Therapy
The invention addresses radioresistance in cancer treatment involving radiotherapy and, in particular, limitations associated with the use of the drug sulfasalazine. Specifically, it provides a series of compounds for use as radiosensitizers in the treatment of cancers such as glioblastomas which are lethal and inherently resistant to radiotherapy. In one embodiment, the invention provides compounds of general formula (I), their stereoisomers and pharmaceutically acceptable salts for use as radiosensitizers in the treatment of cancer: wherein ring A is selected from optionally substituted phenyl, biphenyl and fluorenyl; each X is independently selected from: —C 1-6 alkyl (preferably C 1-3 alkyl, e.g. —CH 3 ), —O—C 1-6 alkyl (preferably —O—C 1-3 alkyl, e.g. —OCH 3 ), —S—C 1-6 alkyl (preferably —S—C 1-3 alkyl, e.g. —SCH 3 ), —OH, —SH, —CO 2 R 1 (where R 1 is H or C 1-6 alkyl, preferably C 1-3 alkyl, e.g. —CH 3 ), —SO 2 —C 1-6 alkyl (preferably —SO 2 —C 1-3 alkyl, e.g. —SO 2 —CH 3 ), —SO 2 —NR 2 R 3 (where R 2 is H and R 3 is optionally substituted phenyl), —NR 4 R 5 (wherein R 4 and R 5 are independently selected from H, C 1-6 alkyl (preferably C 1-3 alkyl, e.g. —CH 3 ), and —CO—C 1-6 alkyl (preferably —CO—C 1-3 alkyl, e.g. —CO—CH 3 ), halogen (e.g. F, Cl or Br), and optionally substituted tetrazolyl; n is an integer from 0 to 5, preferably 0 to 2, e.g. 1 or 2; and denotes an E or Z double bond.
1 . A method of treating cancer, said method comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of general formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, in combination with radiotherapy:
wherein:
ring A is optionally substituted biphenyl;
each X is independently selected from:
—C 1-6 alkyl,
—O—C 1-6 alkyl,
—S—C 1-6 alkyl,
—OH,
—SH,
—CO 2 R 1 where R 1 is H or C 1-6 alkyl,
—SO 2 —C 1-6 alkyl,
—SO 2 —NR 2 R 3 where R 2 is H and R 3 is optionally substituted phenyl,
—NR 4 R 5 wherein R 4 and R 5 are independently selected from H, C 1-6 alkyl, and —CO—C 1-6 alkyl,
halogen, and
optionally substituted tetrazolyl;
n is an integer from 0 to 5; and
denotes an E or Z double bond.
2 . The method of claim 1 , wherein ring A is unsubstituted biphenyl.
3 . A method of treating cancer, said method comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, in combination with radiotherapy, wherein said compound is selected from the following and their stereoisomers, and pharmaceutically acceptable salts:
Compound
Compound name and
No.
CAS No. (where appropriate)
Structure
DC01
(E)-2-methoxy-5-styrylbenzoic acid
DC02
(E)-2-hydroxy-5-styrylbenzoic acid CAS 1072937-49-5
DC03
(Z)-2-methoxy-5-styrylbenzoic acid
DC07
(E)-5-(4-fluorostyryl)-2-hydroxybenzoic acid
DC08
(E)-2-hydroxy-5-(4-(methylthio)styryl)benzoic acid
DC10
(E)-5-(2-([1,1′-biphenyl]-4-yl)vinyl)-2-hydroxybenzoic acid
DC12
(E)-2-ammino-5-styrylbenzoic acid
DC13
(E)-2-hydroxy-5-(4-(methylsulfonyl)styryl)benzoic acid
DC15
(E)-4-styryl-2-(1H-tetrazol-5-yl)phenol
DC16
(E)-2-acetamido-5-styrylbenzoic acid CAS No. 380365-20-8
DC18
(E)-5-(2-([1,1′-biphenyl]-3-yl)vinyl)-2-hydroxybenzoic acid
DC19
(E)-5-(2-([1,1′-biphenyl]-2-yl)vinyl)-2-hydroxybenzoic acid
DC21
(E)-5-(2-(9,9-dimethyl-9H-fluoren-2-yl)vinyl)-2- hydroxybenzoic acid
4 . The method of claim 1 , wherein said cancer is a radioresistant cancer.
5 . A method of treating cancer, said method comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of general formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof, in combination with radiotherapy:
wherein:
ring A is a fluorenyl group substituted by 1 or 2—CH 3 groups;
each X is independently selected from:
—C 1-6 alkyl,
—O—C 1-6 alkyl,
—S—C 1-6 alkyl,
—OH,
—SH,
—CO 2 R 1 where R 1 is H or C 1-6 alkyl,
—SO 2 —C 1-6 alkyl,
—SO 2 —NR 2 R 3 where R 2 is H and R 3 is optionally substituted phenyl,
—NR 4 R 5 wherein R 4 and R 5 are independently selected from H, C 1-6 alkyl, and —CO—C 1-6 alkyl,
halogen, and
optionally substituted tetrazolyl;
n is an integer from 0 to 5; and
denotes an E or Z double bond.
6 . The method of claim 5 , wherein ring A is 9,9-dimethyl-9H-fluorenyl.
7 . The method of claim 4 , wherein said cancer is selected from the following: malignant gliomas, medulloblastoma, neuroblastoma, Kaposi's sarcoma, head and neck squamous cell carcinoma, tongue cancer, esophageal squamous cell carcinoma, thyroid cancer, melanoma, breast cancer, prostate cancer, laryngeal squamous cell carcinoma, lung cancer, mesothelioma, gastric cancer, hepatocellular carcinoma, pancreatic cancer, cholangiocarcinoma, colon cancer, renal cancer, urothelial cancer, testis cancer, endometrial cancer, ovarian cancer, cervical cancer, and metastases from any of these cancers, as well as myeloma, lymphoma and leukemia.
8 . The method of claim 7 , wherein said cancer is glioblastoma multiforme, lung cancer or breast cancer.
9 . The method of claim 7 , wherein said cancer is glioblastoma multiforme.
10 . The method of claim 3 , wherein said cancer is a radioresistant cancer.
11 . The method of claim 10 , wherein said cancer is selected from the following:
malignant gliomas, medulloblastoma, neuroblastoma, Kaposi's sarcoma, head and neck squamous cell carcinoma, tongue cancer, esophageal squamous cell carcinoma, thyroid cancer, melanoma, breast cancer, prostate cancer, laryngeal squamous cell carcinoma, lung cancer, mesothelioma, gastric cancer, hepatocellular carcinoma, pancreatic cancer, cholangiocarcinoma, colon cancer, renal cancer, urothelial cancer, testis cancer, endometrial cancer, ovarian cancer, cervical cancer, and metastases from any of these cancers, as well as myeloma, lymphoma and leukemia.
12 . The method of claim 11 , wherein said cancer is glioblastoma multiforme, lung cancer or breast cancer.
13 . The method of claim 11 , wherein said cancer is glioblastoma multiforme.
14 . The method of claim 5 , wherein said cancer is a radioresistant cancer.
15 . The method of claim 14 , wherein said cancer is selected from the following:
malignant gliomas, medulloblastoma, neuroblastoma, Kaposi's sarcoma, head and neck squamous cell carcinoma, tongue cancer, esophageal squamous cell carcinoma, thyroid cancer, melanoma, breast cancer, prostate cancer, laryngeal squamous cell carcinoma, lung cancer, mesothelioma, gastric cancer, hepatocellular carcinoma, pancreatic cancer, cholangiocarcinoma, colon cancer, renal cancer, urothelial cancer, testis cancer, endometrial cancer, ovarian cancer, cervical cancer, and metastases from any of these cancers, as well as myeloma, lymphoma and leukemia.
16 . The method of claim 15 , wherein said cancer is glioblastoma multiforme, lung cancer or breast cancer.
17 . The method of claim 15 , wherein said cancer is glioblastoma multiforme.