Oligo-benzamide compounds and their use in treating cancers

1. A compound of formula (I or II):

wherein:

R 1 , R 2 and R 3 are each independently H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 1 -C 15 optionally substituted arylalkyl, —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRR′, —(CH 2 ) n —NH(C═NH)NRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —OR, —(CH 2 ) n —SR, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group or

 wherein R is independently a H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 1-15 optionally substituted arylalkyl, hydroxyl, C 1-10 alkoxy, amino, C 1-10 monoalkylamino, C 1-10 dialkylamino, guanidine, nitro, carboxylic acid, C 1-10 alkylcarbonyl, C 1-15 arylcarbonyl, halogen, sulfhydryl, C 1-10 alkylsulfenyl, C 1-10 alkylsulfinyl, C 1-10 alkylsulfonyl, sulfonic acid, sulfate, phosphenyl, phosphinyl, phosphonic acid, phosphate group;

X is a —NRR′ or —NRCOR′, wherein R and R′ are independently H, —CH 2 —Z′, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 arylalkyl, each of which is optionally substituted with —COOR″, —CONR″R′″, —NR″R′″, —NH(C═NH)NR″R′″, —NR″COR′″, —NR″COOR′″, —OR″, —SR″, —SO n R″, or —PO n R″, wherein n may be any number between 0 and 6 and R″ and R′″ may be a H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group, and wherein Z′ is:

 and

Y is —(CH 2 ) n COOR 4 , —(CH 2 ) n CONR 4 R 5 , —(CH 2 ) n NR 4 R 5 , —(CH 2 ) n —NR 4 R 5 , —(CH 2 ) n —NH(C═NH)NR 4 R 5 , —(CH 2 ) n —NR 4 COR 5 , —(CH 2 ) n —NR 4 COOR 5 , —(CH 2 ) n —NR 4 CONR 5 , —(CH 2 ) n —OR 4 , —(CH 2 ) n —SR 4 , —(CH 2 ) n —SO m R 4 , —(CH 2 ) n —PO m R 4 , wherein n and m may be any number between 0 and 6,

R 4 and R 5 are independently selected from —H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group; and A, A′ and A″ are independently —O—, —S—, —NR—, —(CH 2 )n-, —CO—wherein n may be any number between 1-6;

provided that when Y is —(CH 2 ) n COOR 4 , then R 4 is not —H or C 1 -C 10 alkyl.

2. The compound of claim 1 , wherein Y is —C(O)NH 2.

3. The compound of claim 1 , wherein A, A′ and A″ are each O.

4. The compound of claim 3 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl, C 1-10 hydroxyalkyl, C 1-10 alkenyl or C 1 -C 15 arylalkyl.

5. The compound of claim 3 , wherein R 1 , R 2 and R 3 are independently C 1-10 alkyl or C 1-10 hydroxyalkyl.

6. The compound of claim 1 , having the formula selected from:

7. A method of inhibiting a prostate tumor cell in a subject comprising administering to said subject a therapeutically sufficient amount of an oligo-benzamide peptidomimetic compound of formula (I or II):

wherein:

R 1 , R 2 and R 3 are each independently H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 1 -C 15 optionally substituted arylalkyl, —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRR′, —(CH 2 ) n —NH(C═NH)NRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —OR, —(CH 2 ) n —SR, —(CH 2 ) n —SO m —R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group or

 wherein R is independently a H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 1-15 optionally substituted arylalkyl, hydroxyl, C 1-10 alkoxy, amino, C 1-10 monoalkylamino, C 1-10 dialkylamino, guanidine, nitro, carboxylic acid, C 1-10 alkylcarbonyl, C 1-15 arylcarbonyl, halogen, sulfhydryl, C 1-10 alkylsulfenyl, C 1-10 alkylsulfinyl, C 1-10 alkylsulfonyl, sulfonic acid, sulfate, phosphenyl, phosphinyl, phosphonic acid, phosphate group;

X is a —NRR′ or —NRCOR′, wherein R and R′ are independently H, —CH 2 —Z′, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 arylalkyl, each of which is optionally substituted with —COOR″, —CONR″R′″, —NR″R′″, —NH(C═NH)NR″R′″, —NR″COR′″, —NR″COOR′″, —OR″, —SR″, —SO n R″, or —PO n R″, wherein n may be any number between 0 and 6 and R″ and R′″ may be a H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group, and wherein Z′ is:

 and

Y is —(CH 2 ) n COOR 4 , —(CH 2 ) n CONR 4 R 5 , —(CH 2 ) n NR 4 R 5 , —(CH 2 ) n —NR 4 R 5 , —(CH 2 ) n —NH(C═NH)NR 4 R 5 , —(CH 2 ) n —NR 4 COR 5 , —(CH 2 ) n —NR 4 COOR 5 , —(CH 2 ) n —NR 4 CONR 5 , —(CH 2 ) n —OR 4 —(CH 2 ) n —SR 4 , —(CH 2 ) n —SO m R 4 , —(CH 2 ) n —PO m R 4 wherein n and m may be any number between 0 and 6,

R 4 and R 5 are independently selected from —H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group; and A, A′ and A″ are independently —O—, —S—, —NR—, —(CH 2 )n-, —CO—wherein n may be any number between 1-6;

provided that when Y is —(CH 2 ) n COOR 4 then R 4 is not —H or C 1 -C 10 alkyl.

8. The method of claim 7 , wherein the prostate tumor cell is an androgen receptor (AR)- or estrogen receptor (ER)-positive tumor cell.

9. The method of claim 7 , prostate tumor cell is a prostate carcinoma cell.

10. The method of claim 7 , wherein administering comprises local, regional, systemic, or continual administration.

11. The method of claim 7 , wherein said peptidomimetic compound is fused to a cell delivery domain.

12. The method of claim 7 , wherein inhibiting comprises inducing growth arrest of said prostate tumor cell, apoptosis of said prostate tumor cell and/or necrosis of a prostate tumor tissue comprising said prostate tumor cell.

13. The method of claim 7 , further comprising providing to said subject a second anti-cancer therapy.

14. The method of claim 13 , wherein said second anti-cancer therapy is surgery, chemotherapy, radiotherapy, hormonal therapy, toxin therapy, immunotherapy, and cryotherapy.

15. The method of claim 7 , wherein said subject is a human.

16. The method of claim 7 , wherein said compound is administered daily.

17. The method of claim 7 , further comprising assessing AR- or ER-driven gene expression in said prostate tumor cell of said subject after administering said compound.

18. A pharmaceutical composition comprising a compound formula (I or II):

wherein:

R 1 ,R 2 and R 3 are each independently H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, C 1 -C 15 optionally substituted arylalkyl, —(CH 2 ) n —COOR, —(CH 2 ) n —CONRR′, —(CH 2 ) n —NRR′, —(CH 2 ) n —NH(C═NH)NRR′, —(CH 2 ) n —NRCOR′, —(CH 2 ) n —NRCOOR′, —(CH 2 ) n —OR, —(CH 2 ) n —SR, —(CH 2 ) n —SO m R, —(CH 2 ) n —PO m R, wherein n and m may be any number between 0 and 6 and R and R′ may be a H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group or

 wherein R is independently a H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 1-15 optionally substituted arylalkyl, hydroxyl, C 1-10 alkoxy, amino, C 1-10 monoalkylamino, C 1-10 dialkylamino, guanidine, nitro, carboxylic acid, C 1-10 alkylcarbonyl, C 1-15 arylcarbonyl, halogen, sulfhydryl, C 1-10 alkylsulfenyl, C 1-10 alkylsulfinyl, C 1-10 alkylsulfonyl, sulfonic acid, sulfate, phosphenyl, phosphinyl, phosphonic acid, phosphate group;

X is a —NRR′ or —NRCOR′, wherein R and R′ are independently H,—CH 2 —Z′, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 arylalkyl, each of which is optionally substituted with —COOR″, —CONR″R′″, —NR″R′″, —NH(C═NH)NR″R′″, —NR″COR′″, —NR″COOR′″, —OR″, —SR″, —SO n R″ or —PO n R″, wherein n may be any number between 0 and 6 and R″ and R′″ may be a H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group, and wherein Z′ is:

 and

Y is —(CH 2 ) n COOR 4 , —(CH 2 ) n CONR 4 R 5 , —(CH 2 ) n NR 4 R 5 , —(CH 2 ) n NR 4 R 5 —(CH 2 ) n —NH(C═NH)NR 4 R 5 , —(CH 2 ) n —NR 4 COR 5 , —(CH 2 ) n NR 4 COOR 5 , —(CH 2 ) n —NR 4 CONR 5 , —(CH 2 ) n —OR 4 , —(CH 2 ) n —SR 4 , —(CH 2 ) n ,—SO m R 4 , —(CH 2 ) n —PO m R 4 , wherein n and m may be any number between 0 and 6,

R 4 and R 5 are independently selected from —H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 alkynyl, or C 1 -C 15 optionally substituted arylalkyl group; and A, A′ and A″ are independently —O—, —S—, —NR—, —(CH 2 )n-, —CO—wherein n may be any number between 1-6;

provided that when Y is —(CH 2 ) n COOR 4 then R 4 is not —H or C 1 -C 10 alkyl, dispersed in a pharmaceutically acceptable carrier, buffer or diluent.

19. The method of claim 7 , further comprising assessing AR- or ER-driven gene expression in said prostate tumor cell of said subject prior to administering said compound.