Alkyl ketones as potent anti-cancer agents

Details Alkyl ketones as potent anti-cancer agents Alkyl ketones as potent anti-cancer agents

1999-06-29

2001-06-26

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...

C514S629000, C534S564000, C564S209000, C564S215000

Reexamination Certificate

active

06251882

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to alkyl ketone compounds effective for treating tumor cells and particularly effective to induce apoptosis in leukemia cells, breast cancer cells, prostate cancer cells, and brain cancer cells.
BACKGROUND OF THE INVENTION
Cancer is a major disease that continues as one of the leading causes of death at any age.
In the United States alone, it is anticipated that more than a half a million Americans will die of cancer in 1999. Currently, radiotherapy and chemotherapy are two important methods used in the treatment of cancer.
Considerable efforts are underway to develop new chemotherapeutic agents for more potent and specific anti-cancer therapy, presenting effective and efficient cytotoxicity against tumor cells, with minimal interference with normal cell function. Accordingly, there is an urgent need for the development and analysis of novel, effective anti-cancer agents.
SUMMARY OF THE INVENTION
Novel alkyl ketone compounds have been found to be potent cytotoxic agents with potent activity against cancer cells. For example, certain alkyl ketone compounds were found to exhibit potent cytotoxic activity, particularly against human breast cancer and leukemic cell lines, at micromolar concentrations. These compounds were also effective in inhibiting adhesion and invasion by cancer cells.
Accordingly, the present invention includes novel compounds and compositions having potent cytotoxic activity. The present invention also includes methods for treating tumors by administering to a subject an effective amount of a compound of the invention to inhibit growth and/or induce apoptosis of tumor cells. Compositions of the invention contain an effective cytotoxic or inhibitory amount of a compound.
The compounds of the invention have the following formula I:
wherein
p is an integer selected from 0 and 1;
X is O or S;
R
1
is H, hydroxyl, (C
1
-C
30
) alkyl, (C
1
-C
30
) alkenyl, (C
1
-C
30
) haloalkyl, (C
1
-C
30
) diazoalkyl, —CH
2
OC(O)R
5
, —NR
6
R
7
, or —CH
2
—S—R
9
wherein R
5
is independently aryl, (C
1
-C
30
) alkyl, (C
1
-C
30
) haloalkyl, (C
1
-C
30
) alkenyl, (C
1
-C
30
) diazoalkyl, (C
1
-C
24
) cycloalkyl, or (C
1
-C
24
) cycloalkenyl,
R
6
is independently H, (C
1
-C
30
) alkyl, (C
1
-C
30
) haloalkyl, (C
1
-C
30
) diazoalkyl, (C
1
-C
30
) alkenyl, (C
1
-C
30
) haloalkenyl, (C
1
-C
24
) cycloalkyl, or (C
1
-C
24
) cycloalkenyl;
R
7
is —OR
8
,
R
8
is independently (C
1
-C
30
) alkyl, (C
1
-C
30
) haloallyl, (C
1
-C
30
) diazoalkyl, (C
1
-C
30
) alkenyl, (C
1
-C
30
) haloalkenyl, (C
1
-C
24
) cycloalkyl, or (C
1
-C
24
) cycloalkenyl;
R
9
is independently (C
1
-C
30
) alkyl, (C
1
-C
30
) haloalkyl, (C
1
-C
30
) diazoalkyl, (C
1
-C
30
) alkenyl, (C
1
-C
30
) haloalkenyl, (C
1
-C
24
) cycloalkyl, (C
1
-C
24
) cycloalkenyl, or —R
10
CO
2
H;
R
10
is (C
1
-C
30
) alkyl or (C
1
-C
30
) alkenyl,
R
2
is C
1
or C
2
; CH
2
or CH
2
CH
2
R
3
is (C
1
-C
30
) alkyl, (C
1
-C
30
) haloalkyl, (C
1
-C
30
) alkenyl, (C
1
-C
30
) haloalkenyl, (C
1
-C
24
) cycloalkyl, (C
1
-C
24
) cycloalkenyl, (C
1
-C
24
)aryl, anthroquinonylmethyl, naphthylmethyl, —SR
11
, or —CR
12
;
R
11
is independently (C
1
-C
30
) alkyl, (C
1
-C
30
) haloalkyl, (C
1
-C
30
) alkenyl, or (C
1
-C
30
) haloalkenyl;
R
12
is aryl substituted methyl;
R
4
is H, —C(O)R
3
, or —C(O)—O—R
14
;
R
13
and R
14
are each independently (C
1
-C
12
) alkyl, (C
1
-C
12
) haloalkyl, (C
1
-C
12
) alkenyl, (C
1
-C
12
) haloalkenyl, (C
3
-C
12
) cycloalkyl, or (C
3
-C
12
) cycloalkenyl; or a pharmaceutically acceptable acid addition salt thereof.
Preferred compounds of the invention are those where p is the integer 1, R
1
is a haloalkyl, R
2
is C
1
, R
3
is a (C
1
-C
22
) alkyl, and R
4
is acetyl. Most preferred is the compound N-Ac-S-dodecyl-Cys chloromethyl ketone (HI-131).


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