Nature has produced intricate machinery to covalently diversify the structure of proteins after their synthesis in the ribosome. In an attempt to mimic nature, chemists have developed a large set of reactions that enable post-expression modification of proteins at pre-determined sites. These reactions are now used to selectively install particular modifications on proteins for many biological and therapeutic applications. For example, they provide an opportunity to install post-translational modifications on proteins to determine their exact biological roles. Labelling of proteins in live cells with fluorescent dyes allows protein uptake and intracellular trafficking to be tracked and also enables physiological parameters to be measured optically. Through the conjugation of potent cytotoxicants to antibodies, novel anti-cancer drugs with improved efficacy and reduced side effects may be obtained. In this Perspective, we highlight the most exciting current and future applications of chemical site-selective protein modification and consider which hurdles still need to be overcome for more widespread use.
Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host’s liver cells before they are able to infect erythrocytes and cause malaria symptoms. To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development. Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo. Furthermore, decoquinate kills the parasite’s replicative blood stages and is active against developing gametocytes, the forms responsible for transmission. The drug acts by selectively and specifically inhibiting the parasite’s mitochondrial bc1 complex, with little cross-resistance with the antimalarial drug atovaquone. Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compound.
The syntheses of 4-C-Me-DAB [1,4-dideoxy-1,4-imino-4-C-methyl-D-arabinitol] from Lerythronolactone and of 4-C-Me-LAB [from D-erythronolactone] require only a single acetonide protecting group. The effect of pH on the NMR spectra of 4-C-Me-DAB [pK a of the salt around 8.4] is discussed and illustrates the need for care in analysis of both coupling constants and chemical shift. 4-C-Me-DAB (for rat intestinal sucrase K i 0.89 μM, IC 50 0.41 μM) is a competitive -whereas 4-C-Me-LAB (for rat intestinal sucrase K i 0.95 μM, IC 50 0.66 μM) is a noncompetitive -specific and potent α-glucosidase inhibitor. A rationale for the α-glucosidase inhibition by DAB, LAB, 4-C-Me-DAB, 4-C-Me-LAB, and isoDAB -but not isoLAB -is provided. Both are inhibitors of endoplasmic reticulum (ER) resident α-glucosidase I and II. This paper describes the synthesis of the enantiomers 4-C-Me-DAB 1D [1,4-dideoxy-1,4-imino-4-C-methyl-D-arabinitol] and 4-C-Me-LAB 1L with only a single acetonide needed as a protecting group, both of which are micromolar inhibitors of some α-glucosidases; in accord with Asano's hypothesis, i the D-iminosugar 1D is a competitive inhibitor, whereas the enantiomer 1L is a non-competitive inhibitor. Synthetic enantiomers of natural iminosugars Correspondence to: George W. J. Fleet, george.fleet@chem.ox.ac.uk. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. are frequently powerful glycosidase inhibitors. ii Natural and synthetic iminosugars comprise a major family of glycosidase inhibitors. iii The introduction of an alkyl substituent into a sugar mimic usually removes any significant glycosidase inhibition, iv however, introduction of a C6 methyl branch into the piperidine ring of L-swainsonine increases the inhibition of naringinase by an order of magnitude v in comparison to the parent indolizidine, Lswainsonine. vi The natural product DAB 3D is a good -but the enantiomer LAB 3L is a more potent and more specific -inhibitor of α-glucosidases. vii The isomer isoDAB 2D is also a very good inhibitor of α-glucosidases but the enantiomer 2L shows no inhibition of any glycosidase. This paper provides a rationale for isoLAB 2L being the only one of the six simple pyrrolidines 1, 2, and 3 which does not inhibit α-glucosidases; isoLAB 2L is the only one of the sugar mimics which partially rescues the defective F508del-CFTR function in cystic fibrosis. viii N-Alkylation of monocyclic iminosugars can enhance glycosidase inhibition by several orders of magnitude; ix such modification of the alkyl-branched parent structures may access a series of new bioactive compounds. NIH Public...
Novel conjugates of the antimalarial drug primaquine (compound 1) with ferrocene, named primacenes, have been synthesized and screened for their activities against blood stage and liver stage malaria in vitro and host-vector transmission in vivo. Both transmission-blocking and blood-schizontocidal activities of the parent drug were conserved only in primacenes bearing a basic aliphatic amine group. Liver stage activity did not require this structural feature, and all metallocenes tested were comparable to or better than primaquine in this regard. Remarkably, the replacement of primaquine's aliphatic chain by hexylferrocene, as in compound 7, led to a ϳ45-fold-higher level activity against liver stage parasitemia than that of primaquine.
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