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Design, synthesis and pharmaceutical application of novel polycyclic 'cage' diamines.Onajole, Oluseye Kehinde. January 2010 (has links)
Despite over 50 centuries of living with the disease, tuberculosis (TB) still remains one of the
oldest and deadliest diseases known to man and is gradually becoming a serious threat to the
human race. According to the 2009 Global tuberculosis control report of the World Health
Organisation (WHO), it is estimated that about 9.4 million incident cases of TB occurred
globally. Of these cases an estimated 1.4 million were HIV positive of which 78 % were in the
African region while 13 % are located in the South-East Asia Region. An estimate of 1.3
million deaths was reportedly caused by TB among HIV negative people. South Africa has the
highest percentage of HIV patients living with tuberculosis. The design, synthesis and
evaluation of novel polycyclic ‘cage’ amines for their pharmaceutical profiles are presented in
this thesis. In this project a total of 12 novel intermediates and 31 novel products were
synthesised. A thorough NMR elucidation of the various structures was also pursued.
This study was motivated by the reported discovery of SQ109 by Sequella. SQ109 (N-Geranyl-
N’-(2-adamantyl)ethane-1,2-diamine) shares the same 1,2 ethylenediamine pharmacophore with
ethambutol (EMB), a commercial TB-drug. SQ109 also possess remarkable activity against
MDR-TB which includes the EMB resistant strain suggesting that SQ109 is a new anti-TB drug
and not an EMB analogue. SQ109 comprises of a polycyclic adamantane moiety, an isoprenyl
moiety and a diamine.
This study had three main aims, namely (a) the design and synthesis of novel polycyclic ‘cage’
amines derivatives; the polycyclic ‘cage’ moieties investigated in this study includes
adamantane, trishomocubane, oxa-pentacycloundecane, aza-pentacycloundecane,
pentacyclodecane and pentacycloundecane, (b) structural elucidation (using 2D NMR
techniques) of synthesized novel polycyclic ‘cage’ amine derivatives (c) the anti-mycobacterial
screening of novel polycyclic ‘cage’ amines derivatives against H37Rv, MDR (multi-drug
resistant) and XDR (extensively-drug resistant) strains of Mycobacteria tuberculosis and (d) the
anti-bacterial and anti-fungal screening of selected novel polycyclic ‘cage’ amine derivatives.
Furthermore, the design, synthesis and NMR elucidation of a family of similar novel PCU
diamine ligands are also reported herein. The aim of these ligands is to complex and transport
copper ions to the sites of inflammation caused by arthritus. The known pharmaceutical
properties of polycyclic ‘cage’ compounds such as their ability to cross membranes due to
improved drug lipophilicity makes them suitable candidates for such a study. This project stems
from a logic collaboration between UKZN, UCT (University of Cape Town) and CPUT (Cape
Peninsula University of Technology) to test some of these cage diamines for activity against
arthritus. Experimental work in this aspect is performed by the group of Prof. Graham E.
Jackson (UCT) and Dr. Sebusi Odisitse (UPUT). / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2010.
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The role of natural killer cells in preventing HIV-1 acquisition and controlling disease progression.Naranbhai, Vivek. January 2013 (has links)
In sub-Saharan Africa, women carry a disproportionate burden of the Human
Immunodeficiency Virus Type 1 (HIV-1) pandemic. The high risk of HIV
acquisition in these women and the variability in their disease progression is
not fully understood. Natural Killer (NK) cells, which are innate immune
antiviral lymphocytes, present systemically and at mucosal surfaces, may play
a role in preventing HIV acquisition and/or altering disease progression, as
they are key early mediators of the response to viral infections and are
equipped to kill infected cells.
The purpose of this study was to evaluate the role of NK cells in HIV-1
acquisition and following acquisition, in disease progression.
The study participants were selected women who were participating in a
randomized controlled trial assessing the effectiveness of 1% Tenofovir gel in
preventing HIV-1 (CAPRISA 004 trial). The study design was a case-control
study nested within the cohorts followed up in the CAPRISA 004 trial. In this
trial, 889 sexually-active women aged 18-40 years were randomized to
receive Tenofovir or placebo gel and prospectively followed. Assessment of
HIV infection was performed monthly by rapid HIV-1 antibody tests,
supplemented by HIV-1 RNA polymerase chain reaction (PCR), p24 Western
blotting and/or ELISA. Samples obtained prior to the first positive rapid
antibody test were retrospectively tested by HIV specific PCR to identify
window period infections. The date of infection in this study was estimated as
the midpoint between the last negative and first positive antibody test, or 14
days prior to the first HIV-1 RNA-PCR positive result. Multi-parametric flow
cytometry techniques developed and validated in healthy blood donors were
used to asses the bidirectional relationship between NK cells and HIV-1. To
simulate in vivo interaction between NK cells and autologous HIV infected
cells, an in vitro infection and coculture assay was used in addition to
conventional assays of NK cell recognition of HLA-deficient cell lines. These
were supplemented with measurement of plasma cytokines by Luminex and
microbial products by ELISA. In this study, 44 cases who acquired HIV-1 were
sampled prior to infection and 39 controls who remained HIV-1 negative
despite high behavioural exposure at the timepoint when their preceding
sexual activity was highest. To understand how HIV infection affected NK
cells during early HIV-1 infection, the first sample obtained after acquisition
was studied and compared to preinfection samples from the same participant.
The case and control groups were broadly similar in the proportions using
tenofovir gel, proportions infected with HSV-2 and number of sexual partners
but tended to be marginally older than cases (27.6 vs 23.3 years). By design
control women had higher sexual activity than cases (mean 11 vs. 5.7 sex
acts per month).
The frequency of IFN-γ secreting NK cells from women who acquired HIV
infection were significantly lower than from women who remained uninfected
in response to 721 cells-an EBV transformed B cell line (background-adjusted
median 13.7% vs. 21.6%; p=0.03) and to autologous HIV infected T-cells
(background-adjusted median 0.53% vs. 2.09%; p=0.007). NK cells from HIV
acquirers displayed impaired proliferation but enhanced spontaneous
degranulation compared with non-acquirers after co-culture with HIV
uninfected or infected autologous T-cell blasts. Adjusting for age, gel arm,
HSV-2 infection status and levels of NK cell activation, IFN-γ+ NK cell
responses to autologous HIV infected cells were associated with reduced
odds of HIV acquisition (OR 0.582; 95% CI 0.35-0.98; p=0.04). In addition,
even in the absence of ex vivo stimulation, HIV acquirers had higher levels of
generalised innate immune activation measured by systemic cytokine
concentrations (TNF-α, IL2, IL-7 and IL12p40), peripheral blood platelet
concentrations (p=0.038), and non-specific ex vivo NK cell activation
(p<0.001). Generalised NK cell activation measured directly ex vivo without
stimulation was associated with acquisition. Further, if innate immune
activation was assembled as a principal component in an unsupervised
fashion but taking into account all the measures made, it was significantly
associated with HIV acquisition (OR adjusted for age, tenofovir gel use, and
HSV-2 status for PC with innate immune factor loadings 11.27; 95% CI 1.84-
69.09; p=0.009). The causes of preinfection innate immune activation could
not be established in this study but the degree of activation could not be
explained by microbial translocation as both HIV acquirers and non-acquirers
had similar levels of plasma lipopolysaccharide (LPS), soluble CD14 (sCD14)
and intestinal fatty-acid binding protein (I-FABP). Similarly, both HIV acquirers
and non-acquirers had similar NK cell and cytokine responses to Toll-like
Receptor (TLR)-2, 3 or 7/8 agonists 11. During early HIV-infection, NK cells
demonstrated significantly higher activation (p=0.03), expression of Killer-cell
immunoglobulin-like Receptors (KIR) (p=0.006) and expression of chemokine
receptor 7 (CCR7, p<0.0001) compared with prior to acquisition. Although NK
cells had reduced cytolytic potential following HIV acquisition, antiviral IFN-γ
secretion appeared to be preserved. NK cell responses were not different
between tenofovir and placebo gel recipients, but women who acquired HIV
whilst using tenofovir gel had higher gag-specific IFN-γ CD4+ T-cell
responses during early infection.
Overall, the findings suggest that the frequency of NK cells producing IFN-γ
specifically after co-culture with HIV-1 infected target cells was associated
with protection from HIV-1 acquisition but, generalised, non-specific activation
of NK cells and other innate immune components enhanced HIV acquisition.
Since neither microbial translocation nor TLR responsiveness were
associated with pre-existing immune activation further studies will be required
to identify the drivers of generalised innate immune activation. Methods to
dampen generalised innate immune activation and/or augment specific NK
cell antiviral responses in women at risk for HIV-1 may reduce HIV-1
acquisition.
During primary HIV-1 infection, NK cells underwent impairment of cytolytic
function but not IFN-γ secretory function; this may affect their ability to affect
disease progression. Although Tenofovir gel did not alter innate immune
responses in women with breakthrough infection, it preserved HIV-specific Tcell
immune responses, the consequences of which need further exploration.
Understanding how Tenofovir gel mediated preservation of adaptive immune
responses may lead to interventions that will reinforce protective host
responses.
In conclusion, innate immune responses by NK cells have been shown to
impact HIV acquisition; HIV-specific IFN-γ responses by NK cells were
protective while generalised NK activation was detrimental. The causes of
innate immune activation are not known but these effects were independent of
the impact of Tenofovir gel. Future prevention strategies targeting mucosal
transmission of HIV should assess their impact on NK cell responses, to avoid
general innate immune activation and enhance their ability to protect against HIV acquisition. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2013.
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Immune regulation in response to mycobacterial infectionCheung, Ka-wa, Benny, January 2007 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available in print.
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Molecular epidemiology of HIV-1 and characterization of drug resistant HIV-1 in Hong KongChen, H. K., Jonathan. January 2007 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available in print.
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Structural and functional determinants of effective CD8⁺ T cell suppression of HIV-1 replicationSimons, Brenna Colleen. January 2009 (has links)
Thesis (Ph. D. in Microbiology and Immunology)--Vanderbilt University, May 2009. / Title from title screen. Includes bibliographical references.
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Immune regulation in response to mycobacterial infection /Cheung, Ka-wa, Benny, January 2007 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available online.
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The effect of community support groups on psychosocial adjustment, uncertainty, and hopelessness in persons infected with the human immunodeficiency virus /Ramsey, Priscilla Webster. January 1990 (has links)
Thesis (Ph. D.)--University of Virginia, 1990. / Includes bibliographical references (leaves 194-216). Also available online through Digital Dissertations.
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A secondary dimerization site in the 5' leader region of the HIV-1 genome /Miranda, Daniel, Jr. January 2004 (has links)
Thesis (Ph.D.)--University of California, San Francisco, 2004. / Includes bibliographical references. Also available online.
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Mechanisms of HIV-1 Tat induced immune responseLi, Chun-bong, January 2005 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.
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Mechanism of human immunodeficiency virus induced immune dysregulation TAT & IL-18 interaction /Leung, Sze-ki. January 2005 (has links)
Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.
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