CD73 is an extracellular mediator
of purinergic signaling. When
upregulated in the tumor microenvironment, CD73 has been implicated
in the inhibition of immune function through overproduction of adenosine.
Traditional efforts to inhibit CD73 have involved antibody therapy
or the development of small molecules, the most potent of which mimic
the acidic and ionizable structure of the enzyme’s natural
substrate, adenosine 5′-monophosphate (AMP). Here, we report
the systematic discovery of a novel class of non-nucleotide CD73 inhibitors
that are more potent than all other nonphosphonate inhibitor classes
reported to date. These efforts have culminated in the discovery of
4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile
(73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human
CD73 demonstrates a competitive binding mode. These compounds show
promise for the improvement of drug-like character via the attenuation
of the acidity and low membrane permeability inherent to known nucleoside
inhibitors of CD73.
A synthesis fit for a king: The total synthesis of (±)‐kingianins A, D, and F has been achieved in ten steps. Key features include the gram‐scale synthesis and partial reduction of a conjugated tetrayne to a (Z,Z,Z,Z)‐tetraene, the domino 8π–6π electrocyclic ring closure of a (Z,Z,Z,Z)‐tetraene, and the radical‐cation‐catalyzed formal Diels–Alder dimerization of functionalized bicyclo[4.2.0]octadiene precursors.
The pseudopterosins are a family of diterpene marine natural products, which, by virtue of their interesting anti-inflammatory and analgesic properties, have attracted the attentions of many synthetic chemists. The most efficient syntheses reported to date are 14 and 20 steps in the longest linear sequence for chiral pool and enantioselective approaches, respectively, and all start with precursors that are easily mapped onto the natural product structure. Here, we describe an unconventional approach in which a chiral cross-conjugated hydrocarbon is used as the starting material for a series of three cycloadditions. Our approach has led to a significant reduction in the step count required to access these interesting natural products (10 steps chiral pool and 11 steps enantioselective). Furthermore it demonstrates that cross-conjugated hydrocarbons, erroneously considered by many to be too unstable and difficult to handle, are viable precursors for natural product synthesis.
A measure of the strength of a synthetic strategy is its versatility: specifically, whether it allows structurally distinct targets to be prepared. This work describes the total synthesis of natural products of three distinct structural types from a common intermediate.
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