Use of oligopyridylamides to inhibit mutant p53 amyloid formation and restore its tumor suppressor function

A method of treating a cancer associated with aggregation of a p53 protein in a subject in need of such treatment, wherein the cancer is associated with one or more p53 mutations, comprising administering to said subject an effective amount of a compound of formula (I):

• wherein Ra is independently selected at each occurrence from hydrogen, C1-C12 hydrocarbons, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• and —N(R*)2;
• X is independently at each occurrence selected from —O—;
• —S—;
• —NH—;
• —NR*—;
• and —C(R*)2;
• Y is independently at each occurrence selected from —O—;
• —S—;
• —NH—;
• and —NR*—;
• R1 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• R2 is independently at each occurrence selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• R3 is selected from hydrogen or a straight chained, branched or cyclic aliphatic C1-C20 hydrocarbon;
• an aromatic C6-C20 hydrocarbon;
• a heteroaromatic C1-C20 hydrocarbon;
• an aryl C6-C20 hydrocarbon;
• a heteroaryl C1-C20 hydrocarbon, a C1-C12 perfluorocarbon, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S, and each of which is optionally substituted with one or more of —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2 and combinations thereof;
• A is selected from hydrogen, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2;
• C1-C8 perfluorocarbon;
• an aliphatic C1-C12 hydrocarbon;
• an aromatic C1-C12 hydrocarbon;
• and a C1-C12 heteroaryl;
• B is selected from hydrogen, —F;
• —Cl;
• —Br;
• —I;
• —OH, —OR*;
• —NO;
• —NO2;
• —NO3;
• —O—NO;
• —N3;
• —NH2;
• —NHR*;
• —N(R*)2;
• —N(R*)3+;
• —N(R*)—OH;
• —O—N(R*)2;
• —N(R*)—O—R*;
• —CN;
• —NC;
• —(C═O)—R*;
• —CHO;
• —CO2H;
• —CO2R*;
• —(C═O)—S—R*;
• —O—(C═O)—H;
• —O—(C═O)—R*;
• —S—(C═O)—R*;
• —(C═O)—NH2;
• —(C═O)—N(R*)2;
• —(C═O)—NHNH2;
• —O—(C═O)—NHNH2;
• —(C═S)—NH2;
• —(C═S)—N(R*)2;
• —N(R*)—CHO;
• —N(R*)—(C═O)—R*;
• —SCN;
• —NCS;
• —NSO;
• —SSR*;
• —SO2R*;
• —SO2—N(R*)2;
• —S(═O)—OR*;
• —S(═O)—R*;
• —Si(R*)3;
• —CF3;
• —O—CF3;
• —P(R*)2;
• —O—P(═O)(OR*)2;
• —P(═O)(OR*)2;
• C1-C8 perfluorocarbon;
• an aliphatic C1-C12 hydrocarbon;
• an aromatic C1-C12 hydrocarbon;
• and a C1-C12 heteroaryl;
• R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof;
• and
• n is an integer from 0 to 2;
• with the proviso that (i) when n is 0, and Y is O, R1 and R3 are not both —CH2CO2H;
• (ii) when n is 1, Y is O, and R1 and R3 are both —CH2CO2H, R2 is not —CH2CO2H or a straight chained, branched or cyclic aliphatic or aryl C1-C12 hydrocarbon, or R2 does not have the structure —C(CH2CO2H)3;
• (iii) when n is 1, and Y is O, R1 through R3 are not each an unsubstituted C1-C8 hydrocarbon;
• and (iv) when n is 2, and Y is O, R1 through R3 are not —CH2CO2H at all occurrences,
• or a pharmaceutically acceptable salt thereof.