Compositions and methods for selectively depleting senescent cells

The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises piperlongumine (PL) or derivative thereof. The selective killing of senescent cells may delay aging and/or treat age-related disorders.

ABSTRACT

The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises piperlongumine (PL) or derivative thereof. The selective killing of senescent cells may delay aging and/or treat age-related disorders.

CLAIMS

1. A method of selectively killing one or more senescent cells from a cell population or tissue, the method comprising contacting the senescent cells with an effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound comprising Formula (II):wherein: X is selected from the group consisting of C(O), C(S), C(NH) and S(O)2; Y is selected from the group consisting of O, NH and S; n is 1; R1, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF3, CN, OH, OCH3, OR, SR, NRR, NRCOR, NRCONRR, NRCO2R, COR, CO2R, NOR, NO2, CONRR, OC(O)NRR, SO2R, SO2NRR, NRSO2R, NRSO2NRR, C(O)C(O)R, and C(O)CH2C(O)R, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl; R is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur; A is selected from the group consisting ofwherein: R9 and R10 are independently selected from the group consisting of hydrogen, deuterium, halogen, CF3, CN, OH, OCH3, OR′, SR′, NR′R′, NR′COR′, NR′CONR′R′, NR′CO2R′, COR′, CO2R′, NOR′, NO2, CONR′R′, OC(O)NR′R′, SO2R, SO2NR′R′, NR′SO2R′, NR′SO2NR′R′, C(O)C(O)R′, and C(O)CH2C(O)R′, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl; R′ is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R′ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur; Optionally, R9 and R10 are taken together to form a 5-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur; B iswherein: R11, R12, R13, R14, and R15 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF3, CN, OH, OCH3, OR″, SR″, NR″R″, NR″COR″, NR″CONR″R″, NRCO2R″, COR″, CO2R″, NOR″, NO2, CONR″R″, OC(O)NR″R″, SO2R″, SO2NR″R″, NR″SO2R″, NR″SO2NR″R″, C(O)C(O)R″, and C(O)CH2C(O)R″, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl; R″ is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R″ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur; Optionally, R11 and R12, R12 and R13, R13 and R14, and R14 and R15 are taken together to form a 4-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur; m is an integer from 0-6; and or B is one or more monocyclic aryl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur; wherein any and all of the substituted described are substituted with one or more groups that are independently a methyl group or methoxy group.

PATENT INFORMATION


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