Zosuquidar (development code LY-335979) is an experimental antineoplastic drug. Zosquidir inhibits P-glycoproteins. Other drugs with this mechanism include tariquidar and laniquidar. P-glycoproteins are trans-membrane proteins that pump foreign substances out of cells in an ATP dependent fashion. Cancers overexpressing P-glycoproteins are able to pump out therapeutic molecules before they are able to reach their target, effectively making the cancer multi-drug resistant. Zosuquidar inhibits P-glycoproteins, inhibiting the efflux pump and restoring sensitivity to chemotherapeutic agents. and Eli Lilly discontinued its development.
Synthesis
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When dibenzosuberone (1) is treated with difluorocarbene (generated in situ from lithium chlorodifluoroacetate), a cyclopropanation occurs to give 10,11-difluoromethanodibenzosuberone [167155-75-1] (2). Reduction of the ketone with borohydride proceeds to afford the derivative wherein the fused cyclpropyl and alcohol are on the same side of the seven-membered ring to give 1,1-Difluorocyclopropane Dibenzosuberol [797790-94-4]&[172925-68-7] (3). This is halogenated with 48% HBr to give the product where both groups are now positioned anti [312905-19-4] (4). Displacement of the bromide with pyrazine [290-37-9] gives the quat [312905-15-0] (5). Sodium borohydride was able to reduce the aromaticity in the sidechain giving the corresponding piperazine, i.e. Fb=[167155-78-4] HCl=PC9799090 (6).
The reaction of 5-hydroxyquinoline [578-67-6] (7) with (R)-glycidyl nosylate (8) affords (R)-1-(5-Quinolinyloxy)-2,3-epoxypropane [123750-60-7] [118629-64-4] (8). The convergent synthesis between 6 and 9 giveszosuquidar in good yield.