Mitochondrially delivered anti-cancer compounds
AssigneeCancure Limited
InventorsStephen John Ralph, Jiri Neuzil
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Abstract
This invention relates to anti-cancer compounds and to methods for treating or preventing cancer. In one aspect the invention concerns mitochondrially delivered pro-oxidant anti-cancer compounds that generate reactive oxygen species and induce apoptosis of cancerous cells. The delivery moiety can be a lipophilic cation and the pro-oxidant moiety can be a pro-oxidant vitamin E analogue, such as α-tocopheryl succinate, α-tocopheryl maleate, α-tocopheryl maleyl amide, or 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (α-tocopheryloxyacetic acid).
Claims25
A compound for inducing death of a cancerous cell, said compound comprising:
- a pro-oxidant moiety for (i) generating reactive oxygen species within mitochondria of the cancerous cell, (ii) inducing apoptosis of the cancerous cell, and (iii) interacting with mitochondrial complex II of the cancerous cell, wherein the pro-oxidant moiety comprises a vitamin E analogue comprising a functional domain at position C6 of a substituted chromanol ring that is capable of interacting with a Qp ubiquinone binding site of mitochondrial complex II, a domain that includes the substituted chromanol ring, and a hydrophobic domain comprising an at least seven-carbon long aliphatic chain;
- and a delivery moiety for delivering the pro-oxidant moiety to the mitochondria of the cancerous cell and for correctly positioning the functional domain for interaction with the Qp ubiquinone binding site, wherein the delivery moiety comprises a delocalized lipophilic triphenylphosphonium cation and said vitamin E analogue is selected from the group consisting of α-tocopheryl succinate, α-tocopheryl maleate, α-tocopheryl maleyl amide, and 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (α-tocopheryloxyacetic acid)
- triphenylphosphonium tagged 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)-chroman-6-yloxyacetic acid (triphenylphosphonium tagged α-tocopheryloxyacetic acid), and a derivative of any of the foregoing;
- wherein said derivative has a functional domain substituted at position C6 of the chromanol ring of the compound that comprises a functional domain group selected from the group consisting of an ether, ester, amide, dissociated carboxylic acid, and hydrophilic head group comprising a dissociated acid, a charged ammonium group, or both;
- and a physiologically acceptable salt of any of the foregoing.
A compound of Formula (I), or a physiologically acceptable salt thereof:
- wherein the compound is selected from the group consisting of
- wherein R1 comprises a hydrophilic head group comprising a dissociated acid, an ammonium group, or both, and is linked to the chromanol ring through an ester bond, an amide bond, or an ether bond.
A compound of Formula (I), or a physiologically acceptable salt thereof:
- wherein the compound is selected from the group consisting of
- wherein R1 comprises a carboxylate or ammonium group, and is linked to the chromanol ring through an ester bond, an amide bond, or an ether bond.
Dependencies are inferred from the claim text.