145 research outputs found
Structure-based design of a eukaryote-selective antiprotozoal fluorinated aminoglycoside
This work was supported by GrantâinâAid for Young Scientists (B) (No. 26860025) and GrantâinâAid for Scientific Research (C) (No. 17K08248) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT), and partially supported by the Kurata Grant awarded by the Kurata Memorial Hitachi Science and Technology Foundation, the grant provided by the Ichiro Kanehara Foundation and the Platform for Drug Discovery, Informatics, and Structural Life Science from Japan Agency for Medical Research and Development (AMED). H.K. was supported by the Sasakawa Scientific Research Grant from the Japan Science Society and the SUNBOR Scholarship. We thank the Photon Factory for provision of synchrotron radiation facilities (Photon Factory Proposal No. 2014G532) and acknowledge the staff of the NWâ12A and BLâ17A beamlines. We thank our colleague Vu Linh Ly for preparing the hydroxysisomicin intermediate. The Montreal group thanks NSERC for financial support and a fellowship to J.P.M. from the QuĂŠbec Research Fund: Nature and Technology. The T.K.S. group thanks the Medical Research Council (MR/M020118/1) for current financial support.Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6-fluorosisomicin, the first 6-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A-site, as evidenced by X-ray co-crystal structures. The respective dispositions of 6-fluorosisomicin within the bacterial and protozoal A-sites reveal that the fluorine atom acts only as a hydrogen-bond acceptor to favorably interact with G1408 of the protozoal A-site. Unlike aminoglycosides containing a 6-ammonium group, 6-fluorosisomicin cannot participate in the hydrogen-bonding pattern that characterizes stable pseudo-base-pairs with A1408 of the bacterial A-sites. Based on these structural observations it may be possible to shift the biological activity of aminoglycosides to act preferentially as antiprotozoal agents. These findings expand the repertoire of small molecules targeting the eukaryotic ribosome and demonstrate the usefulness of fluorine as a design element.PostprintPeer reviewe
AcademicâIndustrial Collaboration: Toward the Consilience of Two Solitudes
Current major advances in drug discovery can be traced back to pioneering contributions originating from academics over a century ago. Living in a symbiotic yet noninvasive coexistence, the academic community and the pharmaceutical industry have strived, each in their own way, to develop the modern medicines that benefit humankind today. The subject is presented from a historical and personal perspective
Natural products in medicinal chemistry
xxi, 630 pages : illustrations ; 24 cm.The inspiration provided by biologically active natural
products to conceive of hybrids, congeners, analogs and
unnatural variants is discussed by experts in the field in 16
highly informative chapters.
Using well-documented studies over the past decade, this
timely monograph demonstrates the current importance
and future potential of natural products as starting points for
the development of new drugs with improved properties
over their progenitors.
The examples are chosen so as to represent a wide range
of natural products with therapeutic relevance among
others, as anticancer agents, antimicrobials, antifungals,
antisense nucleosides, antidiabetics, and analgesic
Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules.
A review of the synthesis of natural products and bioactive compounds adopting phosphonamide anion technology is presented highlighting the utility of phosphonamide reagents in stereocontrolled bond-forming reactions. Methodologies utilizing phosphonamide anions in asymmetric alkylations, Michael additions, olefinations, and cyclopropanations will be summarized, as well as an overview of the synthesis of the employed phosphonamide reagents
Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules
A review of the synthesis of natural products and bioactive compounds adopting phosphonamide anion technology is presented highlighting the utility of phosphonamide reagents in stereocontrolled bond-forming reactions. Methodologies utilizing phosphonamide anions in asymmetric alkylations, Michael additions, olefinations, and cyclopropanations will be summarized, as well as an overview of the synthesis of the employed phosphonamide reagents
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Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules.
A review of the synthesis of natural products and bioactive compounds adopting phosphonamide anion technology is presented highlighting the utility of phosphonamide reagents in stereocontrolled bond-forming reactions. Methodologies utilizing phosphonamide anions in asymmetric alkylations, Michael additions, olefinations, and cyclopropanations will be summarized, as well as an overview of the synthesis of the employed phosphonamide reagents
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