heterocycles as a core structure. During the course of two decades the Groebke Blackburn Bienaymé (GBB‐3CR) reaction has emerged as a very important multicomponent reaction (MCR), resulting in over a hundred patents and a great number of publications in various fields of interest. Now two compounds derived from GBB‐3CR chemistry received FDA approval. To celebrate the first 20 years of GBB‐chemistry , we present an overview of the chemistry of the GBB‐3CR, including an analysis of each of the three starting material classes, solvents and catalysts. Additionally, a list of patents and their applications and a more in‐depth summary of the biological targets that were addressed, including structural biology analysis, is given

The effect of novel compounds on cell survival and apoptosis in colon cancer cell lines

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Masters of Science in Medicine (Pharmacology) Johannesburg, 2013Colon cancer is the third most common cancer worldwide and the second most common in the western world. More than 40 % of colon cancer sufferers develop metastases and chemotherapy is often used alone or in combination with radiotherapy as adjunctive therapy for the advanced disease. A major effort has been made in the past decade to develop anticancer agents through both empiric screening and rational design of new compounds. These attempts are made to improve the survival rate, reduce the severe adverse effects associated with existing cancer chemotherapeutic agents as well as to reduce the development of drug resistance. In the present study, two colon cancer cell lines were exposed to novel imidazo[1,2-a]pyridines and novel nucleoside analogues, aiming to investigate the cytotoxic efficacy on the cells, the mode of cell death, and to explore the pathways by which cell death was induced

The use of emergency hormonal contraception in South Africa: current and future perspectives

Emergency hormonal contraceptives play an important role in preventing unplanned pregnancies in South Africa. In this review, we discuss the levonorgestrel emergency contraceptive, the combined estrogen and progestin regimen (also known as the Yuzpe method) and the use of Ulipristal acetate. The levonorgestrel and the combined estrogen, progestin regimen are available in South Africa. The specific mechanisms of action of each of these emergency hormonal contraceptives will be discussed as well as their efficacy, the side effects associated with each of these preparations and the drug interactions. Levonorgestrel can be used as a single dose (1.5 mg) instead of two doses (0.75 mg) 12 hours apart. Levonorgestrel is very effective, with fewer adverse effects than the combined estrogen and progestogen administration. Levonorgestrel and the Yuzpe method have demonstrated good efficacy when utilised within 72 hours after unprotected intercourse or contraceptive failure. These emergency hormonal contraceptives should not be used as regular contraception. It is essential that all health professionals and educators inform women of reproductive age about the risks and common side effects of emergency hormonal contraceptives

Long-acting reversible hormonal contraception

Long-acting reversible hormonal contraceptives are effective methods of birth control that provide contraception for an extended period without requiring user action. Long-acting reversible hormonal contraceptives include progesterone only injectables, subdermal implants and the levonorgestrel intrauterine system. These methods have several advantages over other reversible contraceptive methods. More importantly, once in place, they require minimal maintenance and their duration of action ranges from 8 weeks to 5 years. Despite the advantages of long-acting reversible hormonal contraceptive methods, they are infrequently used in South Africa. Short-acting methods, specifically oral contraceptives and condoms, are by far the most commonly used reversible methods. A shift from the use of short-acting methods to long-acting reversible contraceptive methods could help reduce the high rates of unintended pregnancies in South Africa. In this review of long-acting reversible hormonal contraceptive methods, we discuss the long-acting progesterone injectables, the etonogestrel implant and the levonorgestrel intrauterine system available in South Africa, the side effects of each of these preparations and the non-contraceptive benefits. It is imperative that health professionals and educators inform women of reproductive age about the benefits, risks, and common side effects of long-acting reversible hormonal contraception to improve consideration and recognition of these methods

Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues

<div><p>Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC₅₀ values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (<i>p</i>>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (<i>p</i>>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.</p></div

Nucleoside 2 treated vacuolated HT-29 and Caco-2 cells stained with acridine orange shows an absence of lysosomal staining (A) and a nucleoside 2 induced HT-29 multi-lobular structure (B).

<p>Acridine orange stained HT-29 and Caco-2 cells, following exposure to 50 μM of nucleoside 2 (A). HT-29 cells were exposed to 50 μM of nucleoside 1 and the supernatant harvested and centrifuged at 500 x <i>g</i> for 5 mins. The multi-lobular cell was stained with Hoechst 33342 and acridine orange (B). Scalebar: 20 μm.</p

Nucleoside 2 and chloroquine cause the formation of large highly fluorescent autophagic vacuoles in HT-29 cells.

<p>Cells were exposed to nucleoside 1, 2 and 5 at a concentration of 50 μM for three hours. Chloroquine (50 μM) was used as a positive control at and camptothecin (20 μM) was included as a negative control. Arrows indicate autophagic vacuoles. Scalebars: 20 μm.</p

Nucleoside 2 and chloroquine cause the formation of large, highly fluorescent autophagic vacuoles in Caco-2 cells.

<p>Cells were exposed to nucleoside 1, 2 and 5 at a concentration of 50 μM for three hours. Chloroquine (50 μM) was used as a positive control and camptothecin (20 μM) was included as a vacuole negative control. Arrows indicate autophagic vacuoles. Scalebars: 20 μm.</p

Nucleoside-induced morphological changes in Caco-2 cells include rapid perinuclear vacuole formation (nucleoside 1 and 2) and a loss of cellular adherence (nucleoside 5).

<p>Cells were exposed to 50 μM of each nucleoside for the indicated times and the experiments were repeated three times. Scalebar: 20 μm.</p