Indole molecules and use thereof in the inhibition of DNA polymerases
The present disclosure is directed to compositions and methods for the inhibition of DNA polymerases. the compositions disclosed herein include one or more of indole-derived compounds useful in treatment of cancers including those which are resistant to genotoxic therapies.
1 . A compound of Formula (I) or a salt thereof:
wherein R 1 is hydrogen;
wherein R 2 is independently selected from the group consisting of hydrogen, deuterium, halogen, CH 3 , OCH 3 , OH, CN, NH 2 , CH 2 OH, CH 2 NH 2 , OCH 2 CH 2 N(CH 2 H 5 ) 2 , OCH 2 CH 2 N(CH 3 ) 2 , NHSO 2 CH 3 , CF 3 , OCHF 2 , OCH 2 CH 2 NH 2 , COOC 2 H 5 , COOH, COOCH 3 ,
OR′, SR′, NR′R′, NR′COR′, NR′CONR′R′, NR′CO 2 R′, COR′, CO 2 R′, NOR′, NO 2 , CONR′R′, OC(O) NR′R′, SO 2 R′, SO 2 NR′R′, NR′SO 2 R′, NR′SO 2 NR′R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 2 -C 6 alkenyl, a substituted or unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; R′ is independently selected from the group consisting of hydrogen, 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; Y is independently selected from O, NH, or N—CH 3 ;
wherein R 3 and R 4 are hydrogen; and
wherein X is independently selected from CH 2 , CO and SO 2 .
2 . The compound of claim 1 , wherein X is CO.
3 . The compound of claim 1 , wherein X is CH 2 .
4 . The compound of claim 1 , wherein R 2 is a halogen.
5 . The compound of claim 4 , wherein the halogen is Cl.
6 . The compound of claim 1 , wherein the compound is selected from
7 . A pharmaceutical composition comprising a compound of claim 1 .
8 . The pharmaceutical composition of claim 7 , wherein the composition is formulated as a nanoparticle carrier for the compound.
9 . A method of treating glioblastoma, breast cancer, leukemia, or a combination thereof in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 .
10 . The method of claim 9 , wherein the method further comprises administering a genotoxic agent; and wherein the genotoxic agent is an alkylating agent selected from the group consisting chlorambucil, cyclophosphamide, ifosfamide, melphalan, streptozocin, carmustine, lomustine, busulfan, dacarbazine, temozolomide, thiotepa, and altretamine.
11 . The method of claim 10 , wherein the alkylating agent is temozolomide.
12 . The method of claim 9 , wherein the glioblastoma, breast cancer, or leukemia is resistant to a genotoxic therapy.
13 . The method of claim 9 , wherein the glioblastoma, breast cancer, or leukemia has increased expression of DNA-polymerase kappa.
14 . The method of claim 13 , wherein DNA-polymerase kappa binding to DNA is inhibited in the glioblastoma, breast cancer, or leukemia.