Spelling suggestions: "subject:"3structure – activity relationship"" "subject:"bstructure – activity relationship""
41 |
The effect of selected hydroxy flavonoids on the in vitro efflux transport of rhodamine 123 using rat jejunum / S. van HuyssteenVan Huyssteen, Stephanie January 2005 (has links)
Background: Multidrug resistance (MDR) is resistance of cancer cells to multiple
classes of chemotherapeutic drugs that can be structurally unrelated. MDR involves
altered membrane transport that results in a lower cell concentration of cytotoxic drugs
which plays an important role during cancer treatment. P-glycoprotein (Pgp) is localised
at the apical surface of epithelial cell in the intestine and it functions as a biological
barrier by extruding toxic substances and xenobiotics out of cells (Lin, 2003:54). The
ATP-binding-cassette superfamily is a rapidly growing group of membrane transport
proteins and are involved in diverse physiological processes which include antigen
presentation, drug efflux from cancer cells, bacterial nutrient uptake and cystic fibrosis
(Germann, 1996:928; Kerr, 2002:47). A number of drugs have been identified which are
able to reverse the effects of Pgp, multidrug resistance protein (MRPI) and their
associated proteins on multidrug resistance. The first MDR modulators discovered and
studied during clinical trials were associated with definite pharmacological actions, but
the doses required to overcome MDR were associated with the occurrence of
unacceptable side effects. As a consequence, more attention has been given to the
development of modulators with proper potency, selectivity and pharmacokinetic
characteristics that it can be used at a lower dose. Several novel MDR reversing agents
(also known as chemosensitisers) are currently undergoing clinical evaluation for the
treatment of resistant tumours (Teodori et al., 2002:385). Aim: The aim of this study was
to investigate the effect of selected flavonoids (morin, galangin, kaempferol and
quercetin) at two different concentrations (10 μM and 20 μM) on the transport of a known
Pgp substrate, Rhodamine 123 (Rho 123) across rat intestine (jejunum) and to
investigate structure activity relationships (SAR) of the selected flavonoids with
reference to the inhibition of Pgp. Methods: Morin, galangin, kaempferol and quercetin
were evaluated as potential modulators of Rho 123 transport, each at a concentration of
10 μM and 20 μM across rat jejunum using Sweetana-Grass diffusion cells. This study
was done bidirectionally, with two cells measuring transport in the apical to basolateral
direction (AP-BL) and two cells measuring transport in the basolateral to apical direction
(BL-AP). The rate of transport was expressed as the apparent permeability coefficient
(Pap,) and the extent of active transport was expressed by calculating the ratio of BL-AP
to AP-BL. Results: The BL-AP to AP-BL ratio calculated for Rho 123 with no
modulators added was 3.29. Morin decreased the BL-AP to AP-BL ratio to 1.88 at a
concentration of 10 μM and to 1.49 at a concentration of 20 μM. Galangin decreased
the BL-AP to AP-BL ratio to 1.60 at a concentration of 20 μM. These two flavonoids
showed statistically significant results and inhibition of active transport were clearly
demonstrated. However, the other flavonoids inhibited active transport of Rho 123 but
according to statistical analysis, the results were not significantly different. The two
different concentrations (10 μM and 20 μM) indicated that galangin, kaempferol and
quercetin showed practically significant differences according to the effect sizes. Morin,
however, did not show any practically significant differences at the different
concentrations. Regarding .the SAR, it was shown by Boumendjel and co-workers
(2002:512) that the presence of a 5-hydroxyl group and a 3-hydroxyl group as well as
the C2-C3 double bond are required for high potency binding to the nucleotide binding
domain (NBD) of Pgp. All the flavonoids tested had the above-mentioned
characteristics. Conclusion: All the selected flavonoids showed inhibition of active
transport of Rho 123 and should have an effect on the bioavailability of the substrates of
Pgp and other active transporters. This study described the inhibitory interaction of
selected flavonoids on Pgp activity. Practical significant differences between the same
modulator at different concentrations were also observed. Structure activity
relationships were identified describing the inhibitory potency of the flavonoids based on
hydroxyl group positioning / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
|
42 |
Investigating the Importance of Electronic and Hydrophobic Effects for Ice Recrystallization Inhibition Using 'Beta'-'O'-Aryl GlycosidesAlteen, Matthew 17 December 2013 (has links)
The cryopreservation of cells and tissues requires the addition of a cryoprotectant in order to prevent cellular damage caused by ice. Unfortunately, common cryoprotectants such as DMSO and glycerol exhibit significant toxicity which makes their use unfeasible for many clinical procedures. Our laboratory is interested in the development of alternative, non-toxic cryoprotectants which possess ice recrystallization inhibition (IRI) activity. Potent IRI activity has recently been discovered in certain small molecules, but the structural features required for this process are unclear. Herein we report the development of a library of O-aryl glycosides in order to probe the importance of electron density and hydrophobic moieties for IRI activity. It was found that the degree of electron density at the anomeric oxygen does not correlate with IRI ability in para-substituted aryl glycosides, nor does changing the position of the aryl substituent impart a predictable effect on activity. However, the addition of hydrophobic alkyl or acyl chains was beneficial for IRI activity; generally, increasing chain length was found to correlate with increasing activity. In some instances, an optimal alkyl chain length was identified, after which continued lengthening results in a loss of potency. We conclude from this study that a certain extent of hydrophobic character is beneficial for the IRI activity of aryl glycosides, and that a balance between hydrophobicity and hydrophilicity is required for optimum IRI ability. It is hoped that these findings will aid future efforts towards the rational design of novel cryoprotectants.
|
43 |
Studies on HIV-1 core assembly /Abdurahman, Samir, January 2007 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.
|
44 |
Computational studies of HIV-1 protease inhibitors /Schaal, Wesley, January 2002 (has links)
Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.
|
45 |
Non-enveloped virus infection probed with host cellular molecules : a structural study /Xing, Li, January 2002 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 7 uppsatser.
|
46 |
Lysophosphatidic acid : physiological effects and structure-activity relationships /Nilsson, Ulrika K. January 2002 (has links)
Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 4 uppsatser.
|
47 |
Substrate specificities and functional properties of human short-chain dehydrogenases/reductases /Shafqat, Naeem, January 2004 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.
|
48 |
Short-chain dehydrogenases/reductases : structure, function and motifs of hydroxysteroid dehydrogenases /Filling, Charlotta, January 2002 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.
|
49 |
Design and synthesis of steroid mimetic libraries using solid phase techniques /Ruda, Marcus, January 2004 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.
|
50 |
Retinoid processing in vivo - characterization and structure-function analysis of retinol dehydrogenases /Tryggvason, Kristian, January 2003 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.
|
Page generated in 0.1532 seconds