Tubulin binding ligands and corresponding prodrug constructs

Details Tubulin binding ligands and corresponding prodrug constructs Tubulin binding ligands and corresponding prodrug constructs

2001-03-12

2003-07-15

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ether doai

C568S633000, C564S443000, C558S197000

Reexamination Certificate

active

06593374

ABSTRACT:

BACKGROUND
Tubulin is currently among the most attractive therapeutic targets in new drug design for the treatment of solid tumors. The heralded success of vincristine and taxol along with the promise of combretastatin A-4 (CSA-4) prodrug and dolastatin 10, to name just a few, have firmly established the clinical efficacy of these antimitotic agents for cancer treatment.
An aggressive chemotherapeutic strategy toward the treatment and maintenance of solid-tumor cancers continues to rely on the development of architecturally new and biologically more potent anti-tumor, anti-mitotic agents which mediate their effect through a direct binding interaction with tubulin. A variety of clinically-promising compounds which demonstrate potent cytotoxicity and antitumor activity are known to effect their primary mode of action through an efficient inhibition of tubulin polymerization.
1
This class of compounds undergoes an initial interaction (binding) to the ubiquitous protein tubulin which in turn arrests the ability of tubulin to polymerize into microtubules which are essential components for cell maintenance and division.
2
During metaphase of the cell cycle, the nuclear membrane has broken down and the cytoskeletal protein tubulin is able to form centrosomes (also called microtubule organizing centers) and through polymerization and depolymerization of tubulin the dividing chromosomes are separated. Currently, the most recognized and clinically useful members of this class of antimitotic, antitumor agents are vinblastine and vincristine
3
along with taxol.
4
Additionally, the natural products rhizoxin,
5
combretastatin A-4 and A-2,
6
curacin A,
1
podophyllotoxin,
7
epothilones A and B,
8
dolastatin 10
9
and welwistatin
10
(to name just a few) as well as certain synthetic analogues including phenstatin,
11
the 2-styrylquinazolin-4(3H)-ones (SQO),
12
and highly oxygenated derivatives of cis- and trans-stilbene
13
and dihydrostilbene are all known to mediate their cytotoxic activity through a binding interaction with tubulin. The exact nature of this binding site interaction remains largely unknown, and definitely varies between the series of compounds. Photoaffinity labeling and other binding site elucidation techniques have identified several key binding sites on tubulin: colchicine site, vinca alkaloid site, and a site on the polymerized microtubule to which taxol binds.
1a,14
An important aspect of this work requires a detailed understanding, on the molecular level, of the “small molecule” binding domain of both the &agr; and &bgr; subunits of tubulin. The tertiary structure of the &agr;,&bgr; tubulin heterodimer was reported in 1998 by Downing and co-workers at a resolution of 3.7 Å using a technique known as electron crystallography.
15
This brilliant accomplishment culminates decades of work directed toward the elucidation of this structure and should facilitate the identification of small molecule binding sites, such as the colchicine site, through techniques such as photoaffinity and chemical affinity labeling.
BRIEF DESCRIPTION OF THE INVENTION
We have developed a working hypothesis suggesting that the discovery of new antimitotic agents may result from the judicious combination of a molecular template (scaffold) which in appropriately substituted form (ie. phenolic moieties, etc.) interacts with estrogen receptor (ER), suitably modified with structural features deemed imperative for tubulin binding (arylalkoxy groups, certain halogen substitutions, etc.). The methoxy aryl functionality seems especially important for increased interaction at the colchicine binding site in certain analogs.
16
Upon formulation of this hypothesis concerning ER molecular templates, our initial design and synthesis efforts centered on benzo[b]thiophene ligands modeled after raloxifene, the selective estrogen receptor modulator (SERM) developed by Eli Lilly and Co.
17
Our initial studies resulted in the preparation of a very active benzo[b]thiophene-based antitubulin agent.
18-21
In further support of our hypothesis, recent studies have shown that certain estrogen receptor (ER) binding compounds as structurally modified estradiol congeners (2-methoxyestradiol, for example) interact with tubulin and inhibit tubulin polymerization.
22
Estradiol is, of course, perhaps the most important estrogen in humans, and it is intriguing and instructive that the addition of the methoxy aryl motif to this compound makes it interactive with tubulin. It is also noteworthy that 2-methoxyestradiol is a natural mammalian metabolite of estradiol and may play a cell growth regulatory role especially prominent during pregnancy. The term “phenolic moiety” means herein a hydroxy group when it refers to an R group on an aryl ring.


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