# US 7,407,985 B2 · Compounds that abrogate DNA damage induced cell cycle G2 checkpoint and/or augment anti-cancer activity of DNA-damaging treatments > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,407,985 B2 - Document ID: US7407985B2 - Status: Granted - Kind: B2 - Application number: 11/334,160 - Filed: 2006-01-17 - Published: 2006-06-08 - Granted: 2008-08-05 - Earliest claimed: 2002-06-06 - Assignees: CanBas Co., Ltd. - Inventors: Takumi Kawabe; Hidetaka Kobayashi - Web page: https://patentgrep.com/patent/US7407985B2 ## CPC - C07C 327/26: having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of six-membered aromatic rings - A61P 35/00: Antineoplastic agents - C07C 69/76: Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring - C07C 327/36: Esters of dithiocarboxylic acids - C07D 213/65: attached in position 3 or 5 - G01N 33/5011: {for testing antineoplastic activity} - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract The invention provides compositions and methods to inhibit the cell cycle G2 checkpoint, in particular the DNA-damage-induced G2 checkpoint, in mammalian cells including human cells. Specifically, the invention provides compositions and methods to sensitize cells to DNA-damaging agents by abrogating the cell cycle G2 checkpoint. Compounds of the invention are used to treat proliferative disorders such as cancer. The invention provides compositions and methods for selectively sensitizing G1 checkpoint impaired cancer cells to DNA-damaging agents and treatments. ## Claims ### Claim 1 An in vitro method for suppressing or killing a DNA-damaged cell, comprising administering an effective amount of at least one compound that abrogates the cell cycle G2 checkpoint when administered to a cell, wherein the compound has the following structure: where either or both of benzene can be substituted with pyrazine, pyrimidine. piperazine, morpholine, cyclohexane, piperizine or pyridine; R1 is a halogen, bromine (Br), chlorine (Cl), fluorine (F), iodine (I). amino (NH2), nitro (NO2), hydroxy (OH),O-methyl (OCH3), methyl (CH3) or hydrogen (H); R2, R3, R4, R5 and R6 is bromine (Br), chlorine (Cl), fluorine (F), iodine (I), amino (NH2), nitro (NO2), methyl (CH3), O-methyl (OCH3), hydroxy (OH), CH(CH3)2, CHO, CHOCH3, O(CH2)nCH3, OCO(C6H12)Cl, COOCH3 or hydrogen; X1 is nitrogen (NH), oxygen (O) or sulfate (S); and X2 is oxygen (O) or sulfate (S). ### Claim 2 (depends on 1) The method of claim 1, wherein the DNA-damaged cell has a DNA-damage-induced G2 checkpoint. ### Claim 3 (depends on 1) The method of claim 1, wherein the DNA-damaged cell has an impaired G1 checkpoint. ### Claim 4 (depends on 1) The method of claim 1, wherein the DNA-damaged cell is a cancer cell. ### Claim 5 (depends on 1) The method of claim 1, further comprising administering a DNA-damaging agent or a DNA-damaging treatment, wherein administering the compound increases the sensitivity of the cell to the DNA-damaging agent or DNA-damaging treatment. ### Claim 6 (depends on 1) A method of selectively targeting DNA-damaged cells according to the method of claim 1, comprising administering the compound to a population of cells comprising DNA-damaged cells and normal cells, wherein abrogation of the G2 checkpoint suppresses or kills DNA-damaged cells, and has little or no cytotoxic effect on normal cells. ### Claim 7 (depends on 6) The method of claim 6, further comprising administering a DNA-damaging agent or a DNA-damaging treatment. ### Claim 8 (depends on 6) The method of claim 6, wherein the DNA-damaged cells are cancer cells. ### Claim 9 (depends on 1) The method of claim 1, comprising administering at least one compound selected from: 4-chloro-benzoic acid 4-inethoxy-phenyl ester (CDBC004); 4-chloro-benzoic acid p-tolyl ester (CBDC401); 4-bromo-benzoic acid p-tolyl ester (CBDC402); 3,4,5-trifluoro-benzoic acid p-toly1 ester (CBDC403); 4-fluoro-benzoic acid 4-bromo-phenyl ester (CBDC404); 3,4-dichloro-benzoic acid p-tolyl ester (CBDC405); 4-tluoro-benzoic acid p-tolf ester (CBDC407); 4-chloro-benzoic acid 3,4-dimethyl-phenyl ester (CBDC409); 4-chloro-benzoic acid 4-hydroxy-phenyl ester (CBDC410); 4-fluoro-benzoic acid 4-hydroxy-phenyl ester (CBDC411); 4-bromo-benzoic acid 4-fluoro-phenyl ester (CBDC412); 4-brosno-benzoic acid 4-trifluoromethyl-phenyl ester (CBDC413); 4-bromo-benzoic acid 4-hydroxy-phenyl ester (CBDC414); 4-bromo-benzoic acid 4-trifluoromethoxy-phenyl ester (CBDC415); 4-Bromo-benzoic acid 6-methyl-pyridin-3-yl ester (CBDC418); 4-bromo-thiobenzoic acid 0-p-tolyl ester (CBDC440); 4-bromo-dithiobenzoic acid p-tolyl ester (CBDC441); and 4-bromo-thiobenzoic acid S-p-tolyl ester (CBDC442). ### Claim 10 (depends on 1) The method of claim 1, comprising administering 4-chloro-benzoic acid 4-methoxy-phenyl ester (CBDC004) having the structure: ### Claim 11 (depends on 1) The method of claim 1, comprising administering 4-chloro-benzoic acid p-tolyl ester (CBDC401) having the structure: ### Claim 12 (depends on 1) The method of claim 1, comprising administering 4-bromo-benzoic acid p-tolyl ester (CBDC402) having the structure: ### Claim 13 (depends on 1) The method of claim 1, comprising administering 3,4,5-trifluoro-benzoic acid p-tolyl ester (CBDC403) having the structure: ### Claim 14 (depends on 1) The method of claim 1, comprising administering 4-fluoro-benzoic acid 4-bromo-phenyl ester (CBDC404) having the structure: ### Claim 15 (depends on 1) The method of claim 1, comprising administering 3,4-dichioro-benzoic acid p-tolyl ester (CBDC405) having the structure: ### Claim 16 (depends on 1) The method of claim 1, comprising administering 4-fluoro-benzoic acid p-tolyl ester (CBDC407) having the structure: ### Claim 17 (depends on 1) The method of claim 1, comprising administering 4-chloro-benzoic acid 3,4-dimethyl-phenyl ester (CBDC409) having the structure: ### Claim 18 (depends on 1) The method of claim 1, comprising administering 4-chloro-benzoic acid 4-hydroxy-phenyl ester (CBDC410) having the structure: ### Claim 19 (depends on 1) The method of claim 1, comprising administering 4fluoro-benzoic acid 4-hydroxy-phenyl ester (CBDC411) having the structure: ### Claim 20 (depends on 1) The method of claim 1, comprising administering 4- bromo-benzoic acid 4-fluoro-phenyl ester (CBDC412) having the structure: ### Claim 21 (depends on 1) The method of claim 1, comprising administering 4-bromo-benzoic acid 4-trifluoromethyl-phenyl ester (CBDC413) having the structure: ### Claim 22 (depends on 1) The method of claim 1, comprising administering 4-bromo-benzoic acid 4-hydroxy--phenyl ester (CBDC414) having the structure: ### Claim 23 (depends on 1) The method of claim 1, comprising administering 4-bromo-benzoic acid 4-trifluoromethoxy-phenyl ester (CBDC415) having the structure: ### Claim 24 (depends on 1) The method of claim 1, comprising administering 4-bromo-benzoic acid 6-methyl-pyridin--3-yl ester (CBDC418) having the structure: ### Claim 25 (depends on 1) The method of claim 1, comprising administering 4-bromo-thiobenzoic acid 0-p-tolyl ester (CBDC440) having the structure: ### Claim 26 (depends on 1) The method of claim 1, comprising administering 4-bromo-dithiobenzoic acid p-tolyl ester (CBDC441) having the structure: ### Claim 27 (depends on 1) The method of claim 1, comprising administering 4-bromo-thiobenzoic acid S-p-tolyl ester (CBDC442) having the structure: