Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.
Concentrative nucleoside transporters (CNTs) are responsible for cellular entry of nucleosides, which serve as precursors to nucleic acids and act as signaling molecules. CNTs also play a crucial role in the uptake of nucleoside-derived drugs, including anticancer and antiviral agents. Understanding how CNTs recognize and import their substrates could not only lead to a better understanding of nucleoside-related biological processes but also the design of nucleoside-derived drugs that can better reach their targets. Here, we present a combination of X-ray crystallographic and equilibrium-binding studies probing the molecular origins of nucleoside and nucleoside drug selectivity of a CNT from Vibrio cholerae. We then used this information in chemically modifying an anticancer drug so that it is better transported by and selective for a single human CNT subtype. This work provides proof of principle for utilizing transporter structural and functional information for the design of compounds that enter cells more efficiently and selectively.DOI: http://dx.doi.org/10.7554/eLife.03604.001
Divergent total syntheses of (−)-kopsifoline D and (−)-deoxoapodine are detailed from a common pentacyclic intermediate 15, enlisting the late-stage formation of two different key strategic bonds (C21–C3 and C21–O–C6) unique to their hexacyclic ring systems that are complementary to its prior use in the total syntheses of kopsinine (C21–C2 bond formation) and (+)-fendleridine (C21–O–C19 bond formation). The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation for late-stage formation of the C21–C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying Apidosperma skeleton is a powerful intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the functionalized pentacyclic ring system 15 in a single step in which the C3 methyl ester found in the natural products served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels–Alder reaction and stabilizing the intermediate 1,3-dipole.
The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels–Alder reaction of 5-carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related complementary heterocyclic azadiene [4 + 2] cycloaddition reactions permitted the late stage divergent preparation of a series of alternative heterocyclic derivatives not readily accessible by more conventional approaches.
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