Pentacyclic triterpenoid compounds as topoisomerase inhibitors or cell differentiation inducers
AssigneeResearch Triangle Institute
InventorsYue-Wei Lee, Qi-Cheng Fang, Zhen-Guo Wang, De-Hua Li, C. E. Cook
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Abstract
Pentacyclic triterpenoid compounds such as .alpha. boswelic acid and its acetate, .beta.-boswellic acid and its acetate, which have an inhibitory effect on topoisomerase I and topoisomerase II, are disclosed. Compositions based on the pentacyclic triterpenoid compounds which can be used to treat various cancers in mammals are also disclosed.
Claims14
A method for inhibiting topoisomerase I, which comprises contacting topoisomerase I in vitro or in vivo with an inhibitory effective amount of a compound selected from the group consisting of those having the following formulas:
- ##STR3## wherein R.sup.1 is -COOR.sup.4, is a -H;
- C.sub.1-4 alkyl;
- C.sub.2-4 alkenyl;
- C.sub.3-4 alkynyl;
- C.sub.6 -C.sub.8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or di-acetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or
- R.sup.1 is -CONH.sub.2 ;
- -CONHR.sup.5 ;
- or -CONR.sub.2.sup.5, where R.sup.5 is a -CH.sub.3 ;
- -CH.sub.2 COOH;
- -CH.sub.2 CH.sub.2 COOH;
- C.sub.2-8 alkyl;
- C.sub.2-8 alkenyl;
- C.sub.2-8 alkynyl;
- or C.sub.6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or di-acetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and
- R.sup.2 and R.sup.3 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR4## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.2 and R.sup.3 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- R.sup.6 and R.sup.7 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR5## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.6 and R.sup.7 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- pharmaceutically acceptable salts thereof.
A method for inhibiting topoisomerase II, which comprises contacting topoisomerase II in vitro or in vivo with an inhibitory effective amount of a compound selected from the group consisting of those having the following formulas:
- ##STR6## wherein R.sup.1 is -COOR.sup.4, where R.sup.4 is a -H;
- C.sub.1-4 alkyl;
- C.sub.2-4 alkenyl;
- C.sub.3-4 alkynyl;
- C.sub.6 -C.sub.8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or diacetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or
- R.sup.1 is -CONH.sub.2 ;
- -CONHR.sup.5 ;
- or -CONR.sub.2.sup.5, where R.sup.5 is a -CH.sub.3 ;
- -CH.sub.2 COOH;
- -CH.sub.2 CH.sub.2 COOH;
- C.sub.2-8 alkyl;
- C.sub.2-8 alkenyl;
- C.sub.2-8 alkynyl;
- C.sub.6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or di-acetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and
- R.sup.2 and R.sup.3 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR7## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.2 and R.sup.3 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- R.sup.6 and R.sup.7 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR8## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.6 and R.sup.7 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- pharmaceutically acceptable salts thereof.
A composition for treatment of a mammal suffering from a cancer selected from the group consisting of small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, central nervous system cancer, liver cancer and prostate cancer, which comprises:
- a compound selected from the group consisting of those having the following formulas:
- ##STR9## wherein R.sup.1 is -COOR.sup.4, where R.sup.4 is a -H;
- C.sub.1-4 alkyl;
- C.sub.2-4 alkenyl;
- C.sub.3-4 alkynyl;
- C.sub.6 -C.sub.8 aryl-which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or diacetylamino, C.sub.1-4 alkyl, or C.sub.2-4 alkenyl, or
- R.sup.1 is -CONH.sub.2 ;
- -CONHR.sub.5 ;
- or -CONR.sub.2 .sup.5 where R.sup.5 is a -CH.sub.3 ;
- -CH.sub.2 COOH;
- -CH.sub.2 CH.sub.2 COOH;
- C.sub.2-8 alkyl;
- C.sub.2-8 alkenyl;
- C.sub.2-8 alkynyl;
- or C.sub.6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or di-acetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and
- R.sup.2 and R.sup.3 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR10## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.2 and R.sup.3 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- R.sup.6 and R.sup.7 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR11## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.6 and R.sup.7 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- pharmaceutically acceptable salts thereof,
- in combination with an agent for targeting said compound to the site where said cancer is localized in said mammal.
A method for inducing cellular differentiation, which comprises contacting a cancerous cell with an effective amount of a compound selected from the group consisting of those having the following formulas:
- ##STR12## wherein Rhu 1 is -COOR.sup.4, where R.sup.4 is a -H;
- C.sub.1-4 alkyl;
- C.sub.2-4 alkenyl;
- C.sub.3-4 alkynyl;
- C.sub.6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or diacetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or
- R.sup.1 is -CONH.sub.2 ;
- -CONHR.sup.5 ;
- or -CONR.sub.2.sup.5, where R.sup.5 is a -CH.sub.3 ;
- -CH.sub.2 COOH;
- -CH.sub.2 CH.sub.2 COOH;
- C.sub.2-8 alkyl;
- C.sub.2-8 alkenyl;
- C.sub.2-8 alkynyl;
- or C.sub.6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or di-acetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and
- R.sup.2 and R.sup.3 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sub.2.sup.5, ##STR13## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.2 and R.sup.3 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- R.sup.6 and R.sup.7 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR14## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.6 and R.sup.7 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- pharmaceutically acceptable salts thereof.
A method of treating a cancer selected from the group consisting of small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, central nervous system cancer, liver cancer and prostate cancer, which comprises administering to a mammal in need thereof an effective amount of a composition containing as the active ingredient therein a compound selected from the group consisting of those having the following formulas:
- ##STR15## wherein Rhu 1 is -COOR.sup.4, where R.sup.4 is a -H;
- C.sub.1-4 alkyl;
- C.sub.2-4 alkenyl;
- C.sub.3-4 alkynyl;
- C.sub.6 -C.sub.8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or diacetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or
- R.sup.1 -CONH.sub.2 ;
- -CONR.sup.5 ;
- or -CONR.sub.2 .sup.5, where R.sup.5 is a -CH.sub.3 ;
- -CH.sub.2 COOH;
- -CH.sub.2 CH.sub.2 COOH;
- C.sub.2-8 alkyl;
- C.sub.2-8 alkenyl;
- C.sub.2-8 alkynyl;
- or C.sub.6-8 aryl which is unsubstituted or is substituted by halogen, methoxy, ethoxy, sulfonamido, amino, mono- or di-C.sub.1-4 -alkyl-amino, mono- or di-acetylamino, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and
- R.sup.2 and R.sup.3 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR16## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.2 and R.sup.3 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- R.sup.6 and R.sup.7 may be combinations of hydrogen or R.sup.5, with -H, -OR.sup.4, -NH.sub.2, -NHR.sup.5, -NHR.sub.2.sup.5, ##STR17## wherein R.sup.4 and R.sup.5 are as defined above, or R.sup.6 and R.sup.7 together may be =O or =N-OR.sup.4, wherein R.sup.4 is as defined above, and
- pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.