Zosuquidar (development code LY-335979) is an experimental antineoplastic

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

. Zosquidir inhibits

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

s. Other drugs with this mechanism include tariquidar and laniquidar. P-glycoproteins are trans-membrane

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s 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. Zosuqidar was initially characterized by Syntex Corporation, which was acquired by

Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Switzerland, Swiss multinational corporation, multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, ...

in 1990. Roche licensed the drug to

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was a Union Army officer, pharmacist, chemist, and businessman who founded Eli Lilly and Company. Lilly enlisted in the Union Army during the American Civil War and recruited a company of men to ...

in 1997. It was granted

orphan drug status An orphan drug is a pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by the condition ...

by the FDA in 2006 for AML. In 2010, it was announced that a

phase III clinical trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phase ...

for the treatment of

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

(AML) and

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...

did not meet its primary endpoint and Eli Lilly discontinued its development.

Synthesis

When

dibenzosuberone Dibenzosuberone is an organic chemical with use in drug synthesis. Chemically speaking, it is benzophenone bonded by a 2 carbon bridge into a seven membered ring. In contrast to dibenzosuberenone, the 2 carbon bridge is saturated with hydrogen an ...

(1) is treated with difluorocarbene (generated in situ from lithium chlorodifluoroacetate), a cyclopropanation occurs to give 10,11-difluoromethanodibenzosuberone 67155-75-1(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 97790-94-4 72925-68-7(3). This is halogenated with 48% HBr to give the product where both groups are now positioned anti 12905-19-4(4). Displacement of the bromide with pyrazine 90-37-9gives the quat 12905-15-0(5). Sodium borohydride was able to reduce the aromaticity in the sidechain giving the corresponding piperazine, i.e. Fb= 67155-78-4HCl=PC9799090 (6). The reaction of 5-hydroxyquinoline 78-67-6(7) with (R)-glycidyl nosylate (8) affords (R)-1-(5-Quinolinyloxy)-2,3-epoxypropane 23750-60-7 18629-64-4(8). The convergent synthesis between 6 and 9 giveszosuquidar in good yield.

References

{{Reflist Experimental cancer drugs Organofluorides Cyclopropanes Quinolines Piperazines Abandoned drugs