Interferon-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria. Successful intracellular bacterial pathogens have evolved diverse mechanism not only to suppress the IFNγ production, but also to downregulate the responsiveness of macrophages to this cytokine. Therefore we proposed that small molecules that boost macrophage IFNγ response may be a promising therapeutic strategy. An array of rocaglate analogues have been synthesized that in synergy with low dose of IFNγ, induce IRF1 (master regulator of IFNγ pathways), induce autophagy (a major effector mechanism of antimicrobial defense) and increase the anti-oxidative defense of the host. The synthetic route features excited-state intramolecular proton transfer (ESIPT)- mediated [3+2] photocycloaddition of 3-hydroxyflavones and cinnamate- derived dipolarophiles. A continuous flow photoreactor was utilized for photocycloadditions. With the goal to identify the molecular target and mode of action, rocaglate photoaffinity probes<i> </i>were synthesized and evaluated. The presentation will discuss the development of continuous flow reactors for large scale photocycloaddition and highlight the design and synthesis of rocaglate photoaffinity probes.

Synthesis of rocaglate photoaffinity probes for target identification studies

256th National Meeting (2018)

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