Disulfone reagents and methods of preparing and using same

Details Disulfone reagents and methods of preparing and using same Disulfone reagents and methods of preparing and using same

2002-11-05

2004-11-02

Riley, Jezia (Department: 1637)

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus containing

C568S028000, C514S001000

Reexamination Certificate

active

06812365

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to sulfone phosphonate compounds and their use in organic synthesis and, more particularly, to disulfone bis-phosphonates and their preparation and use as reagents in the synthesis of biologically relevant disulfones.
BACKGROUND OF THE INVENTION
Enzymes are biological catalysts which mediate the great majority of biochemical reactions that occur in living organisms. Enzymatically catalyzed reactions typically result in higher reaction rates, under milder reaction conditions, with much greater reaction specificity than other chemical reactions. The specific geometric configuration and identity of the chemical elements that create the reacting group of a reactant or substrate for a particular enzyme are important factors affecting whether that enzyme can catalyze a given reaction. Typically, the amino acids which constitute the enzyme's substrate-binding site form a pocket, or cleft, in the surface of the enzyme which is geometrically and electronically complementary to the particular shape and charge distribution of the substrate's functional groups. Thus, a substrate having the wrong charge distribution, stereochemistry, chirality, et cetera will not fit into the enzymatic binding site.
The highly specific nature of enzyme-substrate binding renders enzymatic reactions particularly susceptible to influence by other substances. Compounds that can combine with an enzyme and/or its substrate may affect either substrate binding or the enzyme's turnover rate. A compound which reduces enzymatic activity by either of these methods is referred to as an inhibitor. In many cases, enzyme inhibitors structurally resemble an enzyme's natural substrate in at least some respects, but the reaction catalyzed by the enzyme when it is bound to its natural substrate either cannot achieve its normal product or will do so at a considerably reduced rate. Such inhibitors are frequently referred to as analogs. Inhibitors can act through several mechanisms, two of which are competitive inhibition and noncompetitive inhibition.
A compound can be a competitive inhibitor of an enzyme if that compound competes directly with a natural substrate for an enzyme's binding site. Structurally, this type of inhibitor usually is sufficiently similar to the normal or natural substrate to enable binding to the enzyme active site, but the inhibitor differs from the natural substrate in that it is comparatively unreactive when bound to the enzyme. Since most competitive inhibitors reversibly bind their target enzyme, such compounds tend to reduce the cellular concentrations of free enzyme available for natural substrate binding, thereby inhibiting productive enzymatic activity and reducing the availability of enzyme reaction products. Inhibitors which irreversibly bind an enzyme active site are referred to as inactivators, or suicide inhibitors, and their effects on free enzyme concentration levels are much longer lived.
A substance may be deemed a noncompetitive inhibitor of an enzyme if the substance can bind the enzyme-substrate complex directly but cannot bind the free enzyme. This inhibitory mechanism likely functions by distorting the structure of the active site and rendering the enzyme incapable of catalyzing the reaction with the substrate. A noncompetitive inhibitor need not resemble the substrate at all, for it has no affect on an enzyme's ability to bind the natural substrate. As such, the noncompetitive inhibitor acts by interfering with an enzyme's catalytic function, not its ability to bind its natural substrate. Since substrate binding is relatively unaffected, this type of inhibition is thought to occur more frequently in the case of multisubstrate enzymes, such as transferase enzymes which catalyze reactions that transfer a specific functional group from one substrate to another.
As enzymatic reactions often play an important role in a variety of biochemical pathways that affect biological systems, enzymes frequently are good targets for strategic efforts to affect disease processes, such as cancer, or viral invasions of a host system, such as by the human immunodeficiency virus (HIV). For example, small cell lung cancer (SCLC), a highly malignant carcinoma that is prevalent in cigarette smokers, has been found to be particularly sensitive to chemotherapy, and there are a number of combination therapies currently in clinical use. Chemotherapeutic agents currently under investigation include camptothecan derivatives, which have been found to inhibit DNA topoisomerase I, and taxol, which is an antitubular agent. While these therapies generally are thought to hold promise for inhibiting cancer cell growth and proliferation in a particular tissue or organ, they do not speak to the issue of cancer metastasis. Metastasis is the mechanism by which cancer cells travel or spread from one area of the body to other, often unrelated, areas, thereby resulting in the development of malignant tumors throughout the body. Tumor metastasis is believed to be one of the leading causes of cancer-related mortality. Since SCLC is a form of cancer that is characterized by early onset of metastatic spread, making it a very difficult cancer to cure, the development of new chemotherapeutics which target invasion and metastasis of malignant cells is a particularly important strategy for combating this type of cancer.
Generally, cancer develops in four principle stages: (1) initiation; (2) promotion of cell growth; (3) invasion and metastasis; and (4) death of the host. Initiation is characterized by hyperproliferation of cells which then continues during the growth stage. During invasion and metastasis, tumors form and the cancer spreads to other tissues. Different forms of cancer respond differently to the variety of treatment protocols, depending upon the type and developmental stage of the cancer. In the case of SCLC, for example, the three primary methods of treatment include surgical removal of cancerous tissue, radiation therapy, and chemotherapy.
Sialyl Lewis X is a cell surface glycoconjugate that serves as a recognition element in cancer metastasis. Structurally, sialyl Lewis X is a tetrasaccharide consisting of N-acetyl neuraminic acid (NeuAc) &agr;-(2→3) linked to galactose, which in turn is &bgr;-(1→4) linked to a glucosamine bearing an &agr;-(1→3) linked fucose residue. Sialyl Lewis X is synthesized in the Golgi apparatus, which is located in the cytoplasm of the cell. As illustrated by the following Reaction Equation,
preparation of sialyl Lewis X begins when an activated sialyl residue (CMP-NeuAc) is transferred to lactosamine using a 2→3-sialyl transferase enzyme. Subsequently, activated fucose (GDP-fucose) is transferred to the molecule by a fucosyl transferase enzyme. The resultant tetrasaccharide is then transported out of the Golgi and to the cell surface. Once at the cell surface, sialyl Lewis X serves as a cell recognition element for other molecules, such as selectin proteins (P-selectins), which are on the surface of other cells. Thus, cells having P-selectins at their surface, for example, are able to recognize and adhere to cells which have sialyl Lewis X on their surface. Studies have shown that selectin recognition of sialyl Lewis X at the cell surface is most efficient when both the fucosyl and sialyl residues are present on the sialyl Lewis X molecule. (See e.g., Einhorn L. H., Bond W. H., Hornback N., and Joe B. T. “Long-Term Results in Combined-Modality Treatment of Small Cell Carcinoma of the Lung.”
Sem. Oncol.
1978, 5, 309-313; Bolscher J., Bruyneel E., Rooy H., Schallier D., Marcel M., and Smets L. “Decreased Fucose Incorporation in Cell Surface Carbohydrates is Associated with Inhibition of Invasion.”
Clinical and Experimental Metastasis.
1989, 7(5), 557-569; Yamada N., Chung Y. S., Takatsuka S., Arimoto Y., Sawada T., Dohi T., and Sowa M. “Increased Sialyl Lewis A Expression and Fucosyl Transferase Activity with Acquisition of a High Metastatic Capacity in a Colon Cancer

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