The Efficient Synthesis of Azasugars from Pentoses

<p>Azasugars [e.g., 1-deoxy-aza-xylopyranose (1) Figure 1] are structural analogues of sugars [e.g., α-D-xylopyranose (2)] where the ring oxygen is substituted by a nitrogen atom. The resemblance of azasugars to their carbohydrate counterparts gives them various biological properties, such as the inhibition of glycosidase and glycosyltransferase enzymes, and as such, these compounds have been in clinical trials for the treatment of AIDS, diabetes,and cancer. Synthetic routes to azasugars have often involved the use of protecting groups, and therefore have generally reduced efficiency by requiring additional steps to apply or remove protecting groups or requiring adjustment of stereochemistry during the synthesis. This thesis presents the first example of a synthesis of four sterochemically different piperidine triols through a four-step methodology minimising the use of protecting groups starting from pentoses. The synthesis of D-xylose derived (3R,4r,5S)-piperidine triol was previously obtained in 40% yield over five steps, but was afforded in 45% overall yield over four steps using the methodology described within this thesis. Next, D-ribose derived (3R,4s,5S)-piperidine triol was obtained in 40% overall yield over four steps, which afforded a vast improvement on the previous most efficient synthetic route obtaining the azasugar in 24% yield over four steps. This four-step three-pot methodology has thus allowed for the synthesis of these piperidine triols in overall yields ranging from 4-69%, surpassing previous total syntheses in efficiency and improving overall atom economy. To further probe the applicability of the methodology, N-alkyl analogues (such as butyl-, phenylethyl-, and hydroxyethyl-analogues) of all four different piperidine triols were synthesised in comparable or greater overall yields compared to literature reports without any required adaptation to the original procedure. Included in these N-alkyl analogues are seven novel azasugars which were obtained in overall yields ranging from 6-35%.</p>

The Efficient Synthesis of Azasugars from Pentoses

<p>Azasugars [e.g., 1-deoxy-aza-xylopyranose (1) Figure 1] are structural analogues of sugars [e.g., α-D-xylopyranose (2)] where the ring oxygen is substituted by a nitrogen atom. The resemblance of azasugars to their carbohydrate counterparts gives them various biological properties, such as the inhibition of glycosidase and glycosyltransferase enzymes, and as such, these compounds have been in clinical trials for the treatment of AIDS, diabetes,and cancer. Synthetic routes to azasugars have often involved the use of protecting groups, and therefore have generally reduced efficiency by requiring additional steps to apply or remove protecting groups or requiring adjustment of stereochemistry during the synthesis. This thesis presents the first example of a synthesis of four sterochemically different piperidine triols through a four-step methodology minimising the use of protecting groups starting from pentoses. The synthesis of D-xylose derived (3R,4r,5S)-piperidine triol was previously obtained in 40% yield over five steps, but was afforded in 45% overall yield over four steps using the methodology described within this thesis. Next, D-ribose derived (3R,4s,5S)-piperidine triol was obtained in 40% overall yield over four steps, which afforded a vast improvement on the previous most efficient synthetic route obtaining the azasugar in 24% yield over four steps. This four-step three-pot methodology has thus allowed for the synthesis of these piperidine triols in overall yields ranging from 4-69%, surpassing previous total syntheses in efficiency and improving overall atom economy. To further probe the applicability of the methodology, N-alkyl analogues (such as butyl-, phenylethyl-, and hydroxyethyl-analogues) of all four different piperidine triols were synthesised in comparable or greater overall yields compared to literature reports without any required adaptation to the original procedure. Included in these N-alkyl analogues are seven novel azasugars which were obtained in overall yields ranging from 6-35%.</p>

The efficient synthesis of 1-deoxymannojirimycin and its derivatives

<p>Azasugars are structural analogues of carbohydrates whereby the oxygen in the heterocyclic ring is substituted for a nitrogen. These carbohydrates are an important class of compounds with medicinal bioactivities and have shown potential for the treatment of diabetes, viral-infection, cancers, and lysosomal storage diseases. 1-deoxymannojirimycin (DMJ), is a mannosidase inhibiting azasugar which has shown anti-cancer and anti-viral activity. There has been significant effort put towards developing methodology to produce this compound and libraries of its derivatives. This thesis presents the synthesis of DMJ and a selection of its derivatives via an efficient 4 step methodology from a carbohydrate starting material, exploiting chemo and regioselective reactions to allow for a total synthesis with minimal use of protecting groups. The synthesis of DMJ, using the methodology developed herein, surpasses published syntheses in efficiency. This synthetic strategy was then used for the preparation of N-functionalised DMJ derivatives without the requirement of additional synthetic steps. To illustrate the versatility of this methodology, a selection of derivatives incorporating different functionalities have been synthesised.</p>

The efficient synthesis of 1-deoxymannojirimycin and its derivatives

<p>Azasugars are structural analogues of carbohydrates whereby the oxygen in the heterocyclic ring is substituted for a nitrogen. These carbohydrates are an important class of compounds with medicinal bioactivities and have shown potential for the treatment of diabetes, viral-infection, cancers, and lysosomal storage diseases. 1-deoxymannojirimycin (DMJ), is a mannosidase inhibiting azasugar which has shown anti-cancer and anti-viral activity. There has been significant effort put towards developing methodology to produce this compound and libraries of its derivatives. This thesis presents the synthesis of DMJ and a selection of its derivatives via an efficient 4 step methodology from a carbohydrate starting material, exploiting chemo and regioselective reactions to allow for a total synthesis with minimal use of protecting groups. The synthesis of DMJ, using the methodology developed herein, surpasses published syntheses in efficiency. This synthetic strategy was then used for the preparation of N-functionalised DMJ derivatives without the requirement of additional synthetic steps. To illustrate the versatility of this methodology, a selection of derivatives incorporating different functionalities have been synthesised.</p>

Acaricidal properties of 5-methylfurfural identified from Valeriana fauriei and its structural analogues against synanthropic mites and Asian longhorned tick with color alterations

Acaricidal activities and color alterations of 5-methylfurfural derived from Valeriana fauriei essential oil and its structural analogues against Dermatophagoides farinae, D. pteronyssinus, Haemaphysalis longicornis and Tyrophagus putrescentiae were evaluated in the present study. Based on the LD50 values of 5-methylfurfural and its analogues, 4,5-dimethylfurfural showed the highest acaricidal activity (LD50; 9.95, 9.91, and 7.12 μg/cm2), followed by 5-methylfurfural (11.87, 11.00, and 8.59 μg/cm2), furfural (12.94, 13.25, and 10.36 μg/cm2), and V. fauriei essential oil (15.15, 13.64, and 10.14 μg/cm2) against D. farinae, D. pteronyssinus and T. putrescentiae, respectively. However, all tested compounds did not show the acaricidal activities against H. longicornis. Interestingly, the color alterations of the mites and ticks were observed by furfural, 5-methylfurfural, and 4,5-dimethylfurfural from colorless to red brown during the acaricidal experiments. Furthermore, 4,5-dimethylfurfural which exhibited the highest acaricidal activity was formulated as nanoemulsion. The nanoemulsion of 4,5-dimethylfurfural showed higher acaricidal activity than it was emulsified in ethanol. The nanoemulsion was also found to show color changes of the mites and ticks from colorless to red brown. The results suggest that 5-methylfurfural and its analogues could be developed as an effective and easy-to-recognize acaricides to mites and ticks.

Ecdysteroids

Ecdysteroid: member of a class of polyhydroxylated steroids found in invertebrate animals (zooecdysteroids; moulting hormones), plants (phytoecdysteroids) and fungi (mycoecdysteroids). Over 500 structural analogues are currently known. Biosynthetically, they derive from C27-, C28- or C29-sterols. The most frequently encountered analogue (in arthropods and plants) is 20-hydroxyecdysone (2β,3β,14α, 20R,22R,25-hexahydroxycholest-7-en-6-one). In arthropods, ecdysteroids occur universally and regulate development by inducing moulting and reproduction, where their action is mediated by high-affinity binding to an intracellular member of the class of nuclear receptor (NR) proteins (ecdysteroid receptor; EcR) dimerised with a second NR (USP/RxR). This receptor complex binds to specific DNA promoter sites and regulates gene expression. In plants, ecdysteroids are a class of secondary compounds, occurring in varying amounts in certain species, but not all in others. Phytoecdysteroids are believed to contribute to the reduction of invertebrate predation by acting as feeding deterrents or endocrine disruptors. Ecdysteroids also possess a wide range of positive pharmacological effects in mammals, where the mode of action involves moderate-affinity binding to plasma-membrane-bound receptors and not interaction with the classical NRs for vertebrate steroid hormones.

Behavioural Pharmacology of Novel Kappa Opioid Compounds

<p><b>Rationale: Kappa opioid receptor (KOPr) activation by traditional agonists has been shown to produce anti-addiction behaviours. However, adverse effects such as sedation, aversion and depression have limited their clinical development. Recently, salvinorin A (Sal A), an active component of the plant Salvia divinorum was shown to be a potent and selective KOPr agonist. Sal A has a short duration of effect and quick onset of action. It also produces similar behavioural pharmacology to traditional KOPr agonists. However, little is known about the anti-addiction profile of Sal A. If Sal A and its structural analogues produce anti-addiction properties with fewer adverse effects compared to traditional KOPr agonists, they have potential to be developed into antiaddiction pharmacotherapies. Therefore, Sal A and its structural analogues (DS1, MOM Sal B, EOM Sal B, herkinorin) and Mu opioid receptor (MOPr) antagonist/partial KOPr agonist, nalmefene were tested for their behavioural anti-addiction and adverse effect profiles in rats.</b></p> <p>Methods: To test the anti-addiction profile, a within session cocaine prime induced reinstatement paradigm was used. The selectivity of KOPr agonists in attenuating cocaine seeking behaviours was tested using sucrose reinforcement (anhedonia) and cocaine induced hyperactivity in self-administering rats (sedation during reinstatement test). Furthermore, behavioural adverse effects were screened using spontaneous open field activity (motor suppression), conditioned taste aversion (aversion) and forced swim test (depression) in rats. To further quantify the anti-addiction behaviours, the effect of KOPr agonists which attenuated drug seeking selectively without producing motor suppression by themselves were tested for cocaine produced motor function (hyperactivity and behavioural sensitization) in rats. The effect of serotonin transporter blockade on KOPr agonist induced depressive behaviour was also tested. The effects of KOPr activation on in vitro serotonin transporter function were also determined. Results: Sal A, DS1 and nalmefene attenuated cocaine prime induced drug-seeking, in a selective manner, via KOPr activation. MOM Sal B, a more potent and long acting Sal A analogue attenuated cocaine seeking in a non-selective manner. Sal A, DS1 and nalmefene did not induce aversion, however nalmefene suppressed motor function, which was not seen with Sal A and DS1. Furthermore, Sal A and DS1 suppressed cocaine behavioural sensitization. All three compounds (Sal A, DS1, nalmefene) produced depression. The depressive effects produced by Sal A and DS1 were diminished by blocking the serotonin transporter. Live-cell serotonin transporter assays showed potential differences between traditional (U50488H) and novel (Sal A, DS1) KOPr agonists in their ability to modulate serotonin transporter function. Conclusion: Out of six KOPr compounds tested, Sal A, DS1, MOM Sal B and nalmefene produced anti-addiction behaviours. However, MOM Sal B exposure also suppressed natural reward seeking behaviour. Sal A and DS1 had a better adverse effect profile than nalmefene. Thus, the order of efficacy for the compounds tested were DS1 ≥ Sal A > nalmefene > MOM Sal B. However depression was noted with all three compounds tested (Sal A, DS1, nalmefene) and our study provides evidence to suggest the involvement of the serotonin system in Sal A and DS1 induced depression. Moreover, a difference in modulation of serotonin transporter function by novel and traditional KOPr agonists was observed.</p>

Behavioural Pharmacology of Novel Kappa Opioid Compounds

<p><b>Rationale: Kappa opioid receptor (KOPr) activation by traditional agonists has been shown to produce anti-addiction behaviours. However, adverse effects such as sedation, aversion and depression have limited their clinical development. Recently, salvinorin A (Sal A), an active component of the plant Salvia divinorum was shown to be a potent and selective KOPr agonist. Sal A has a short duration of effect and quick onset of action. It also produces similar behavioural pharmacology to traditional KOPr agonists. However, little is known about the anti-addiction profile of Sal A. If Sal A and its structural analogues produce anti-addiction properties with fewer adverse effects compared to traditional KOPr agonists, they have potential to be developed into antiaddiction pharmacotherapies. Therefore, Sal A and its structural analogues (DS1, MOM Sal B, EOM Sal B, herkinorin) and Mu opioid receptor (MOPr) antagonist/partial KOPr agonist, nalmefene were tested for their behavioural anti-addiction and adverse effect profiles in rats.</b></p> <p>Methods: To test the anti-addiction profile, a within session cocaine prime induced reinstatement paradigm was used. The selectivity of KOPr agonists in attenuating cocaine seeking behaviours was tested using sucrose reinforcement (anhedonia) and cocaine induced hyperactivity in self-administering rats (sedation during reinstatement test). Furthermore, behavioural adverse effects were screened using spontaneous open field activity (motor suppression), conditioned taste aversion (aversion) and forced swim test (depression) in rats. To further quantify the anti-addiction behaviours, the effect of KOPr agonists which attenuated drug seeking selectively without producing motor suppression by themselves were tested for cocaine produced motor function (hyperactivity and behavioural sensitization) in rats. The effect of serotonin transporter blockade on KOPr agonist induced depressive behaviour was also tested. The effects of KOPr activation on in vitro serotonin transporter function were also determined. Results: Sal A, DS1 and nalmefene attenuated cocaine prime induced drug-seeking, in a selective manner, via KOPr activation. MOM Sal B, a more potent and long acting Sal A analogue attenuated cocaine seeking in a non-selective manner. Sal A, DS1 and nalmefene did not induce aversion, however nalmefene suppressed motor function, which was not seen with Sal A and DS1. Furthermore, Sal A and DS1 suppressed cocaine behavioural sensitization. All three compounds (Sal A, DS1, nalmefene) produced depression. The depressive effects produced by Sal A and DS1 were diminished by blocking the serotonin transporter. Live-cell serotonin transporter assays showed potential differences between traditional (U50488H) and novel (Sal A, DS1) KOPr agonists in their ability to modulate serotonin transporter function. Conclusion: Out of six KOPr compounds tested, Sal A, DS1, MOM Sal B and nalmefene produced anti-addiction behaviours. However, MOM Sal B exposure also suppressed natural reward seeking behaviour. Sal A and DS1 had a better adverse effect profile than nalmefene. Thus, the order of efficacy for the compounds tested were DS1 ≥ Sal A > nalmefene > MOM Sal B. However depression was noted with all three compounds tested (Sal A, DS1, nalmefene) and our study provides evidence to suggest the involvement of the serotonin system in Sal A and DS1 induced depression. Moreover, a difference in modulation of serotonin transporter function by novel and traditional KOPr agonists was observed.</p>

Isolation, Chemical Characterization, Evaluation of Analgesic and Anti-Inflammatory Activities of Triterpenoids from the Tubers of Raphionacme vignei E. A. Bruce (Apocynaceae)

Raphionacme vignei E. A. Bruce (Apocynaceae) is a plant of the traditional African pharmacopoeia, whose parts are used in the treatment of various pathologies. Water-soaked R. vignei tubers are edible. The objective of this study was to isolate triterpenoids from the acetonic extract of R. vignei tubers, evaluate the analgesic and anti-inflammatory activities of each molecule. The isolated compounds, characterized by NMR and mass spectrometry, is composed of six triterpenoids: beta-amyrin dodecanoate 1(DDQ1), lupeol dodecanoate 2(DDQ2), beta-amyrin acetate 3(DDQ3), lupeol acetate 4(DDQ4), luepol 5(DDQ5) and β-sitosterol 6(DDQ6). These molecules (DDQ2, DDQ3, DDQ4, DDQ5, DDQ6) are anti-inflammatory in carrageenan induced rat paw edema, with better anti-inflammatory power for DDQ2 and DDQ4, which would be related to the presence of acetate function and cycle E. DDQ2 and DDQ4 are also analgesic in acetic acid induced contortions and the removal test of rat tail on the heating plate. The analgesic action of DDQ2 and DDQ4, superior to that salicylic acetyl acid, identical to that morphine, suggests a central action of these two molecules. The potent analgesic effect of DDQ2 and DDQ4, could be attributed to the presence of cyclopentane and isoprene substitution in position 19 of the lupane family. DDQ2 and DDQ4 represent a potential for the synthesis of structural analogues with analgesic and/or anti-inflammatory properties.