Synthetic spiroketal pyranes as potent anti-cancer agents

Details Synthetic spiroketal pyranes as potent anti-cancer agents Synthetic spiroketal pyranes as potent anti-cancer agents

1999-06-29

2002-01-01

Lambkin, Deborah C. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S451000, C549S343000

Reexamination Certificate

active

06335364

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to novel tubulin depolymerization agents, SPIKET, as potent 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 and other cell proliferative disorders, 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
. Agents which induce depolymerization of tubulin and/or inhibit the polymerization of tubulin provide a therapeutic approach to the treatment of cell proliferation disorders such as cancer.
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 inhibition of cellular proliferation and treatment of cancer.
Spongistatin (SP) (
FIG. 1
) is a potent tubulin depolymerizing natural product isolated from an Eastern Indian Ocean sponge in the genus Spongia
7
. Spongistatins are 32-membered macrocyclic lactone compounds with a spongipyran ring system containing 4 pyran-type rings incorporated into two spiro[5.5]ketal moieties
7
. In cytotoxicity assays, spongistatin (SP) exhibited potent cytotoxicity with subnanomolar IC
50
values against an NCI panel of 60 human cancer cell lines
7
. SP was found to inhibit the binding of vinc alkaloids (but not colchicin) to tubulin
8
, indicating that the binding site for this potent tubulin depolymerizing agent may also serve as a binding region for vinc alkaloids.
Novel tubulin binding compounds, which, upon binding to tubulin, interfere with tubulin assembly, for example by causing depolymerization of tubulin or by inhibiting tubulin polymerization, would provide novel agents for the prevention of cellular proliferation, for example in the inhibition of tumor cell growth and 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 spiroketal pyrane compounds of the invention. Binding of the spiroketal pyranes (SPIKETs) to tubulin causes tubulin depolymerization, and/or inhibits tubulin polymerization. The siroketal pyranes of the invention are therapeutically effective as cytotoxic agents, to inhibit cellular proliferation, and as effective anti-cancer agents.
The compounds of the invention have the general structure shown in formula I, and are designed to include moieties and/or substitutions capable of favorable interaction with amino acid residues in the SPIKET binding pocket of tubulin. For example, R
1
, R
2
, S
1
, and S
2
preferably contain functional groups and/or substitutions designed to favor hydrophobic interaction and/or Van der Waals interaction with hydrophobic residues of the SPIKET binding pocket, as described more fully below.
wherein
X
1
, X
2
, and X
3
are the same or different, and are each independently O, C, or S;
R
1
and R
2
are the same or different and are each independently H, provided both R
1
and R
2
are not H, or (C
1
-C
8
)alkyl, (C
1
-C
8
)cycloalkyl, (C
1
-C
8
)alkoxy, (C
1
-C
8
)aryloxy, (C
1
-C
8
)arylthio, (C
1
-C
8
)aryl, (C
1
-C
8
)heteroaryl, C(=)NR
a
R
b
or NR
a
R
b
; wherein R
a
and R
b
are each independently hydrogen, acyl, (C
1
-C
8
)alkyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl, or (C
6
-C
10
)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;
n and m are the same or different, and are each independently 0 to 7;
S
1
and S
2
can be the same or different, and are each independently OH, SH, CO
2
H, halogen, CN, acyl, thioacyl, ester, thioester, (C
1
-C
6
)alkoxy, (C
1
-C
6
)aryloxy, (C
1
-C
6
)alkylthio, (C
1
-C
6
)arylthio, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkenyl, (C
1
-C
6
)alkynyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl, or (C
6
-C
10
)heteroaryl, C(═O)NR
a
R
b
or NR
a
R
b
; wherein R
a
and R
b
are each independently hydrogen, acyl, (C
1
-C
6
)alkyl, (C
3
-C
7
)cycloalkyl, (C
6
-C
10
)aryl, or (C
6
-C
10
)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;
taken together, any two S
1
and S
2
can form a ring, and any two adjacent substituents can form a double bond between the two carbons to which they are attached. The hydrocarbon moieties of R
1
, R
2
, S
1
, and S
2
may be substituted or unsubstituted.
Particular embodiments of the claimed compounds, for example, those compounds depicted in formulae II-V and preferred compounds of the invention are described below in the Detailed Description, Examples, and Claims. Particularly preferred compounds of the invention are:
[(2R,8R)-8-(hydroxymethyl)-1,7-dioxaspiro[5,5]undec-2-yl]methan-1-ol(SPIKET-P1);
Benzyl-protected SPIKET-P1 (SPIKET-P1-P); and
1,13-dibenzyloxy-5,9-dihydroxy-spiroketal (NP25).
The compounds of the invention are combined with a suitable carrier to form compositions suitable for use in binding tubulin, inducing depolymerization of tubulin, inhibiting proliferation of cells, and in the treatment of cancer.
The SPIKET binding pocket on tubulin is useful for designing and screening tubulin binding molecules, anti-cell proliferation agents, and cancer therapeutic agents. Useful agents are designed to fit the pocket and to favorably interact with the pocket for enhanced binding and anti-tubulin activity.
Additional embodiments of the invention are described more fully below.


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patent: 5322854 (1994-06-01), Isono et al.
patent: 0 491 956 (1992-07-01), None
Avila, J., (1992),Life Sci., 50(5): 327-334 “Microtubule Functions ”.
Bai, R. et al., (Oct. 1993),Molecular Pharmacology, 44(4):757-766 “Spongistatin 1, a Highly Cytotoxic, Sponge—Derived, Marine Natural Product that Inhibits Mitosis, Microtubule Assembly, and the Binding of Vinblastine to Tubulin”.
Bai, R. et al., (Aug. 1, 1995),Biochemistry, 34(30):9714-9721 “The Spongistatins, Potently Cytotoxic Inhibitors of Tubulin Polymerization, Bind in a Distinct Region of the Vinca Domain”.
Böhm, H., (Dec. 1992),J. Comput. Aided Mol. Des., 6(6):593-606 “LUDI: rule—based automatic design of new substituents for enzyme inhibitor leads”.
Böhm, H., (Jun. 1994),J. Comput. Aided Mol. Des., 8(3):243-256 “The development of a simple empirical scoring function to estimate the binding constant for a protein—ligand complex of known three—dimensional structure”.
Cohen, T. et al., (Mar. 2, 1990),J. Org. Chem., 55(5):1528-1536 “Synthetically Useful &bgr;—Lithioalkoxides from Reductive Lithiation of Epoxides by Aromatic Radical An

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