Tubulin binding compounds (COBRA)

Details Tubulin binding compounds (COBRA) Tubulin binding compounds (COBRA)

1999-06-29

2001-07-10

Dentz, Bernard (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S152000, C548S517000, C549S502000

Reexamination Certificate

active

06258841

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a novel binding pocket of tubulin, and to novel compounds tubulin-binding compounds designed and configured to fit and interact favorably with residues of the novel binding pocket. These tubulin-binding compounds are potent inhibitors of tubulin polymerization and active anti-cancer agents.
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.
Cellular proliferation, for example, in cancer, occurs as a result of cell division, or mitosis. Microtubules play a pivotal role in mitotic spindle assembly and cell division
1-5
. These cytoskeletal elements are formed by the self-association of the &agr;&bgr; tubulin heterodimers
1-5
.
Recently, the structure of the &agr;&bgr; tubulin dimer was resolved by electron crystallography of zinc-induced tubulin sheets
6
. According to the reported atomic model, each 46×40×65 Å tubulin monomer is made up of a 205 amino acid N-terminal GTP/GDP binding domain with a Rossman fold topology typical for nucleotide-binding proteins, a 180 amino acid intermediate domain comprised of a mixed &bgr; sheet and five helices which contain the taxol binding site, and a predominantly helical C-terminal domain implicated in binding of microtubule-associated protein (MAP) and motor proteins
2, 5
.
Novel tubulin-binding molecules which, upon binding to tubulin, interfere with tubulin polymerization, can provide novel agents for the treatment of cancer.
SUMMARY OF THE INVENTION
A novel binding pocket has been identified in tubulin, which binding pocket accepts and binds novel, small molecule tubulin binding compounds of the invention. Binding of the compounds of the invention to tubulin causes tubulin depolymerization and/or inhibits tubulin polymerization. The tubulin binding compounds of the invention are therapeutically effective to inhibit cellular proliferation, for example, as effective anti-cancer agents.
The first embodiment of the invention are the compounds represented by the general formula I:
where
X is O, S, C, or NR
a
R
b
;
R is a saturated or unsaturated (C
7
-C
15
) hydrocarbon chain;
R
1
and R
2
are independently H, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkenyl, C
1
-C
6
)alkynyl, (C
3
-C
7
)cycloalkyl, aryl, or heteroaryl, and may be substituted or unsubstituted;
Y
1
and Y
2
are independently H, OH, SH, CN, halogen, acyl, (C
1
-C
6
) alkoxy, thioacyl, (C
1
-C
6
)alkylthio, or NR
a
R
b
, provided that Y
1
and Y
2
are not both hydrogen;
n is 1 to 3;
m is 0 to 10; and
each S is independently OH, SH, CO
2
H, halogen, CN, acyl, thioacyl, ester, thioester, alkoxy, aryloxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, (C
3
-C
7
)cycloalkyl, aryl, heteroaryl, C(═O)NR
a
R
b
, or NR
a
R
b,
, which may be substituted or unsubstituted. Taken together, two of S can form a ring, or any two adjacent S can form a double bond between two carbons to which they are attached. Any two adjacent carbons can form a double bond.
R
a
and R
b
are each independently hydrogen, acyl, alkyl, (C
3
-C
7
)cycloalkyl, aryl, or heteroaryl; or R
a
and R
b
together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino.
Preferred compounds of formula I are shown in the structures below:
The second embodiment of the invention are the compounds represented by the general formula VI:
where
R is a saturated or unsaturated (C
7
-C
15
) hydrocarbon chain;
Y is H, OH, SH, CN, halogen, acyl, (C
1
-C
6
)alkoxy, thioacyl, (C
1
-C
6
)alkylthio, or NR
a
R
b
; where R
a
and R
b
are each independently wherein R
a
and R
b
are each independently hydrogen, acyl, (C
1
-C
6
)alkyl, (C
3
-C
7
)cycloalkyl, aryl, or heteroaryl; or R
a
and R
b
together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino;
D is a (C
5
-C
12
) hydrocarbon comprising at least one heteroatom, and having at least one polar group; and
X comprises C, S, N, P, or O.
A Preferred compounds of formula VI is shown in the structure below:
Specific compounds, compositions, and methods for use of the binding pocket and compounds of the invention are shown more fully in the detailed description below.


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