Neochrysosporazines: Precursor-Directed Biosynthesis Defines a Marine-Derived Fungal Natural Product P‑Glycoprotein Inhibitory Pharmacophore

Upregulation
of ATP binding cassette (ABC) transporter efflux pumps
(i.e. P-glycoprotein, P-gp) can impart multidrug
resistance, rendering many chemotherapeutics ineffective and seriously
limiting treatment regimes. While ABC transporters remain an attractive
target for therapeutic intervention, the development of clinically
useful small-molecule inhibitors has proved challenging. In this report,
we describe the structure–activity relationship (SAR) analysis
of a newly discovered P-gp inhibitory pharmacophore, phenylpropanoid
piperazine chrysosporazines, produced by co-isolated marine-derived
fungi. In the absence of any total syntheses, we apply an innovative
precursor-directed biosynthesis strategy that successfully repurposed
fungal biosynthetic output, allowing us to isolate, characterize,
and identify the structurally diverse neochrysosporazines A–Q.
SAR analysis utilizing all known (and new) neochrysosporazines, chrysosporazines,
and azachrysosporazines, plus semi-synthetic analogues, established
the key structure requirements for the P-gp inhibitory pharmacophore,
and, in addition, identified non-essential sites that allow for the
design of affinity and other conjugated probes.