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.

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.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 7 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.