Structure-based design, synthesis and preliminary anti-inflammatory activity of bolinaquinone analogues

As a part of our drug discovery efforts we developed a series of simplified derivatives of bolinaquinone (BLQ), a hydroxyquinone marine metabolite, showing potent anti-inflammatory activity. Thirteen new hydroxyquinone derivatives closely related to BLQ were synthesized and tested on mouse macrophage-like RAW 264.7 cell line in order to investigate their ability to modulate the production of Prostaglandin E2 (PGE2). This optimization process led to the identification of three strictly correlated compounds with comparable and higher inhibitory potency than BLQ on PGE2 production. To evaluate the affinity of BLQ and its analogues for hsPLA2, surface plasmon resonance (SPR) experiments were performed.

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► 2-Hydroxyl-1,4-benzoquinone is a new class of anti-inflammatory compounds.
► PGE2 production on mouse macrophage cell line RAW 264.7 depends on the substituent at position 5 in the 2-hydroxy-1,4-benzoquinone ring.
► The hsPLA2 interaction would appear to require a bicycle ring in the hydrophobic pocket and to tolerate various building blocks including large and hydrophobic aryl ring.