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'''Zosuquidar''' is an experimental [[antineoplastic]] [[drug]] currently under development. It is now in [[Phases of clinical research|Phase 3]] clinical trials in the United States. |
'''Zosuquidar''' is an experimental [[antineoplastic]] [[drug]] currently under development. It is now in [[Phases of clinical research|Phase 3]] clinical trials in the United States. It [[Enzyme inhibition|inhibits]] [[P-glycoprotein]]s. Other drugs with this mechanism include [[tariquidar]] and [[laniquidar]]. P-glycoproteins are trans-membrane [[protein]]s that pump foreign substances out of cells in an [[Adenosine triphosphate|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. |
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convert the [[energy]] derived from the [[hydrolysis]] of [[Adenosine triphosphate|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 cell]]s, it discharges much of the antineoplastic drugs from the cells, making [[cancer cell]]s [[Drug tolerance|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. |
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==Chemistry== |
==Chemistry== |
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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. |
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[[File:Zosuquidar synthesis.png|700px]] |
[[File:Zosuquidar synthesis.png|700px]] |
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Revision as of 12:37, 7 April 2015
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ECHA InfoCard | 100.236.552 |
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Formula | C32H31F2N3O2 |
Molar mass | 527.61 g/mol g·mol−1 |
3D model (JSmol) | |
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Zosuquidar is an experimental antineoplastic drug currently under development. It is now in Phase 3 clinical trials in the United States. It 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.
Chemistry
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
- ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/0960-894X(95)00426-T, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with
|doi=10.1016/0960-894X(95)00426-T
instead.