Synthesis of chromium carbene scaffolds for use in medicinal chemistry
- Rafael, Christopher Carlos Ferreira
- Authors: Rafael, Christopher Carlos Ferreira
- Date: 2014
- Subjects: Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4456 , http://hdl.handle.net/10962/d1010863 , Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Description: This study involves using methyllithium to synthesize Fischer carbene complexes as precursors for metal templated α,β-unsaturated complexes with potential as acceptors in the Baylis Hillman reaction as well as in Dötz benzannulation. Fischer carbene complexes contain low oxidation state metal centers, are electrophilic in nature and are stabilized by π-donating substituents such as alkoxy and amino groups. The increased electron withdrawing nature of the metal carbonyl moiety was expected to improve the rates of reaction compared to organic carbonyls. Four Fischer carbenes were synthesized via nucleophilic addition of MeLi to chromium and tungsten hexacarbonyl at low temperatures followed by alkylation using either a Meerwein salt (Me₃OBF₄) to give the desired Fischer metal methyl methoxy carbenes or Et₄NBr/alkylhalide to make the corresponding ethoxy and allyloxy carbenes. Characterization was by means of ¹³C NMR, ¹H NMR, and IR. In silico studies were carried out looking at the effect of substituents on the carbene bond. Synthesis of α,β-unsaturated complexes was effected via the aldol condensation route and found to be unfavorable using enolizable aldehydes, although the use of two aryl aldehydes resulted in successful preparation of two α,β-unsaturated complexes. Difficulty in the purification of these complexes hindered their full characterization. Computational studies looked at the effect of substituents on the system as well as variation of the metal from Cr to Mo and W. Synthesis of Baylis Hillman adducts using α,β-unsaturated complexes as acceptors was unsuccessful due to the ease of product oxidization. One potential product was obtained in its crude form although purification was not possible due to oxidation. Computational studies suggested that the oxygen on the ligand negatively impacts the stability of these Fischer carbene derived Baylis Hillman adducts promoting intramolecular oxidation of the metal. The α,β-unsaturated complexes and Baylis Hillman adducts were considered to be candidates to undergo Dötz benzannulation methodology. The use of the α,β-unsaturated complexes in this reaction was generally unsuccessful, both in the microwave and in conventional reflux conditions. Computational studies of these compounds were carried out to facilitate understanding of their stability and configuration.
- Full Text:
- Date Issued: 2014
- Authors: Rafael, Christopher Carlos Ferreira
- Date: 2014
- Subjects: Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4456 , http://hdl.handle.net/10962/d1010863 , Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Description: This study involves using methyllithium to synthesize Fischer carbene complexes as precursors for metal templated α,β-unsaturated complexes with potential as acceptors in the Baylis Hillman reaction as well as in Dötz benzannulation. Fischer carbene complexes contain low oxidation state metal centers, are electrophilic in nature and are stabilized by π-donating substituents such as alkoxy and amino groups. The increased electron withdrawing nature of the metal carbonyl moiety was expected to improve the rates of reaction compared to organic carbonyls. Four Fischer carbenes were synthesized via nucleophilic addition of MeLi to chromium and tungsten hexacarbonyl at low temperatures followed by alkylation using either a Meerwein salt (Me₃OBF₄) to give the desired Fischer metal methyl methoxy carbenes or Et₄NBr/alkylhalide to make the corresponding ethoxy and allyloxy carbenes. Characterization was by means of ¹³C NMR, ¹H NMR, and IR. In silico studies were carried out looking at the effect of substituents on the carbene bond. Synthesis of α,β-unsaturated complexes was effected via the aldol condensation route and found to be unfavorable using enolizable aldehydes, although the use of two aryl aldehydes resulted in successful preparation of two α,β-unsaturated complexes. Difficulty in the purification of these complexes hindered their full characterization. Computational studies looked at the effect of substituents on the system as well as variation of the metal from Cr to Mo and W. Synthesis of Baylis Hillman adducts using α,β-unsaturated complexes as acceptors was unsuccessful due to the ease of product oxidization. One potential product was obtained in its crude form although purification was not possible due to oxidation. Computational studies suggested that the oxygen on the ligand negatively impacts the stability of these Fischer carbene derived Baylis Hillman adducts promoting intramolecular oxidation of the metal. The α,β-unsaturated complexes and Baylis Hillman adducts were considered to be candidates to undergo Dötz benzannulation methodology. The use of the α,β-unsaturated complexes in this reaction was generally unsuccessful, both in the microwave and in conventional reflux conditions. Computational studies of these compounds were carried out to facilitate understanding of their stability and configuration.
- Full Text:
- Date Issued: 2014
The medicinal chemistry of Cyclo (D-PHE-4I-PRO) and Cyclo (L-PHE-4I-PRO)
- Authors: Qhola, Lipolelo
- Date: 2012
- Subjects: Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10152 , http://hdl.handle.net/10948/d1011619 , Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Description: 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.
- Full Text:
- Date Issued: 2012
- Authors: Qhola, Lipolelo
- Date: 2012
- Subjects: Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10152 , http://hdl.handle.net/10948/d1011619 , Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Description: 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.
- Full Text:
- Date Issued: 2012
The medicinal chemistry of cyclo(Phe-4CI-Pro) and Cyclo(D-Phe-4CI-Pro)
- Authors: Milne, Marnus
- Date: 2012
- Subjects: Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10157 , http://hdl.handle.net/10948/d1011848 , Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Description: Cyclic dipeptides have limited conformational freedom due to their diketopiperazine backbone and their small size. They are relatively simple to synthesise, making them ideal subjects for investigation into their biological effects. Cyclic dipeptides have also been known for their multitude of biological activities, including antimicrobial, anticancer and haematological properties. In this study the cyclic dipeptides, cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro), were synthesised from their corresponding linear precursors using a modified phenol-induced cyclisation procedure. The phenol induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physiochemical properties of the cyclic dipeptides was achieved using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Structural elucidation of the cyclic dipeptides was done by means of infrared spectroscopy, mass spectroscopy, nuclear magnetic resonance spectroscopy and molecular modelling. The study‟s aim was to determine the biological activity of cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) with respect to their anticancer, antimicrobial, haematological and ant-diabetic studies. Anticancer studies revealed that cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF-7 (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Both cyclic dipeptides caused a significant shortening of the APTT and PT clotting times and an increase in the fibrin and D-Dimer formation. Cyclo(D-Phe-4Cl-Pro) at a screening concentration of 12.5 mM and 3.125 mM, showed significant anti-platelet activity. Both cyclic dipeptides failed to produce any inhibition of the α-Glucosidase enzyme and very limited inhibition of the α-Amylase enzyme.
- Full Text:
- Date Issued: 2012
- Authors: Milne, Marnus
- Date: 2012
- Subjects: Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10157 , http://hdl.handle.net/10948/d1011848 , Cyclic peptides , Pharmaceutical chemistry , Peptide drugs
- Description: Cyclic dipeptides have limited conformational freedom due to their diketopiperazine backbone and their small size. They are relatively simple to synthesise, making them ideal subjects for investigation into their biological effects. Cyclic dipeptides have also been known for their multitude of biological activities, including antimicrobial, anticancer and haematological properties. In this study the cyclic dipeptides, cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro), were synthesised from their corresponding linear precursors using a modified phenol-induced cyclisation procedure. The phenol induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physiochemical properties of the cyclic dipeptides was achieved using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Structural elucidation of the cyclic dipeptides was done by means of infrared spectroscopy, mass spectroscopy, nuclear magnetic resonance spectroscopy and molecular modelling. The study‟s aim was to determine the biological activity of cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) with respect to their anticancer, antimicrobial, haematological and ant-diabetic studies. Anticancer studies revealed that cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF-7 (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Both cyclic dipeptides caused a significant shortening of the APTT and PT clotting times and an increase in the fibrin and D-Dimer formation. Cyclo(D-Phe-4Cl-Pro) at a screening concentration of 12.5 mM and 3.125 mM, showed significant anti-platelet activity. Both cyclic dipeptides failed to produce any inhibition of the α-Glucosidase enzyme and very limited inhibition of the α-Amylase enzyme.
- Full Text:
- Date Issued: 2012
Solid-phase extraction based sample preparation for the determination of drug and organic pollutant residue
- Authors: Pule, Bellah Oreeditse
- Date: 2011 , 2011-02-08
- Subjects: Food contamination , Drugs -- Analysis , Pharmaceutical chemistry , Extraction (Chemistry) , Sorbents
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4406 , http://hdl.handle.net/10962/d1006711 , Food contamination , Drugs -- Analysis , Pharmaceutical chemistry , Extraction (Chemistry) , Sorbents
- Description: This thesis presents solid phase extraction (SPE) methodologies based on mixed-mode polymeric sorbents; a mixed mode strong anion exchanger (Agilent SampliQ SAX) and a mixed mode strong cation exchanger (Agilent SampliQ SCX). Furthermore, dispersive-SPE based on a quick, easy, cheap, effective, rugged and safe (QuEChERS) method was assessed for applicability in the determination of drug residues. The mixed-mode polymeric sorbents were evaluated for the simultaneous fractionation of drugs that exhibit diverse polarities with acidic, basic and neutral functionalities in biological matrices (plasma and urine). The polymeric skeleton of these sorbents entails an exchanger group and therefore provides two retention mechanisms, strong cation or anion exchange retention mechanisms with hydrophobic interactions. It was demonstrated that with a sequential elution protocol for sample clean-up analytes were fractionated into acidic, basic and neutral classes. The SAX was employed for analysis of ketoprofen, naproxen (acidic drugs), nortriptyline (basic) and secobarbital (neutral) from urine sample. The SCX was used for fractionating phenobarbital, p-toluamide (acidic), amphetamine, m-toluidine (basic) and acetaminophen (neutral drug) from plasma sample. QuEChERS method was employed for quantitative determination of 16 polycyclic aromatic hydrocarbons (PAHs) from fish fillets and soil; 9 sulfonamides (SAs) from chicken muscles and acrylamide (AA) in cooking oil. The analyte recoveries ranged from 79.6 - 109% with RSDs ranging from 0.06 - 1.9% at three different fortification levels. Good linearity (r2 > 0.9990) was attained for most analytes. The limits of detection and quantification ranged from 0.03 - 0.84 μg/ml and 0.81 - 1.89 μg/ml respectively for analytes in biological samples. LODs and LOQs for analytes in food and environmental samples ranged from 0.02 to 0.39 and 0.25 to 1.30 ng/g respectively.
- Full Text:
- Date Issued: 2011
- Authors: Pule, Bellah Oreeditse
- Date: 2011 , 2011-02-08
- Subjects: Food contamination , Drugs -- Analysis , Pharmaceutical chemistry , Extraction (Chemistry) , Sorbents
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4406 , http://hdl.handle.net/10962/d1006711 , Food contamination , Drugs -- Analysis , Pharmaceutical chemistry , Extraction (Chemistry) , Sorbents
- Description: This thesis presents solid phase extraction (SPE) methodologies based on mixed-mode polymeric sorbents; a mixed mode strong anion exchanger (Agilent SampliQ SAX) and a mixed mode strong cation exchanger (Agilent SampliQ SCX). Furthermore, dispersive-SPE based on a quick, easy, cheap, effective, rugged and safe (QuEChERS) method was assessed for applicability in the determination of drug residues. The mixed-mode polymeric sorbents were evaluated for the simultaneous fractionation of drugs that exhibit diverse polarities with acidic, basic and neutral functionalities in biological matrices (plasma and urine). The polymeric skeleton of these sorbents entails an exchanger group and therefore provides two retention mechanisms, strong cation or anion exchange retention mechanisms with hydrophobic interactions. It was demonstrated that with a sequential elution protocol for sample clean-up analytes were fractionated into acidic, basic and neutral classes. The SAX was employed for analysis of ketoprofen, naproxen (acidic drugs), nortriptyline (basic) and secobarbital (neutral) from urine sample. The SCX was used for fractionating phenobarbital, p-toluamide (acidic), amphetamine, m-toluidine (basic) and acetaminophen (neutral drug) from plasma sample. QuEChERS method was employed for quantitative determination of 16 polycyclic aromatic hydrocarbons (PAHs) from fish fillets and soil; 9 sulfonamides (SAs) from chicken muscles and acrylamide (AA) in cooking oil. The analyte recoveries ranged from 79.6 - 109% with RSDs ranging from 0.06 - 1.9% at three different fortification levels. Good linearity (r2 > 0.9990) was attained for most analytes. The limits of detection and quantification ranged from 0.03 - 0.84 μg/ml and 0.81 - 1.89 μg/ml respectively for analytes in biological samples. LODs and LOQs for analytes in food and environmental samples ranged from 0.02 to 0.39 and 0.25 to 1.30 ng/g respectively.
- Full Text:
- Date Issued: 2011
An investigation into the introduction of process analytical technology, using near infrared analysis, to selected pharmaceutical processes
- Authors: Naicker, Krishnaveni
- Date: 2007
- Subjects: Near infrared spectroscopy , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10153 , http://hdl.handle.net/10948/577 , http://hdl.handle.net/10948/d1011710 , Near infrared spectroscopy , Pharmaceutical chemistry
- Description: Introduction: Process analytical technologies are systems for the analysis and control of manufacturing processes to assure acceptable end-product quality. This is achieved by timely measurements of critical parameters and performance attributes of raw material and in-process material and processes. The introduction of process analytical technology using near infrared analysis was investigated in three areas, namely incoming raw material analysis, blend uniformity analysis and moisture determination in the fluid bed dryer. Methodology: Incoming raw material identification - The FOSS XDS rapid content analyzer was used for the development of a NIR method for the identification and material qualification of starch maize and lactose monohydrate. Blend uniformity analysis – The SP15 Laboratory Blender fitted with near infrared probe was utilized for the study. Two types of blend experiments were designed to monitor the distribution of magnesium stearate (lubricant) in the blend, namely, a powder blend utilizing lactose monohydrate and a granule blend utilizing Ridaq® granule. Software methods were developed to monitor the standard deviation of the absorbance at the wavelengths that were specific for lactose monohydrate, Ridaq® granule and magnesium stearate. To confirm the prediction of end-point using near infrared, results were verified using an atomic absorption method for magnesium stearate. The blends were sampled at the selected time intervals corresponding to three states of the blend, namely, before end-point, at end-point and after end-point using a sampling plan. An additional six blends were conducted for the granule blend and sampled when the standard deviation had reached a value below 3 x 10-6 at the magnesium stearate wavelength at four consecutive data points (standard deviation value extrapolated from blends carried out to predetermined time intervals). Moisture determination in the fluid bed dryer – Moisture values for two products (Product A and Product B) were retrospectively collected from past production batches. A process capability study was conducted on the moisture values to determine if the current process was in a state of control. Results and Discussion: Incoming raw material identification – The algorithms used for the spectral library were able to distinguish between the raw materials selected. The spectral library positively identified the starch maize and lactose monohydrate samples that were not present in the library. The negative challenge with pregelatinised starch and tablettose demonstrated that the spectral library was able to differentiate between closely related compounds. Blend uniformity analysis – Blends sampled at the predetermined time intervals demonstrated a homogeneous state when the standard deviation of the absorbance was low and a non-homogeneous state when the standard deviation of the absorbance was high, thus near infrared prediction on the state of the blend was confirmed by the standard analytical methods. The series of Ridaq® granule and magnesium stearate blends sampled when the standard deviation was below 3 x 10-6 were homogeneous with the exception of one blend that was marginally out of specification. Blend durations were significantly lower than the standard blend durations used in the facility and ranged from 112 to 198 seconds. Moisture determination in the fluid bed dryer – From the process capability study of the two products it was noted that Product A is stable but can still be optimized while Product B is at a desirable state. The statistical evaluation of the moisture values for Product A and Product B demonstrated that the use of the product temperature to monitor the moisture gave consistent results. The current process is stable and capable of producing repeatable results although near infrared provides a means for continuously monitoring the product moisture and allows one to take action to prevent over-drying or under-drying. Conclusion: From the investigations conducted, it can be seen that there is definitely a niche for process analytical technology at this pharmaceutical company. The implementation is a gradual process of change, which may take time, probably several years (Heinze & Hansen 2005).
- Full Text:
- Date Issued: 2007
- Authors: Naicker, Krishnaveni
- Date: 2007
- Subjects: Near infrared spectroscopy , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10153 , http://hdl.handle.net/10948/577 , http://hdl.handle.net/10948/d1011710 , Near infrared spectroscopy , Pharmaceutical chemistry
- Description: Introduction: Process analytical technologies are systems for the analysis and control of manufacturing processes to assure acceptable end-product quality. This is achieved by timely measurements of critical parameters and performance attributes of raw material and in-process material and processes. The introduction of process analytical technology using near infrared analysis was investigated in three areas, namely incoming raw material analysis, blend uniformity analysis and moisture determination in the fluid bed dryer. Methodology: Incoming raw material identification - The FOSS XDS rapid content analyzer was used for the development of a NIR method for the identification and material qualification of starch maize and lactose monohydrate. Blend uniformity analysis – The SP15 Laboratory Blender fitted with near infrared probe was utilized for the study. Two types of blend experiments were designed to monitor the distribution of magnesium stearate (lubricant) in the blend, namely, a powder blend utilizing lactose monohydrate and a granule blend utilizing Ridaq® granule. Software methods were developed to monitor the standard deviation of the absorbance at the wavelengths that were specific for lactose monohydrate, Ridaq® granule and magnesium stearate. To confirm the prediction of end-point using near infrared, results were verified using an atomic absorption method for magnesium stearate. The blends were sampled at the selected time intervals corresponding to three states of the blend, namely, before end-point, at end-point and after end-point using a sampling plan. An additional six blends were conducted for the granule blend and sampled when the standard deviation had reached a value below 3 x 10-6 at the magnesium stearate wavelength at four consecutive data points (standard deviation value extrapolated from blends carried out to predetermined time intervals). Moisture determination in the fluid bed dryer – Moisture values for two products (Product A and Product B) were retrospectively collected from past production batches. A process capability study was conducted on the moisture values to determine if the current process was in a state of control. Results and Discussion: Incoming raw material identification – The algorithms used for the spectral library were able to distinguish between the raw materials selected. The spectral library positively identified the starch maize and lactose monohydrate samples that were not present in the library. The negative challenge with pregelatinised starch and tablettose demonstrated that the spectral library was able to differentiate between closely related compounds. Blend uniformity analysis – Blends sampled at the predetermined time intervals demonstrated a homogeneous state when the standard deviation of the absorbance was low and a non-homogeneous state when the standard deviation of the absorbance was high, thus near infrared prediction on the state of the blend was confirmed by the standard analytical methods. The series of Ridaq® granule and magnesium stearate blends sampled when the standard deviation was below 3 x 10-6 were homogeneous with the exception of one blend that was marginally out of specification. Blend durations were significantly lower than the standard blend durations used in the facility and ranged from 112 to 198 seconds. Moisture determination in the fluid bed dryer – From the process capability study of the two products it was noted that Product A is stable but can still be optimized while Product B is at a desirable state. The statistical evaluation of the moisture values for Product A and Product B demonstrated that the use of the product temperature to monitor the moisture gave consistent results. The current process is stable and capable of producing repeatable results although near infrared provides a means for continuously monitoring the product moisture and allows one to take action to prevent over-drying or under-drying. Conclusion: From the investigations conducted, it can be seen that there is definitely a niche for process analytical technology at this pharmaceutical company. The implementation is a gradual process of change, which may take time, probably several years (Heinze & Hansen 2005).
- Full Text:
- Date Issued: 2007
The medicinal chemistry of cyclo (Ser-Ser) and cyclo (Ser-Tyr)
- Authors: Kritzinger, André Louis
- Date: 2007
- Subjects: Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10155 , http://hdl.handle.net/10948/537 , http://hdl.handle.net/10948/d1011712 , Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Description: Cyclic dipeptides are widely used as models for larger peptides because of their simplicity and limited conformational freedom. Some cyclic dipeptides have been shown to produce antiviral, antibiotic and anti-tumour activity (Milne et al., 1998). In this study the cyclic dipeptides, cyclo(Ser-Ser) and cyclo(Ser-Tyr), were synthesised from their corresponding linear precursors using a modified phenolinduced cyclisation procedure. The phenol-induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physicochemical properties of the cyclic dipeptides was achieved by using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. The structures of the synthesised cyclic dipeptides were elucidated using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy and molecular modelling. The study aimed to determine the biological activity of cyclo(Ser-Ser) and cyclo(Ser-Tyr) with respect to their anticancer, antimicrobial, haematological and cardiac effects. Anticancer studies revealed that cyclo(Ser-Ser) and cyclo(Ser- Tyr) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Cyclo(Ser-Tyr) exhibited significant activity in the haematological studies, where it increased the rate of calcium induced-coagulation, and decreased the rate of streptokinase-induced fibrinolysis. Both cyclic dipeptides, however, failed to produce any significant effects on thrombin-substrate binding and ADPinduced platelet aggregation. Cardiac studies revealed that cyclo(Ser-Ser) and especially cyclo(Ser-Tyr) reduced the heart rate, coronary flow rate and ventricular pressure of isolated rat hearts.
- Full Text:
- Date Issued: 2007
- Authors: Kritzinger, André Louis
- Date: 2007
- Subjects: Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10155 , http://hdl.handle.net/10948/537 , http://hdl.handle.net/10948/d1011712 , Cyclic peptides , Peptide drugs -- Therapeutic use , Haematostasis , Pharmaceutical chemistry
- Description: Cyclic dipeptides are widely used as models for larger peptides because of their simplicity and limited conformational freedom. Some cyclic dipeptides have been shown to produce antiviral, antibiotic and anti-tumour activity (Milne et al., 1998). In this study the cyclic dipeptides, cyclo(Ser-Ser) and cyclo(Ser-Tyr), were synthesised from their corresponding linear precursors using a modified phenolinduced cyclisation procedure. The phenol-induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physicochemical properties of the cyclic dipeptides was achieved by using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. The structures of the synthesised cyclic dipeptides were elucidated using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy and molecular modelling. The study aimed to determine the biological activity of cyclo(Ser-Ser) and cyclo(Ser-Tyr) with respect to their anticancer, antimicrobial, haematological and cardiac effects. Anticancer studies revealed that cyclo(Ser-Ser) and cyclo(Ser- Tyr) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Cyclo(Ser-Tyr) exhibited significant activity in the haematological studies, where it increased the rate of calcium induced-coagulation, and decreased the rate of streptokinase-induced fibrinolysis. Both cyclic dipeptides, however, failed to produce any significant effects on thrombin-substrate binding and ADPinduced platelet aggregation. Cardiac studies revealed that cyclo(Ser-Ser) and especially cyclo(Ser-Tyr) reduced the heart rate, coronary flow rate and ventricular pressure of isolated rat hearts.
- Full Text:
- Date Issued: 2007
The medicinal chemistry of the isomers of the cyclic dipeptide: cyclo(Trp-Pro)
- Authors: Jamie, Hajierah
- Date: 2002
- Subjects: Pharmaceutical chemistry , Cyclic compounds
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:11023 , http://hdl.handle.net/10948/281 , Pharmaceutical chemistry , 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.
- Full Text:
- Date Issued: 2002
- Authors: Jamie, Hajierah
- Date: 2002
- Subjects: Pharmaceutical chemistry , Cyclic compounds
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:11023 , http://hdl.handle.net/10948/281 , Pharmaceutical chemistry , 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.
- Full Text:
- Date Issued: 2002
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