Synthesis and Evaluation of Eight- and Four-membered Iminosugar Analogues as Inhibitors of Testicular Ceramide-specific Glucosyltransferase, Testicular β-Glucosidase 2, and other Glycosidases

Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible male contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve: ringclosing metathesis and Sharpless asymmetric dihydroxylation, and for the four-membered analogues: Sharpless epoxidation, epoxide ring opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6), was moderately active against rat-derived ceramide-specific glucosyltransferase and four of the other eight-membered analogues were weakly active against rat-derived β-glucosidase 2. Among the four-membered analogues, ((2R,3s,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25), displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat-derived enzyme. ((2S,4S)-3-Hydroxy-1-nonyl-azetidine-2,4-diyl)dimethanol (27) was found to be a selective inhibitor of β-glucosidase 2, with potency similar to NB-DNJ. Additional glycosidase assays were performed to identify potential other therapeutic applications. The eight-membered iminosugars exhibited specificity for almond-derived β-glucosidase and the 1-nonylazetidine 25 inhibited α-glucosidase (Saccharomyces cerevisiae) with an IC50 of 600 nM and β-glucosidase (almond) with an IC50 of 20 µM. Only N-nonyl derivatives were active, emphasizing the importance of a long lipophilic side chain for inhibitory activity of the analogues studied

Stereoselective total synthesis of 5(S), 6(R), 15(S)-trihydroxy-7(E), 9(E), 11(Z),13(E)-eicosatetraenoic acid (lipoxin A)

A stereoselective synthesis of the title compound from D-xylose using zinc mediated deoxygenation of 4-hydroxy-2-butenoic acid moiety and base induced double elimination of 4,5-epoxy allyl chloride as key steps is described

A highly efficient practical method for the synthesis of chiral polyhydroxy-(E,E)-1-chlorodienols and (E)-5-hydroxy enynes

An efficient protocol for the synthesis of chiral polyhydroxy-(E,E)-1-chlorodienols and (E)-5-hydroxy enynes from chiral 4,5-epoxy trans allyl chlorides and 4,5-O-isopropylidene allyl chlorides is described by using stoichiometric amount of LiNH2 or LDA in HMPA:THF (1:5) useful in the synthesis of biologically active natural products

Stereoselective total syntheses of 9(S)- and 9(R)-HETE

A simple and efficient stereoselective total synthesis of methyl 9(S)-and 9(R)-hydroxy-5(Z), 7(E), 11(Z), 14(Z)-eicosatetraenoates using base induced opening of chiral 2,3-epoxy chlorides is described

Transcending sovereignty : locating Indigenous peoples in transboundary water law

All people rely upon water for life. Indigenous peoples are especially vulnerable to water conflicts and yet lack recognition in international water law. This thesis adopts Critical Race Theory to examine the intersection between transboundary water law, the doctrine of sovereignty and the international law of Indigenous peoples. The methodology adopted in this thesis includes: (i) a deconstruction of the UN Watercourse Convention and the doctrine of sovereignty; (ii) a review of Indigenous perspectives on sovereignty; and (iii) a proposal for the reconstruction of transboundary water law in a manner that recognizes the internationally affirmed rights of Indigenous peoples. A deconstruction of the UN Watercourse Convention and related discourse reveals that state-centric approaches to transboundary water law fail to recognize Indigenous peoples’ international rights or the pivotal role that Indigenous peoples’ traditional knowledge might play in transcending conflict. Case examples are provided (Columbia River and Tsangpo-Brahmaputra River) that illustrate the vulnerability of Indigenous peoples in the face of state development agreements. The inequities that exist in international water law are rooted in the historical doctrine of sovereignty which has evolved to subordinate Indigenous peoples’ interests to state interests. Indigenous perspectives regarding sovereignty provide a counter-point to the dominant legal discourse and weave an alternate narrative that challenges the myth of objectivity and neutrality that surrounds the doctrine of sovereignty and international law generally. Once we recognize that sovereignty is a social construct, we can recognize our collective ability to reconstruct international laws in a manner that transcends the sovereign discourse and recognizes the rights of Indigenous peoples. Endorsement of the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP) is indicative of states’ commitment to recognize Indigenous peoples’ rights throughout the international legal system. This thesis concludes by offering a proposal for reconstructing transboundary water law through a return to ethics and coalition building. Future reform should be directed towards (a) articulating an international water ethic with the critical engagement of Indigenous peoples; and (b) ensuring that river basin organizations are established on every transboundary river in a manner consistent with this shared international water ethic.Law, Faculty ofGraduat