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Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 148-151). Also available in electronic version. Access restricted to campus users.

Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

Thesis (M.S.)--University of Texas at Dallas, 2008. / Includes vita. Includes bibliographical references (leaves 113-118)

Thesis (M.S.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009. / Committee Chair: Weck, Marcus; Committee Member: Collard, David; Committee Member: Kubanek, Julia. Part of the SMARTech Electronic Thesis and Dissertation Collection.

Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (Ph.D.) -- University of Rhode Island, 2008. / Typescript. Includes bibliographical references (leaves 203-211).

Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

An increasing number of cyclic dipeptides (CDPs) have been shown to exhibit important biological activity including antifungal, antibacterial, anticonvulsant and immunomodulatory activity. Furthermore, some CDP derivatives have been shown to exhibit antitumour activity in vitro and in vivo. Several proline-based CDPs that exhibit biological activity have been detected in various processed foods and beverages. In the present study, the potential of seven proline-based CDPs to inhibit cancer cell growth was investigated in HT-29 (colon), HeLa (cervical), MCF-7 (breast) and WHCO3 (oesophageal) cancer cell lines. The CDPs used in this study were cyclo(Phe-Pro), cyclo(Tyr-Pro), cyclo(Gly-Pro), cyclo(Pro- Pro), cyclo(His-Pro), cyclo(Leu-Pro) and cyclo(Thr-Pro). The sulforhodamine B (SRB) cell growth assay was used in an initial screening phase to investigate the effects of the CDPs in HT-29, HeLa and MCF-7 cells. After exposing the cells to 10mM of the respective CDPs for 48 hours, the SRB assay results showed that only cyclo(Phe-Pro) exhibited more than 50% growth inhibition (p<0.01) in the three cell lines. The other CDPs showed comparatively marginal growth-inhibitory effects, except for cyclo(Tyr-Pro), which exhibited a pronounced effect in MCF-7 cells compared to HT-29 and HeLa cells. The MTT assay was used to confirm the SRB assay results for cyclo(Phe-Pro) and cyclo(Tyr-Pro), extending the investigation to the use of the fourth cell line WHCO3 and using a longer exposure time of 72 hours. The MTT assay demonstrated a dosedependent (0.008-10 mM) growth inhibition by cyclo(Phe-Pro) with an IC50 value of 4.04 ± 1.15 mM for HT-29 cells. Cyclo(Phe-Pro) was subsequently used to investigate whether the growth-inhibitory effects of this CDP were related to the induction of apoptosis in HT-29 cells. Hoechst 33342 staining showed that 5mM cyclo(Phe-Pro) induced characteristic chromatin condensation and nuclear fragmentation in 18.3 ± 2.8% (p<0.01) of HT-29 cells after 72 hours. Furthermore, annexin V binding revealed that HT-29 cells treated with 5 mM cyclo(Phe-Pro) displayed phosphatidylserine externalization after 48 hours. In addition, it was shown that 10 mM cyclo(Phe-Pro) induced poly(ADP-ribose)polymerase PARP cleavage, one of the hallmark events of apoptosis. The use of the broad-range caspase inhibitor Z-VAD-FMK, showed that this PARP cleavage was caspase-dependent, which in turn was confirmed by demonstrating an increase in caspase-3 activity (p<0.01) in cyclo(Phe- Pro)-treated HT-29 cells. In conclusion, these findings demonstrate that cyclo(Phe-Pro) inhibited the growth of HT- 29, MCF-7, HeLa and WHCO3 cells, and induced apoptosis in HT-29 colon cancer cells, suggesting the potential antitumour activity of cyclo(Phe-Pro)-related CDPs.

Cyclic dipeptides have been widely used as pharmaceutical agents due to their favourable properties and the fact that they are more stable and membrane permeable than their linear analogues. These characteristics make cyclic dipeptides attractive to protein-based drug developers (Martins & Carvalho, 2007). In this research study, the method of Milne et al. (1992) was used to synthesize the protected linear dipeptide esters. This was followed by boiling the unprotected, linear dipeptide esters under reflux in an oil bath (Sec-butanol: toluene (4:1)). This method gave good yields and pure cyclic dipeptides. Scanning electron microscopy, thermal analysis, X-ray powder diffraction and differential scanning calorimetry were used for evaluation of the physiochemical properties of the cyclic dipeptides. High-performance liquid chromatography and thin layer chromatography were used to determine the purity of the cyclic dipeptides. The structures of the cyclic dipeptides were elucidated using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy and molecular modeling and computational chemistry. The aim of the study was to determine the possible therapeutic activity of cyclo(D-Phe-4I-Pro) and cyclo(L-Phe-4I-Pro) with regard to antimicrobial, anticancer, antidiabetes and haematological effects. Both cyclic dipeptides showed a significant growth inhibition of Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Anticancer studies showed that both cyclic dipeptides caused growth inhibition of the MCF-7, HT-29 and HeLa cancer cell lines. Both cyclic dipeptides showed no antidiabetic activity. Haematological studies revealed that both cyclic dipeptides caused a significant effect on the clotting time and platelet aggregation. They caused an increase in clotting time and also inhibited platelet aggregation.