Zosuquidar

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Zosuquidar
Zosuquidar.svg
Systematic (IUPAC) name
(2R)-​1-​{4-​[(1aR,10bS)-​1,1-​difluoro-​1,1a,6,10b-​tetrahydrodibenzo​[a,e]​cyclopropa​[c]​[7]​annulen-​6-​yl}-​3-​(quinolin-​5-​yloxy)​propan-​2-​ol
Clinical data
Legal status
?
Identifiers
CAS number 167354-41-8 N
ATC code None
PubChem CID 153997
ChemSpider 24599682 YesY
UNII AB5K82X98Y YesY
KEGG D06387 YesY
ChEMBL CHEMBL444172 YesY
Chemical data
Formula C32H31F2N3O2 
Mol. mass 527.61 g/mol
 N (what is this?)  (verify)

Zosuquidar is a compound of antineoplastic drug candidates currently under development. It is now in "Phase 3" of clinical tests in the United States. Its action mechanism consists of the inhibition of P-glycoproteins; other drugs with this mechanism include tariquidar and laniquidar. P-glycoproteins are proteins which convert the energy derived from the hydrolysis of ATP to structural changes in protein molecules, in order to perform coupling, thus discharging medicine from cells. If P-glycoprotein coded with the MDR1 gene manifests itself in cancer cells, it discharges much of the antineoplastic drugs from the cells, making cancer cells medicine tolerant, and rendering antineoplastic drugs ineffective. This protein also manifests itself in normal organs not affected by the cancer (such as the liver, small intestine, and skin cells in blood vessels of the brain), and participates in the transportation of medicine. The compound zosuquidar inhibits this P-glycoprotein, causing the cancer cells to lose their medicine tolerance, and making antineoplastic drugs effective.

Chemistry[edit]

Multidrug resistance, as noted earlier, is the all too prevalent phenomenon where a patient’s resistance to one class of cancer chemotherapy agents comes to encompass mechanistically quite different drugs. Compounds with a wide variety of structural features have shown at least preliminary activity in resolving this problem. The structurally rather complex agent zosuquidar (10) has shown promising activity against this problem.

Zosuquidar synthesis.png

Reaction of dibenzosuberone (1) with the difluorocarbene from chlorodifluoroacetate (2) affords the cyclopropyl adduct (3). 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 (4). The carbinol is then converted to the halide with thionyl chloride apparently with retention of configuration (5). Displacement with piperazine monoformamide (6) leads to the alkylated product in which the groups are now anti. Hydrolysis of the formamide grouping then affords secondary amine (7). In a convergent sequence, 5-hydroxyquinoline (8) is allowed to react with the tosyl derivative of chiral glycidol (9), thus affording the final product in good yield.[1]

References[edit]

  1. ^ Pfister, J. R.; Makra, F.; Muehldorf, A. V.; Wu, H.; Nelson, J. T.; Cheung, P.; Bruno, N. A.; Casey, S. M.; Zutshi, N.; Slate, D. L. (1995). "Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents". Bioorganic & Medicinal Chemistry Letters 5 (21): 2473. doi:10.1016/0960-894X(95)00426-T.  edit