Migrastatin analogs in the treatment of cancer
In one aspect, the present invention provides a method for treating colon and/or ovarian cancer in a subject comprising administering to a subject in need thereof a compound of general formula (I): wherein R1-R6, R, -R, Q, Y1, Y2 and n are as defined herein, wherein the compound is present in an amount effective to inhibit colon and/or ovarian tumor metastasis.
1. A method for treating ovarian cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure:
or pharmaceutically acceptable salt thereof;
wherein R 1 and R 2 are each hydrogen;
R 3 is hydrogen or methyl;
R 4 is —OH, OAc, NH 2 , or F, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:
R 5 is hydrogen or methyl;
R 6 is hydrogen or methyl;
R a and R b are hydrogen;
R c is hydrogen;
n is 3;
X 1 is O, NR X1 or CR X1 R X2 ; wherein R X1 and R X2 are hydrogen;
Q is hydrogen; and
Y 1 and Y 2 are hydrogen, or Y 1 and Y 2 together with the carbon atom to which they are attached form a moiety having the structure:
wherein the compound is administered at a dosage from about 1 mg/kg to about 70 mg/kg, or wherein the compound is administered at a dosage of about 70 mg/kg or greater; and wherein the compound is present in an amount effective to inhibit ovarian tumor metastasis.
2. A method for treating colon cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structure:
or pharmaceutically acceptable salt thereof;
wherein R 1 and R 2 are each hydrogen;
R 3 is hydrogen or methyl;
R 4 is —OH, OAc, NH 2 , or F, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:
R 5 is hydrogen or methyl;
R 6 is hydrogen or methyl;
R a and R b are hydrogen;
R c is hydrogen;
n is 3;
X 1 is O;
Q is hydrogen; and
Y 1 and Y 2 are hydrogen, or Y 1 and Y 2 together with the carbon atom to which they are attached form a moiety having the structure
wherein the compound is administered at a dosage from about 1 mg/kg to about 70 mg/kg, or wherein the compound is administered at a dosage of about 70 mg/kg or greater; and wherein the compound is present in an amount effective to inhibit colon tumor metastasis.
3. A method for treating colon or ovarian cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:
a pharmaceutically acceptable carrier, adjuvant or vehicle; and
a therapeutically effective amount of a compound having the structure:
or pharmaceutically acceptable salt thereof;
wherein R 1 and R 2 are hydrogen;
R 3 is hydrogen or methyl;
R 4 is —OH, OAc, NH 2 , or F, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:
R 5 is hydrogen or methyl;
R 6 is hydrogen or methyl;
R a and R b are hydrogen;
R c is hydrogen;
n is 3;
X 1 is O;
Q is hydrogen; and
Y 1 and Y 2 are hydrogen, or Y 1 and Y 2 together with the carbon atom to which they are attached form a moiety having the structure:
whereby the composition is formulated for administration to a subject at a dosage between about 1 mg/kg to about 70 mg/kg, or wherein the composition is formulated for administration to a subject at a dosage of about 70 mg/kg or greater.
4. The method of claim 3 , wherein the dosage is between about 20 mg/kg to about 60 mg/kg of body weight.
5. The method of claim 3 , wherein the dosage is between about 5 mg/kg to about 20 mg/kg of body weight.
6. The method of claim 3 , wherein the dosage is between about 150 mg/kg to about 250 mg/kg of body weight.
7. The method of claim 1 , wherein the compound is:
8. The method of claim 1 , wherein in the compound, R 5 and R 6 are each methyl.
9. The method of claim 1 , wherein in the compound, R 3 is methyl.
10. The method of claim 1 , wherein in the compound, R 4 is OH, NH 2 or F.
11. The method of claim 1 , wherein the compound has the structure:
12. The method of claim 1 , wherein the compound has the structure:
13. The method of claim 11 , wherein in the compound, R 3 is methyl.
14. The method of claim 11 , wherein in the compound, the stereocenter
has the following stereochemistry
15. The method of claim 11 , wherein in the compound, the stereocenter
has the following stereochemistry
16. The method of claim 1 , wherein the compound has one of the structures:
17. The method of claim 1 , wherein the compound has one of the structures:
18. The method of claim 16 wherein the compound has the structure:
19. The method of claim 17 wherein the compound has the structure:
20. The method of claim 18 , wherein R 5 and R 6 are each methyl.
21. The method of claim 18 , wherein R 3 is methyl.
22. The method of claim 1 , wherein the compound has one of the following structures:
23. The method of claim 2 , wherein the compound is present in an amount effective to inhibit metastasis of colon tumor cells.
24. The method of claim 1 , wherein the compound is present in an amount effective to inhibit metastasis of ovarian tumor cells.
25. The method of claim 1 , further comprising a cytotoxic agent.
26. The method of claim 25 , wherein the cytotoxic agent is an anticancer agent.
27. The method of claim 1 , further comprising a palliative agent.
28. The method of claim 22 , wherein the composition is administered at a dosage between about 20 mg/kg to about 60 mg/kg of body weight.
29. The method of claim 22 , further comprising administering a cytotoxic agent.
30. The method of claim 29 , wherein the cytotoxic agent is an anticancer agent.
31. The method of claim 22 , further comprising administering a palliative agent.
32. The method of claim 1 , wherein the subject is a mammal.
33. The method of claim 32 , wherein the subject is a human.
34. A compound of formula:
or a pharmaceutically acceptable salt thereof.
35. The method of claim 2 , wherein the compound is present in an amount effective to inhibit migration of tumor cells from a primary colon tumor site to a secondary metastasis site.
36. The method of claim 1 , wherein the compound is present in an amount effective to inhibit migration of tumor cells from a primary ovarian tumor site to a secondary metastasis site.
37. The method of claim 2 , wherein the compound has the structure:
38. The method of claim 2 , wherein the compound has the structure:
39. The method of claim 2 , wherein the compound has one of the following structures: