The medicinal chemistry of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro)
- Authors: Ndung'u, Susan Wanjiru
- Date: 2011
- Subjects: Peptide drugs , Cyclic peptides , Pharmaceutical chemistry , Peptides -- Synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10948/7083 , vital:21223
- Description: Although peptides and proteins are considered as lead compounds for the discovery and development of new therapeutic agents, poor metabolic and physical properties have limited their optimisation as drug candidates (Adessi & Soto, 2002). Research by medicinal chemists however, generated the discovery of structural similarities between some peptides and diketopiperazines and the common occurrence of such compounds in natural products. This discovery initiated the synthesis of diketopiperazines from amino acids in an attempt to bypass the previously mentioned limitations of using peptides as drug candidates (Dinsmore & Beshore, 2002). Diketopiperazines (DKPs) are the simplest form of cyclic dipeptides, and a class of unexplored bioactive peptides that have great potential for the future. The compounds are relatively simple to synthesise and are prevalent in nature (Prasad, 1995). The DKP backbone is rigid and therefore poses conformational constraint on the compounds. This rigidity allows for simple conformational analysis of the compounds and also gives insight into the conformational requirements for interaction with the targets involved in their biological activity. The reduced conformational freedom also increases the receptor specificity and thus the compounds are proposed to have less unfavourable effects (Anteunis, 1978). The aim of the study was to synthesise compounds that would exhibit metabolic stability, receptor specificity and enhanced lipophilicity which would increase the bioavailability of the compounds. This was to be achieved by the introduction of fluorine and chlorine elements into the DKPs. The structure of the DKPs would be altered which in turn would improve the physicochemical properties and the biological activity of the compounds (Naumann, 1999). Cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) were synthesised using the method of Milne et al. (1992) and by boiling the linear counterparts under reflux in sec-butanol-toluene. The structures of the synthesised DKPs were elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy and molecular modeling. Qualitative analysis and evaluation of the physicochemical properties of the DKPs were performed using high-performance liquid chromatography, scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry and x-ray powder diffraction. The study aimed to determine the biological activity of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) with respect to their anticancer, antimicrobial, haematological and antidiabetic effects. The anticancer results obtained indicated that the percentage inhibition produced by both DKPs were lower than those proposed by Graz et al. (2000) for proline-containing DKPs where, a greater than 50% inhibition was observed for cyclo(Phe-Pro). Antimicrobial studies revealed that both DKPs demonstrated marginal effects on Gram-positive and Gram-negative organisms but showed significant effects against C. albicans. The haematological studies revealed that cyclo(D-Phe-2Cl-Pro) at a screening concentration of 12.5 mM, significantly decreased the levels of D-dimer (P < 0.0001). The antidiabetics studies showed limited activity of the DKPs in inhibiting the activity of α-glucosidase and α-amylase enzymes.
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- Date Issued: 2011
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.
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- Date Issued: 2011