- Title
- The medicinal chemistry of the isomers of the cyclic dipeptide: cyclo(Trp-Pro)
- Creator
- Jamie, Hajierah
- Subject
- Pharmaceutical chemistry
- Subject
- Cyclic compounds
- Date Issued
- 2002
- Date
- 2002
- Type
- Thesis
- Type
- Doctoral
- Type
- PhD
- Identifier
- vital:11023
- Identifier
- http://hdl.handle.net/10948/281
- Identifier
- Pharmaceutical chemistry
- Identifier
- Cyclic compounds
- Description
- The isomers of cyclo(Trp-Pro) (cyclo(L-Trp-L-Pro), cyclo(L-Trp-D-Pro), cyclo(D-Trp-LPro) and cyclo(D-Trp-D-Pro)) have been successfully synthesized and screened for biological activity. High percentage yields were obtained by using the three phase synthesis system, which involves the synthesis of the intermediate protected linear dipeptides, followed by the removal of the protecting Boc groups. This step is followed by cyclization and crystallization of the isomers. The diketopiperazines rings of cyclo(L-Trp-L-Pro) and cyclo(D-Trp-D-Pro) contain cisamide bonds, while cyclo(L-Trp-D-Pro) and cyclo(D-Trp-L-Pro) contain trans-amide bonds. These bonds govern the conformation of the diketopiperazines ring. The isomers have shown different degrees of biological activity, possibly as a result of the orientation of the side chain of tryptophan and this difference in conformation, leading to varying interactions between isomer and a range of receptors. Under experimental conditions, 10-3 M cyclo(L-Trp-D-Pro) and cyclo(D-Trp-L-Pro) showed effective anticancer activity against the cervical cancer cell line, HeLa, resulting in a <50% reduction in cell viability. Cytotoxicity screening with cyclo(D-Trp-L-Pro) indicated that it was hepatocyte-specific in its toxicity, whilst the other isomers were cytotoxic against the other cell types tested. At 1mg/ml, cyclo(L-Trp-L-Pro) proved to be an effective antimicrobial agent against Gram positive bacteria, while cyclo(L-Trp-DPro) effectively inhibited the growth of the Gram negative bacteria, Esherichia coli. Cyclo(D-Trp-L-Pro) proved to be effective against Streptococcus, while cyclo(D-Trp-DPro) effectively reduced viability of the yeast, Candida albicans. Cyclo(D-Trp-L-Pro) was the only isomer to show Ca2+-channel antagonism, whilst the other isomers resulted in opening of the Ca2+-channel. No effects were observed on K+-channel activity for all the isomers tested. The isomers also proved to be valuable antiarrhythmic agents by effectively reducing the time spent in ventricular tachycardia and arrhythmia, as well as decreasing the time for the heart rate to return to a normal sinus rhythm. Furthermore, cyclo(L-Trp-D-Pro) showed positive chronotropic activity, while cyclo(D-Trp-L-Pro) ii showed negative chronotropic activity. In addition, cyclo(L-Trp-D-Pro) and cyclo(D-Trp- L-Pro) also increased the coronary flow rate. 0.125 1 mM Cyclo(L-Trp-D-Pro) decreased aggregation in washed platelets induced by thrombin. All isomers increased adhesion to an artificial surface when the platelets were stimulated by ADP, yet caused reduced adhesion when the platelets were stimulated by thrombin. These results prove the potential of these compounds as novel agents in a range of biological fields, indicating that a combination of L- and D- amino acids may prove more effective than an agent consisting solely of L-amino acids.
- Format
- 426 p
- Format
- Publisher
- University of Port Elizabeth
- Publisher
- Faculty of Health Sciences
- Language
- English
- Rights
- Nelson Mandela Metropolitan University
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