Anchimerically Activatable Antiviral ProTides

This work describes the synthesis and biological evaluation of an anchimerically activated proTide of 2′-<i>C</i>-β-methylguanosine as an inhibitor of dengue virus 2 (DENV-2). The proTide incorporates a chemically cleavable 2-(methylthio)­ethyl moiety and a HINT1 hydrolyzable tryptamine phosphoramidate. Inhibition of DENV-2 replication by proTide <b>6</b> was 5-fold greater than the parent nucleoside while displaying no apparent cytotoxicity. Furthermore, we demonstrate with a HINT1 inhibitor that the anti DENV-2 activity of the proTide correlates with the activity of HINT1. Taken together, these results demonstrate that a phosphoramidate based pronucleotide that undergoes an initial nonenzymatic activation step based on anchimeric assistance followed by P–N bond cleavage by HINT1 can be prepared

Compositionality and Sandbag Semantics

It is a common view that radical contextualism about linguistic meaning is incompatible with a compositional explanation of linguistic comprehension. Recently, some philosophers of language have proposed theories of 'pragmatic' compositionality challenging this assumption. This paper takes a close look at a prominent proposal of this kind due to François Recanati. The objective is to give a plausible formulation of the view. The major results are threefold. First, a basic distinction that contextualists make between mandatory and optional pragmatic processes needs to be revised. Second, the pragmatic theory can withstand a Davidsonian objection only by rejecting the importance of a distinction between primitive and non-primitive semantic items. Thirdly, however, the theory is now open to a worry about how it should be understood: either the theory consists in a very broad functionalist generalization about communication, which makes it explanatorily inert, or it boils down to a highly particularist view about linguistic meaning. Finally, I argue that Recanati's notion of 'occasion meaning' is problematic and suggest replacing it with the notion of speaker meaning, which is explanatorily more basic