C-H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity.
ABSTRACT: We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C-H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (-)-quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (-)-quinine both in?vitro and in mice infected with Plasmodium berghei.
Project description:Concise stereoselective syntheses of (+/-)-quinine and (+/-)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophilic features of the Tsuji-Trost reaction. Cyclization of enone-allyl carbonate 11 delivers the product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr) followed by exchange of the N-protecting group provides the saturated N-Boc-protected methyl ketone 19, which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine. Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17 provides (+/-)-7-hydroxyquinine in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal. Notably, highly stereoselective formation of five contiguous stereocenters is achieved through a series of 1,2-asymmetric induction events. Deoxygenation of the N-Cbz-protected allylic acetate 22 provides olefin 23, which previously has been converted to quinine. Thus, (+/-)-quinine is accessible in 16 steps and 4% overall yield from commercial aminoacetaldehyde diethyl acetal.
Project description:The major antimalarial drug quinine perturbs uptake of the essential amino acid tryptophan, and patients with low plasma tryptophan are predisposed to adverse quinine reactions; symptoms of which are similar to indications of tryptophan depletion. As tryptophan is a precursor of the neurotransmitter serotonin (5-HT), here we test the hypothesis that quinine disrupts serotonin function. Quinine inhibited serotonin-induced proliferation of yeast as well as human (SHSY5Y) cells. One possible cause of this effect is through inhibition of 5-HT receptor activation by quinine, as we observed here. Furthermore, cells exhibited marked decreases in serotonin production during incubation with quinine. By assaying activity and kinetics of the rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase (TPH2), we showed that quinine competitively inhibits TPH2 in the presence of the substrate tryptophan. The study shows that quinine disrupts both serotonin biosynthesis and function, giving important new insight to the action of quinine on mammalian cells.
Project description:Quinine is a major drug of choice for the treatment of malaria. However, the primary mode of quinine action is unclear, and its efficacy is marred by adverse reactions among patients. To help address these issues, a genome-wide screen for quinine sensitivity was carried out using the yeast deletion strain collection. Quinine-sensitive mutants identified in the screen included several that were defective for tryptophan biosynthesis (trp strains). This sensitivity was confirmed in independent assays and was suppressible with exogenous Trp, suggesting that quinine caused Trp starvation. Accordingly, quinine was found to inhibit [(3)H]Trp uptake by cells, and the quinine sensitivity of a trp1Delta mutant could be rescued by overexpression of Trp permeases, encoded by TAT1 and TAT2. The site of quinine action was identified specifically as the high affinity Trp/Tyr permease, Tat2p, with which quinine associated in a Trp-suppressible manner. A resultant action also on Tyr levels was reflected by the Tyr-suppressible quinine hypersensitivity of an aro7Delta deletion strain, which is auxotrophic for Tyr (and Phe). The present genome-wide dataset provides an important resource for discovering modes of quinine toxicity. That potential was validated with our demonstration that Trp and Tyr uptake via Tat2p is a major target of cellular quinine toxicity. The results also suggest that dietary tryptophan supplements could help to avert the toxic effects of quinine.
Project description:BACKGROUND AND PURPOSE:The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT(3) receptor antagonists. They may therefore act at 5-HT(3) receptors. EXPERIMENTAL APPROACH:The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT(3A) receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. KEY RESULTS:5-HT(3) responses were blocked with IC (50) values of 13.4 microM, 11.8 microM and 9.36 microM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA (2) values of 4.92 (K (B)=12.0 microM) and 4.97 (K (B)=16.4 microM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [(3)H]granisetron with K (i) values of 15.0, 24.2 and 35.7 microM. Docking of quinine into a homology model of the 5-HT(3) receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226. CONCLUSIONS AND IMPLICATIONS:This study shows that quinine and chloroquine competitively inhibit 5-HT(3) receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT(3) receptor antagonists.
Project description:In this study, we used the eukaryotic model Saccharomyces cerevisiae to better understand quinine’s mode of action and the mechanisms underlying the cell response to the drug. We performed a transcriptional profiling of the yeast response to a quinine concentration that exerted a very slight effect over cellular growth. Overall design: Four arrays, corresponding to two replicates of each condition under study, were analysed.
Project description:In this study, we used the eukaryotic model Saccharomyces cerevisiae to better understand quinine’s mode of action and the mechanisms underlying the cell response to the drug. We performed a transcriptional profiling of the yeast response to a quinine concentration that exerted a very slight effect over cellular growth. Experiment Overall Design: Four arrays, corresponding to two replicates of each condition under study, were analysed.
Project description:We report a concise, enantioselective, and highly efficient synthesis of the marine actinomycete-derived natural product saliniketal B. Our approach was motivated with an eye toward future structure-function studies of this inhibitor of phorbol ester-mediated ornithine decarboxylase induction via an unknown mechanism. Our strategy highlights the utility of Pt(II)-mediated cycloisomerization of alkynediols developed in our laboratory to construct the dioxabicyclo[3.2.1]octane ring system, a highly selective aldol fragment coupling whose stereochemical outcome is influenced by a gamma-stereogenic methyl group, and an interesting one-pot desilylation/dihydropyranone fragmentation/amidation sequence. As such, saliniketal B was obtained in 11 steps and 23% overall yield from commercially available starting material via a convergent coupling of two equally complex fragments assembled in seven and eight steps (39 and 45%), respectively.
Project description:The enzymatic basis for quinine <b>1</b> biosynthesis was investigated. Transcriptomic data from the producing plant led to the discovery of three enzymes involved in the early and late steps of the pathway. A medium-chain alcohol dehydrogenase (CpDCS) and an esterase (CpDCE) yielded the biosynthetic intermediate dihydrocorynantheal <b>2</b> from strictosidine aglycone <b>3</b>. Additionally, the discovery of an <i>O</i>-methyltransferase specific for 6'-hydroxycinchoninone <b>4</b> suggested the final step order to be cinchoninone <b>16/17</b> hydroxylation, methylation, and keto-reduction.
Project description:We describe a versatile, efficient method for the preparation of ether analogues of (S,S)-lysobisphosphatidic acid (LBPA) and its enantiomer from (S)-solketal. Phosphorylation of a protected sn-2-O-octadecenyl glyceryl ether with 2-cyanoethyl bis-N,N-diisopropylamino phosphine and subsequent deprotection generated the bisether LBPA analogues. By simply changing the sequence of deprotection steps, we obtained the (R,R)- and (S,S)-enantiomers of 2,2'-bisether LBPA. An ELISA assay with anti-LBPA monoclonal antibodies showed that the bisether LBPAs were recognized with the same affinity as the natural 2,2'-bisoleolyl LBPA. [reaction: see text]
Project description:Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, some as complex as the natural product and some much simplified and easier to access. Each analogue was tested for blood-stage antimalarial activity using both drug-sensitive and -resistant P. falciparum strains. Many considerably simpler analogues of the kalihinols retained potent activity, as did a compound with a different decalin scaffold made in only three steps from sclareolide. Finally, one representative compound showed reasonable stability toward microsomal metabolism, suggesting that the isonitrile functional group that is critical for activity is not an inherent liability in these compounds.