Sulfur centered radicals are widely employed in chemical synthesis, in particular for alkene and alkyne hydrothiolation towards thioether bioconjugates. The steadfast radical chain process that enables efficient hydrothiolation has been explored in the context of cascade reactions to furnish complex molecular architectures. The use of thiyl radicals offers a much cheaper and less toxic alternative to the archetypal organotin-based radical methods. This review outlines the development of thiyl radicals as reactive intermediates for initiating carbocyclization cascades. Key developments in cascade cyclization methodology are presented and applications for natural product synthesis are discussed. The review provides a chronological account of the field, beginning in the early seventies up to very recent examples; a span of almost 50 years.
Real-time tracking of prodrug uptake, delivery and activation in vivo represents a major challenge for prodrug development. Herein, we demonstrate the use of novel glycosylated theranostics of the cancer pharmacophore Amonafide in highly-selective, enzymatic triggered release. We show that the use of endogenous enzymes for activated release of the therapeutic component can be observed, in real time, and monitored using one and two-photon bioimaging, offering unique insight into the prodrug pharmacokinetic profile. Furthermore, we demonstrate that the potent cytotoxicity of Amonafide is preserved using this targeted approach.
Macrophages are key
immune cells for combatting Mycobacterium
tuberculosis. However, M. tuberculosis possesses
means to evade macrophage bactericidal responses by, for instance,
secretion of the immunomodulatory para-hydroxybenzoic
acid derivatives (pHBADs). While these molecules
have been implicated in inhibiting macrophage responses in an acute
context, little is known about their ability to reprogram macrophages
via induction of long-term innate memory. Since innate memory has
been highlighted as a promising strategy to augment bactericidal immune
responses against M. tuberculosis, investigating
corresponding immune evasion mechanisms is highly relevant. Our results
reveal for the first time that pHBAD I and related
molecules (unmethylated pHBAD I and the hexose l-rhamnose) reduce macrophage bactericidal mechanisms in both
the short- and the long-term. Moreover, we demonstrate how methyl-p-anisate hinders bactericidal responses soon after exposure
yet results in enhanced pro-inflammatory responses in the long-term.
This work highlights new roles for these compounds in M. tuberculosis pathogenesis.
Trehalase is an important enzyme in the metabolic cascades of many organisms, catalysing the hydrolysis of the disaccharide trehalose. Herein we describe the first examples of fluorometric nanoprobes for detection...
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