Indole-3-carbinol (I3C) derivatives and methods

• US 6,656,963 B2
• Filed: 04/08/2002
• Issued: 12/02/2003
• Est. Priority Date: 05/30/1997
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Bjeldanes, Leonard F., Firestone, Gary L., Cover, Carolyn M.
• Primary Examiner(s): Reamer, James H
• Application Number:
  US10/118,607
• Publication Number:
  US 20030087946A1
• Time in Patent Office: 603 Days
• Field of Search: 514/415, 514/419
• US Class Current: 514/415
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The invention provides methods and compositions relating to novel bioactive derivatives of indole-3-carbinol (I3C), including pharmaceuticals comprising a pharmaceutically acceptable excipient and a compound of the general formula:

which inhibits tumor cell growth. Methods of inhibiting targeted cell growth include contacting a target cell with a disclosed compound under conditions whereby the growth the target cell is inhibited, and methods for evaluating the growth inhibitory activity of the compounds include contacting a cell with an effective amount of the compound and measuring the CDK6 expression in the cell, wherein a reduction in CDK6 expression correlates with the growth inhibitory activity of the compound.

Claims

1. A pharmaceutical compostition comprising a compound of any of Tables VI-IX and, or a pharmaceutically acceptable salt or ester thereof, wherein said compound inhibits tumor cell growth, is other than indole-3-carbinol (I3C), 3,3′

-diinodolylmethane (DIM) and indole[3,2-b]carbazole (ICZ); and

a pharmaceutically acceptable excipient.

2. A composition according to claim 1, wherein the compound is of Table VI.

3. A composition according to claim 1, wherein the compound is of Table VIIA, 20 column 2 (HBC001-4 compounds).

4. A composition according to claim 1, wherein the compound is of Table VIIA or Table VIIB.

5. A composition according to claim 1, wherein the compound is of Table VIII.

6. A composition according to claim 1, wherein the compound is of Table IX.

7. A composition according to claim 1, wherein said compound is other than a natural gastric acid metabolite of I3C.

8. A composition according to claim 1, wherein said compound inhibits cell growth in an estrogen-independent manner.

9. A composition according to claim 1, wherein said compound inhibits CDK6 activity.

10. A composition according to claim 1, wherein said compound demonstrates enhanced metabolic stability over I3C.

11. A composition according to claim 1 further comprising an antiestrogen.

12. A composition according to claim 1 further comprising an antiestrogen selected from tamoxifen, ICI 164384 and raloxifene.

13. A method of inhibiting cell growth comprising contacting a target cell with a compound of claim 1 under conditions whereby the growth of said target cell is inhibited.

14. A method of inhibiting cell growth comprising contacting a target cell with a compound of claim 2 under conditions whereby the growth of said target cell is inhibited.

15. A method of inhibiting cell growth comprising contacting a target cell with a compound of claim 3 under conditions whereby the growth of said target cell is inhibited.

16. A method of inhibiting cell growth comprising contacting a target cell with a compound of claim 4 under conditions whereby the growth of said target cell is inhibited.

17. A method of inhibiting cell growth comprising contacting a target cell with a compound of claim 5 under conditions whereby the growth of said target cell is inhibited.

18. A method of inhibiting cell growth comprising contacting a target cell with a compound of the general formula:

or a pharmaceutically acceptable salt or ester thereof, wherein;

R_1-5 are independently selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, and aryl; and

wherein said compound inhibits tumor cell growth and said compound is other than indole-3-carbinol (I3C), 3,3′

-diinodolylmethane (DIM) and indole[3,2-b]carbazole (ICZ), under conditions whereby the growth said target cell is inhibited.

19. A method according to claim 18, wherein the method is a method of inhibiting tumor cell growth comprising contacting a target tumor cell with, or administering to an individual in need thereof, an effective amount of an indole-3-carbinol compound or a derivative thereof, wherein said compound is stable in acidic aqueous solution, said inhibition is estrogen-independent and said compound is not indole-3-carbinol, 3,3′

-diinodolylmethane or indole[3,2-b]carbazole (ICZ).

20. A method for evaluating the growth inhibitory activity of an I3C derivative, said method comprising the steps of:

treating cultured MCF7 human breast cancer cells with an effective amount of an I3C derivative; and

measuring the CDK6 expression in said cells;

wherein a reduction in CDK6 expression in said cells as compared with otherwise comparable but untreated cells is indicative of growth inhibitory activity of said derivative.

21. The method of claim 20, wherein the treating step comprises treating the cells with a combination of the I3C derivative and an anti-estrogen.