Compounds for proteasome enzyme inhibition

Abstract

A compound having a formula III structure or a pharmaceutically acceptable salt thereof, wherein X is O; R1, R2, R3 and R4 are all hydrogen; R 5 and R 7 are independently C1-6 aralkyl optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxylic ester, thiol and thioether; and R6 and R8 are independently C1-6 alkyl substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxylic ester, thiol and thioether; where the term "C1-6 alkyl" refers to saturated hydrocarbon groups, including straight-chain alkyl groups and branched-chain alkyl groups containing 1 to 6 carbon atoms in the chain, including haloalkyl groups, the term "C1-6 aralkyl" refers to a C1-6 alkyl group substituted with an aryl group, and the term "aryl" includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is aromatic.

Description

Technical field This invention relates to compounds and processes for enzyme inhibition. In particular, the invention relates to compounds for use in therapeutic processes based on enzyme inhibition. Background of the invention In eukaryotes, protein degradation is predominantly mediated by the ubiquitin pathway, in which proteins marked for destruction are linked to the 76-amino-acid polypeptide ubiquitin. Once marked, ubiquitinated proteins then serve as substrates for the 26S proteasome, a multicatalytic protease that cleaves proteins into short peptides through its three main proteolytic activities. Although it has a general function in intracellular protein turnover, proteasome-mediated degradation also plays a key role in many processes, such as major histocompatibility complex (MHC) class I presentation, apoptosis, cell growth regulation, NF-κB activation, antigen processing, and inflammatory signal transduction. The 20S proteasome is a cylindrical, 700 kDa multicatalytic protease complex composed of 28 subunits arranged in four rings. In yeast and other eukaryotes, seven different α subunits form the outer rings, and seven different β subunits form the inner rings. The α subunits serve as binding sites for the 19S (PA700) and 11S (PA28) regulatory complexes, and also act as a physical barrier for the inner proteolytic chamber formed by the two β subunit rings.Thus, in vivo, the proteasome is believed to exist as a 26S particle (“the 26S proteasome”). In vivo experiments have shown that inhibition of the 20S form of the proteasome can be very easily correlated with inhibition of the 26S proteasome. Cleavage of the amino-terminal prosequences of the β subunits during particle formation exposes the amino-terminal threonine residues, which serve as the catalytic nucleophiles. The subunits responsible for catalytic activity in proteasomes thus possess an amino-terminal nucleophilic residue, and these subunits belong to the family of N-terminal nucleophilic (Ntn) hydrolases (where the N-terminal nucleophilic residue is, for example, Cys, Ser, Thr, and other nucleophilic residues). This family includes, for example, penicillin G acylase (PGA), penicillin V acylase (PVA), glutamine PRP amidotransferase, and Bacterial glycosylasparaginase.In addition to the ubiquitously expressed β subunits, higher vertebrates also possess three interferon-α-inducible β subunits (LMP7, LMP2, and MECL1), which replace their normal homologs, X, Y, and Z, respectively, thereby altering the catalytic activities of the proteasome. Through the use of different peptide substrates, three main proteolytic activities have been defined for the eukaryotic 20S proteasome: chymotrypsin-like (CTL) activity, which cleaves downstream of large hydrophobic residues; trypsin-like (TL) activity, which cleaves downstream of basic residues; and peptidylglutamyl peptide-hydrolyzing (PGPH) activity, which cleaves downstream of acidic residues. Two additional, less well-characterized activities have been attributed to the proteasome: BrAAP activity, which cleaves downstream of branched amino acids; and SNAAP activity, which cleaves after small neutral amino acids.The main proteolytic activities of the proteasome appear to be contributed by different catalytic sites, since inhibitors, point mutations in the β subunits, and interferon-Σ-induced β subunit exchange alter these activities to varying degrees. There are several examples of small molecules that have been used to inhibit proteasome activity; however, these compounds generally lack the specificity, stability, or potency needed to explore and exploit the roles of the proteasome at the cellular and molecular level. Therefore, the synthesis of small-molecule inhibitor(s) with increased site specificity, improved stability and solubility, and increased potency is needed to enable the exploration of proteasome roles at the cellular and molecular level. For example, peptides as proteasome inhibitors are disclosed in document W001 / 28579, in Elofsson M. et al.: "Towards Subunit-Specific Proteasome Inhibitors: Synthesis and Evaluation of Peptide Alpha', Beta'-Epoxyketones", Chemistry and Biology, Current Biology, London, GB, volume 6, no. 11, 1995, pages 811-822; Myung J. et al.: "Lack of Proteasome Active Site Allostere as Revealed by Subunit-Specific Inhibitors", Molecular Cell, February 2001, volume 7, no. 2, February 2001 (2001-02), pages 411-420; and Myung et al.: "The Ubiquitin-Proteasome Pathway and Proteasome Inhibitors", Medicinal Research Reviews, New York, NY, US, volume 21, no.: 4, July 2001 (2001-07), pages 245-273. In addition, peptides as compounds for enzyme inhibition are disclosed in document W02005 / 105827, published on November 10, 2005. Summary of the invention The invention relates to classes of molecules known as α',β'-epoxide peptides. The parent molecules are understood to bind efficiently, irreversibly, and selectively to N-terminal nucleophilic hydrolases (Ntn) and can specifically inhibit particular activities of enzymes that have multiple catalytic activities. It was once thought that the proteasome consisted merely of denatured and misfolded proteins; however, it is now accepted that the proteasome constitutes a proteolytic machinery that regulates the levels of various intracellular proteins through their signal-dependent degradation. Thus, there is great interest in identifying reagents that can specifically disrupt the activities of the proteasome and other Ntn hydrolases and therefore be used as probes to study the role of these enzymes in biological processes. This paper describes, synthesizes, and investigates compounds that target Ntn hydrolases. Peptide epoxides that can potently, selectively, and irreversibly inhibit specific proteasome activities are described and claimed. Unlike several other peptide-based inhibitors, the peptide epoxides described herein are not expected to substantially inhibit non-proteasomal proteases such as trypsin, chymotrypsin, cathepsin B, papain, and calpain at concentrations up to 50 µM. At higher concentrations, inhibition may be observed, but it would be expected to be competitive and not irreversible, if the inhibitor simply competes with the substrate. The novel peptide epoxides are also expected to inhibit NF-κB activation and stabilize p53 levels in cell culture. Furthermore, these compounds are expected to have anti-inflammatory activity. Thus, these compounds may be unique molecular probes, offering the versatility to explore the function of non-transient enzymes in normal biological and pathological processes. In one aspect, the invention provides inhibitors comprising a three-membered ring containing a heteroatom as defined by Formula III below. These inhibitors can inhibit the catalytic activity of N-terminal nucleophilic hydrolase enzymes (e.g., the 20S proteasome or the 26S proteasome) when the inhibitor is present at concentrations below approximately 50 µM. With respect to the 20S proteasome, the particular hydrolase inhibitors inhibit chymotrypsin-like activity of the 20S proteasome when the inhibitor is present at concentrations below approximately 5 µM and do not inhibit trypsin-like or PGPH activity of the 20S proteasome when the inhibitor is present at concentrations below approximately 5 µM. The hydrolase inhibitor is an α',β'-epoxyketone peptide. The peptide may include branched and unbranched side chains such as C1.6 alkyl, C1.6 hydroxyalkyl, C1.6 alkoxyalkyl.6, aryl, C1.6 aralkyl, C1.6 alkylamide, C1.6 alkylamine, C1.6 carboxylic acid, C1.6 carboxylic ester, C1.6 alkylthiol, or C1.6 alkylthioether, for example isobutyl, phenylmethyl, and 2-phenylethyl. The α'-carbon of the α',΢'-epoxyketone may be a chiral carbon atom, such as a carbon configured (R) or ΢, as these are defined herein. In another aspect, the invention provides pharmaceutical compositions, including a pharmaceutically acceptable vehicle and a pharmaceutically effective amount of the hydrolase inhibitor, that improve the effects of neurodegenerative disease (such as Alzheimer's disease), muscular atrophy diseases, cancer, chronic infectious diseases, fever, muscle inactivity, denervation, nerve damage, fasting, and immune system-related conditions, among others. In another aspect, the invention provides anti-inflammatory compositions. In another aspect, the invention provides compounds for use in the following: inhibiting or reducing HIV infection in a subject; affecting the level of viral gene expression in a subject; altering the diversity of antigenic peptides produced by the proteasome in an organism; determining whether a cellular, developmental, physiological, or production process in an organism is regulated by the proteolytic activity of a particular Ntn hydrolase; treating Alzheimer's disease in a subject; reducing the rate of intracellular protein degradation in a cell; reducing the rate of p53 protein degradation in a cell; inhibiting the growth of p53-related cancers in a subject; inhibiting antigen presentation in a cell; suppressing the immune system of a subject; inhibiting IKBα degradation in an organism; reducing the NF-κB content in a cell, muscle, organ, or subject; and affecting cyclin-dependent eukaryotic cell cycles.to treat proliferative disease in a subject; to affect proteasome-dependent regulation of oncoproteins in a cell; to treat cancer growth in a subject; and to treat p53-related apoptosis in a subject. Each of these uses involves administering or contacting an effective amount of a composition comprising the hydrolase inhibitors described herein to a subject, cell, tissue, organ, or organism. Other features and advantages of the invention will be apparent from the following detailed description and the claims. Detailed description of the invention The invention involves compounds useful as enzyme inhibitors. These compounds are generally useful for inhibiting enzymes that have a nucleophilic group at their N-terminal end. For example, the activities of enzymes or enzyme subunits that have N-terminal amino acids with nucleophiles in their side chains, such as threonine, serine, or cysteine, can be successfully inhibited by the enzyme inhibitors described herein. The activities of enzymes or enzyme subunits that do not have any amino acid nucleophilic group at their N-terminal ends, such as, for example, protecting groups or carbohydrates, can also be successfully inhibited by the enzyme inhibitors described herein. Although the inventors of the present invention are not bound to any particular theory of action, it is believed that such N-terminal nucleophiles of Ntn form covalent adducts with the epoxide functional group of the Enzyme inhibitors described herein. For example, in the β35 / Pre2 subunit of the 20S proteasome, the N-terminal threonine is believed to irreversibly form a morpholino adduct upon reaction with a peptide epoxide such as those described below. Such adduct formation would involve ring-opening cleavage of the epoxide. In embodiments including such groups attached to κ' carbons, the stereochemistry of the α' carbon (that carbon forming part of the epoxide ring) may be (R) or (S). The invention is based, in part, on the structure-function information disclosed herein, which suggests the following preferred stereochemical relationships.Note that a preferred compound may have a number of stereocenters having the above-below relationship (or â-á, where â as drawn here is above the plane of the page) or (R) - (S) (i.e., it is not required that every stereocenter in the compound be set according to the preferences). In some preferred embodiments, the stereochemistry of carbon á' is (R), i.e., atom X is â, or is above the plane of the molecule. With respect to stereochemistry, the Cahn-Ingold-Prelog rules are followed to determine absolute stereochemistry. These rules are described, for example, in Organic Chemistry, Fox and Whitesell; Jones and Bartlett Publishers, Boston, MA (1994); Section 5-6, pages 177-178. Peptides may have a repeating backbone structure with side chains extending from the backbone units. Generally, each backbone unit has one side chain associated with it, although in some cases, the side chain is a hydrogen atom. Side chains extending from backbone units may include aliphatic or aromatic amino acid side chains, such as methyl (alanine), isopropyl (valine), sec-butyl (isoleucine), isobutyl (leucine), and phenylmethyl (phenylalanine). Side chains may also be other branched or unbranched aliphatic groups such as ethyl, n-propyl, n-butyl, t-butyl, and aryl-substituted derivatives such as 1-phenylethyl, 2-phenylethyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, and similar compounds. In some embodiments, polar or charged residues can be incorporated into peptide epoxides. For example, naturally occurring amino acids such as those containing sulfur (Met, Cys) can be incorporated, as well as non-essential amino acids such as citrulline, cystine, ornithine, norleucine, and others.Side-chain substituents not found in nature with charged or polar moieties may also be included, such as, for example, C1-6 sulfide, thio, carboxyl, ester, amido, or amino groups, or such substituents substituted with one or more halogen atoms. In some preferred embodiments, at least one aryl group is present on a side chain of the peptide moiety. The backbone units are amide units [-NH-CHR-C (=O) -], in which R is the side chain. In further embodiments that employ amino acid groups, D amino acids can be used. The subject compounds have a Formula III structure or a pharmaceutically acceptable salt thereof, ** (See formula) ** III wherein X is O; R1, R2, R3 and R4 are all hydrogen; and R6 and R8 are independently C1-6 alkyl and R5 and R7 are independently C1-6 aralkyl each of which is optionally substituted with a selected amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxylic ester, thiol and thioether group. In certain preferred embodiments, R6 and R8 are both isobutyl, R5 is phenylethyl, and R7 is phenylmethyl. In certain embodiments, a compound of formula III has the following stereochemistry: In preferred embodiments, the compound has a structure of formula IV or a pharmaceutically acceptable salt thereof, ** (See formula) ** ** (See formula) ** wherein X is O; R1, R2, R3 and R4 are all hydrogen; and R6 and R8 are independently selected from C1-6 alkyl substituted with a selected amide group, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxylic ester, thiol, and thioether. In certain preferred embodiments, R6 and R8 are both isobutyl. In certain embodiments, a compound of formula III has the following structure: ** (See formula) ** The compounds of the invention can be used in or on a medical device, for example, a medical device that includes a composition described herein that includes an inhibitor having the structure of any one of formulas III or IV. In one embodiment, the composition is incorporated within a medical device. In certain embodiments, the medical device is a gel comprising a polymeric or ceramic matrix and an inhibitor. This polymer may be naturally occurring or synthetic. In another embodiment, this gel serves as a drug reservoir, adhesive, suture, barrier, or sealant. Another aspect relates to a medical device comprising a substrate having a surface on which an inhibitor having a structure of any one of formulas II or IV is disposed. In one embodiment, the inhibitor is disposed directly on a medical device. In another embodiment, a coating is thus disposed, the coating comprising a polymeric or ceramic matrix with an inhibitor having a structure of any one of formulas III or IV dispersed or dissolved therein. In one embodiment, the medical device is a coronary, vascular, peripheral, or biliary endoprosthesis. More particularly, the endoprosthesis is an expandable endoprosthesis. When coated with a matrix containing an inhibitor having a structure of any one of formulas III or IV, the matrix is ​​flexible to accommodate the compressed and expanded states of such an expandable endoprosthesis. In another embodiment, the endoprosthesis has at least one insertable or implantable portion within a patient's body, wherein the portion has a surface adapted for exposure to body tissue and wherein at least a portion of the surface is coated with an inhibitor having a structure of any one of formulas III or IV, or has dispersed or dissolved therein a coating comprising a matrix having an inhibitor having a structure of any one of formulas III or IV.An example of a suitable device is described in United States Patent No. 4,733,665. In another embodiment, the medical device is a surgical implement such as a vascular implant, an intraluminal device, a surgical sealant, or a vascular scaffold. More particularly, the medical device is a catheter, an implantable vascular access port, a central venous catheter, an arterial catheter, a vascular graft, an intra-aortic balloon pump, a suture, a ventricular assist device, a drug elution barrier, an adhesive, a vascular coating, an extra / perivascular scaffold, a blood filter, or a filter adapted for use in a blood vessel, coated with an inhibitor having a structure of any one of Formulas III or IV. In certain embodiments, the intraluminal medical device is coated with an inhibitor having a structure of any one of formulas III or IV, a coating comprising a biologically tolerated matrix and an inhibitor having a structure of any one of formulas III or IV dispersed in the polymer, said device having an inner surface and an outer surface, the coating being applied to at least a portion of the inner surface, the outer surface, or both. In certain embodiments, the medical device may be useful in preventing restenosis after angioplasty. The medical device may be useful for the treatment of various diseases and conditions by providing the localized delivery of an inhibitor having a structure of either Formula III or IV. Such diseases and conditions include restenosis, inflammation, rheumatoid arthritis, tissue damage due to inflammation, hyperproliferative diseases, severe or arthritic psoriasis, amyotrophic diseases, chronic infectious diseases, abnormal immune response, conditions involving vulnerable plaques, damage related to ischemic conditions, and viral proliferation and infection.Examples of diseases and conditions that are treated with the drug-coated medical devices of the present invention include atherosclerosis, acute coronary syndrome, Alzheimer's disease, cancer, fever, muscle wasting (atrophy), denervation, vascular occlusions, stroke, HIV infection, nerve damage, renal failure associated with acidosis, and hepatic failure. See, for example, Goldberg, U.S. Patent No. 5,340,736. The term "Cx-y alkyl" refers to saturated hydrocarbon groups, including straight-chain alkyl groups and branched-chain alkyl groups containing x and y carbon atoms in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. The terms "C2.y alkenyl" and "C2.y alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond, respectively. The term "alkoxy" refers to an alkyl group that has an oxygen atom bonded to it. Alkoxy groups Representative examples include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently bonded by an oxygen atom. Accordingly, the substituent on an alkyl group that makes that alkyl group an ether is, or resembles, an alkoxy. The term "C1-6 alkoxyalkyl" refers to a C1-6 alkyl group substituted with an alkoxy group, thus forming an ether. The term "C1-6 aralkyl", as used herein, refers to a C1-6 alkyl group substituted with an alkyl group. The terms "amine" and "amino" are recognized by the technique and refer to both unsubstituted and substituted amines as well as their salts, for example, a residue that can be represented by the general formulas: ** (See formula) ** either wherein R9, R10, and R10' each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)mR8, or R9 and R10 taken together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure; R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, or a polycyclyl; and m is zero or an integer from 1 to 8. In preferred embodiments, only one of R9 or R10 may be a carbonyl, e.g., R9, R10, and the nitrogen together do not form an imide. In still more preferred embodiments, R9 and R10 (and optionally R10') each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R8. In certain embodiments, the amino group is basic, meaning that the protonated form has a pKa of 7.00. The terms "amide" and "amido" are recognized in the art and include a residue that can be represented by the general formula: ** (See formula) ** wherein R9 and R10 are as defined above. Preferred embodiments of the amide will not include imides 15 that may be unstable. The term "aryl" as used herein includes single-ring aromatic groups of 5-, 6-, and 7-membered rings in which every ring atom is carbon. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings, and in which at least one of the rings is aromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, and the like. The terms "carbocycle" and "carbocyclyl," as used herein, refer to a substituted or unsubstituted non-aromatic ring in which every ring atom is carbon. The terms "carbocycle" and "carbocyclyl" also include polycyclic ring systems having two or more cyclic rings in which one or more carbon atoms are common to two adjacent rings, and in which at least one of the rings is carbocyclic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. The term "carbonyl" is recognized in the art and includes residues such as those that can be represented by the general formula: ** (See formula) ** either wherein X is a bond or represents an oxygen or a sulfur atom and R11 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R8, or a pharmaceutically acceptable salt, R11' represents a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R8, where m and R8 are as defined above. Where X is an oxygen atom and R11 or R11' is not a hydrogen atom, the formula represents an "ester". Where X is an oxygen atom, and R11 is a hydrogen atom, the formula represents a "carboxylic acid". As used herein, "enzyme" can be a partially or wholly protein molecule that catalyzes a chemical reaction. Such enzymes can be native enzymes, condensation enzymes, proenzymes, apoenzymes, denatured enzymes, farnesylated enzymes, ubiquitinated enzymes, fatty acylated enzymes, gerangeranylated enzymes, GPI-bound enzymes, lipid-bound enzymes, prenylated enzymes, naturally occurring or artificially generated mutant enzymes, enzymes with side-chain or backbone modifications, enzymes with leader sequences, and enzymes that form complexes with non-protein material, such as proteoglycans and proteoliposomes. Enzymes can be synthesized by any means, including natural expression, promoted expression, cloning, various solution-based and solid-based peptide syntheses, and similar procedures known to those skilled in the technique. The term "C1-6 heteroaryl", as used herein, refers to a C1-6 alkyl group substituted with a heteroaryl group. The term "heteroaryl" includes substituted and unsubstituted aromatic 5- to 7-membered ring structures, more preferably 5- to 6-membered rings, whose ring structures include one to four heteroatoms. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which is heteroaromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. The preferred heteroatoms are nitrogen, oxygen, phosphorus, and sulfur. The terms "heterocyclyl" or "heterocyclic group" refer to non-aromatic, substituted or unsubstituted, 3- to 10-membered ring structures, most preferably 3- to 7-membered rings, containing one to four heteroatoms. The terms "heterocyclyl" or "heterocyclic group" also include polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to two adjacent rings, at least one of which is heterocyclic. For example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The term "C1-6 hydroxyalkyl" refers to a C1-6 alkyl group substituted with a hydroxyl group. As used herein, the term "inhibitor" is intended to describe a compound that blocks or reduces the activity of an enzyme (e.g., inhibition of proteolytic cleavage of standard fluorogenic peptide substrates such as suc-LLVY-AMC, Caja-LLR-AMC, and Z-LLE-AMC, inhibition of various catalytic activities of the 20S proteasome). An inhibitor can act through competitive, uncompetitive, or non-competitive inhibition. An inhibitor can bind reversibly or irreversibly, and therefore the term includes compounds that are suicide substrates of an enzyme. An inhibitor can modify one or more sites in or near the enzyme's active site, or it can cause a conformational change elsewhere in the enzyme. As used herein, the term "peptide" includes not only standard amide linkages with standard substituents, but also commonly used peptidomimetics, other unmodified linkages, unmodified side chains, and side-chain modifications, as detailed below. The terms "polycycline" or "polycyclic" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more carbon atoms are common to two adjacent rings; for example, the rings are "fused rings." Each of the rings in the polycycle may be substituted or unsubstituted. The term "prevention" is recognized in the technique and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, or a complex syndrome such as kidney failure. or any other medical condition, is well understood in the art and includes the administration of a composition that reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject not receiving the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment relative to an untreated control population, and / or delaying the onset of detectable cancerous growths in a treated population relative to an untreated control population, for example, by a statistically and / or clinically significant amount. Infection prevention includes, for example, reducing the number of diagnoses of the infection in a treated population relative to an untreated control population, and / or delaying the onset of symptoms of the infection in a treated population relative to an untreated control population.Pain prevention includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population compared to an untreated control population. The term "prodrug" comprises compounds that, under physiological conditions, are converted into therapeutically active agents. A common procedure for preparing a prodrug involves including selected moieties that are hydrolyzed under physiological conditions to yield the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity of the host animal. The term "prophylactic or therapeutic" treatment is recognized in the art and includes the administration to the host of one or more of the subject compositions. If it is administered before the clinical manifestation of the undesired condition (e.g., disease or other undesired state of the host animal), then the treatment is prophylactic (i.e., it protects the host against the development of an undesired disease), whereas if it is administered after the manifestation of the undesired condition, the treatment is therapeutic (i.e., it is intended to lessen, improve, or stabilize the existing undesired condition or its side effects). The term "proteasome" as used herein is intended to include immunoproteasomes and constitutive proteasomes. The term "substituted" refers to residues having substituents that replace a hydrogen atom on one or more carbon atoms of the backbone. "Substitution" or "substituted with" is understood to include the implicit condition that such substitution is in accordance with the permitted valency of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents may be one or more, and may be the same or different for the appropriate organic compounds.For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valencies of the heteroatoms. Substituents may include, for example, a halogen group, a hydroxyl group, a carbonyl group (such as a carboxyl, alkoxycarbonyl, formyl, or acyl group), a thiocarbonyl group (such as a thioester, thioacetate, or thioformate), an alkoxy group, a phosphoryl group, a phosphate group, a phosphonate, an amino group, an amido group, an amidine, an imine, a cyano group, a nitro group, an azide group, a sulfhydryl group, an alkylthio group, a sulfate group, a sulfonate group, a sulfamoyl group, a sulfonamido group, a sulfonyl group, a heterocyclyl group, an aralkyl group, or an aromatic or heteroaromatic group. It shall be understood by those skilled in the art that substituted groups in the hydrocarbon chain may themselves be substituted, if appropriate. A "therapeutically effective amount" of a compound with respect to the procedure being treated refers to an amount of the compound(s) in a preparation that, when administered as part of a desired dosing regimen (for a mammal, preferably a human), relieves a symptom, improves a condition, or slows the onset of morbid conditions in accordance with clinically acceptable standards for the disorder or condition being treated or for the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment. The term "thioether" refers to an alkyl group, as defined above, having a sulfur moiety attached to it. In preferred embodiments, the "thioether" is represented by -S-alkyl. Representative thioether groups include methylthio, ethylthio, and the like. As used herein, the term “treating” or “treatment” means to reverse, reduce, or stop the symptoms, clinical signs, and underlying pathology of a condition so as to improve or stabilize a subject’s condition. 20S proteasome selectivity The enzyme inhibitors described herein are useful in part because they inhibit the action of the 20S proteasome. Furthermore, unlike other 20S proteasome inhibitors, the compounds described herein are highly selective for the 20S proteasome compared to other protease enzymes. That is, these compounds exhibit selectivity for the 20S proteasome over other proteases such as cathepsins, calpains, papain, chymotrypsin, trypsin, and tripeptidyl peptidase II. The selectivities of enzyme inhibitors for the 20S proteasome are such that at concentrations below approximately 50 µM, the enzyme inhibitors show inhibition of the catalytic activity of the 20S proteasome, while they do not show inhibition of the catalytic activity of other proteases such as cathepsins, calpains, papain, chymotrypsin, trypsin, tripeptidyl peptidase II.In preferred embodiments, the enzyme inhibitors exhibit inhibition of the catalytic activity of the 20S proteasome at concentrations below approximately 10 µM, while showing no inhibition of the catalytic activity of other proteases at these concentrations. In even more preferred embodiments, the enzyme inhibitors exhibit inhibition of the catalytic activity of the 20S proteasome at concentrations below approximately 1 µM, while showing no inhibition of the catalytic activity of other proteases at these concentrations. Enzyme kinetic assays are described in U.S. Patent Application No. 09 / 569748, Example 2, and in Stein et al., Biochem. (1996), 35, 3899–3908. Selectivity for Chymotrypsin-Like Activity The specific embodiments of the enzyme-inhibiting compounds described herein are additionally useful because they can efficiently and selectively inhibit the chymotrypsin-like activity of the 20S proteasome, as compared to the trypsin-like and PGPH activities. The chymotrypsin-like activity of the 20S proteasome is characterized by peptide cleavage in the immediate vicinity of large hydrophobic residues. In particular, the chymotrypsin-like activity of Ntn hydrolases in the proteasome can be determined by cleavage of a standard substrate. Examples of such substrates are known in the art. For instance, a leucylvalinyltyrosine derivative can be used. Enzyme kinetic assays are described in U.S. Patent Application No. 09 / 569748, Example 2, and in Stein et al., Biochem. (1996), 35, 3899–3908. Uses of Enzyme Inhibitors The biological consequences of proteasome inhibition are numerous. At the cellular level, the accumulation of polyubiquitinated proteins, cellular morphological changes, and apoptosis have been reported following cell treatment with various proteasome inhibitors. Proteasome inhibition has also been suggested as a potential antitumor therapeutic strategy. The fact that epoxomycin was initially identified in a screening for antitumor compounds validates the proteasome as an antitumor chemotherapeutic target. Accordingly, these compounds are useful for treating cancer. Proteasome inhibition has also been associated with inhibition of NF-κB activation and stabilization of p53 levels. Thus, the compounds of the invention can also be used to inhibit NF-κB activation and to stabilize p53 levels in cell culture.Since NF-κB is a key regulator of inflammation, it is an attractive target for anti-inflammatory therapeutic intervention. Thus, the compounds of the invention may be useful for the treatment of conditions associated with chronic inflammation, including, but not limited to, COPD, psoriasis, bronchitis, emphysema, and cystic fibrosis. The disclosed compounds can be used to treat conditions directly mediated by the proteolytic function of the proteasome, such as muscle wasting, or indirectly mediated by proteins processed by the proteasome, such as NF-κB. The proteasome participates in the rapid clearance and post-translational processing of proteins (e.g., enzymes) involved in cellular regulation (e.g., cell cycle, gene transcription, and metabolic pathways), intercellular communication, and the immune response (e.g., antigen presentation). Specific examples discussed later include β-amyloid protein and regulatory proteins such as cyclins, TGF-β, and the transcription factor NF-κB. Another embodiment of the invention relates to compounds disclosed herein for use in the treatment of neurodegenerative diseases and conditions, including, but not limited to, stroke, ischemic damage to the nervous system,neural trauma (e.g., percussive brain injury, spinal cord injury, and traumatic nervous system injury), multiple sclerosis and other immune-mediated neuropathies (e.g., Guillain-Barré syndrome and its variants, acute motor axonal neuropathy, acute inflammatory demyelinating polyneuropathy, and Fisher syndrome), HIV / AIDS dementia complex, axonomia, diabetic neuropathy, Parkinson's disease, Huntington's disease, multiple sclerosis, bacterial meningitis, parasitic meningitis, fungal meningitis, and viral meningitis, encephalitis, vascular dementia, multi-infarct dementia, Lewy body dementia, frontal lobe dementia such as Pick's disease, subcortical dementias (such as Huntington's disease or progressive supranuclear palsy), focal cortical atrophy syndromes (such as primary aphasia),Dementias of metabolic syndromes (such as chronic hypothyroidism or B12 deficiency) and dementias caused by infections (such as syphilis or chronic meningitis). Alzheimer's disease is characterized by extracellular deposits of β-amyloid protein (β-AP) in senile plaques and cerebral vessels. β-AP is a peptide fragment of 39 to 42 amino acids derived from an amyloid protein precursor (APP). At least three APP isoforms are known (695, 751, and 770 amino acids). Alternative mRNA splicing generates these isoforms; normal processing affects a portion of the β-AP sequence, thus preventing the generation of β-AP. Abnormal protein processing by the proteasome is thought to contribute to the abundance of β-AP in the Alzheimer's brain. The APP-processing enzyme in rats contains approximately ten different subunits (22 kDa–32 kDa). The 25 kDa subunit has an N-terminal sequence of X-Gln-Asn-Pro-Met-X-Thr-Gly-Thr-Ser, which is identical to the β subunit of human macropain (Kojima, S. et al., Fed. Eur. Biochem. Soc., (1992) 304: 57-60).The APP processing enzyme cleaves at the Gln15-Lys16 linkage; in the presence of calcium ion, the enzyme also cleaves at the Met-1-Asp1 linkage and the Asp1-Ala2 linkages to release the extracellular domain of β-AP. An embodiment, therefore, refers to compounds for use in treating Alzheimer's disease, including administering to a subject an effective amount of a compound (e.g., pharmaceutical composition) disclosed herein. Such treatment includes reducing the rate of β-AP plaque formation, reducing the rate of β-AP generation, and reducing the clinical signs of Alzheimer's disease. Other embodiments of the invention relate to cachexia and muscle wasting diseases. The proteasome degrades many proteins during reticulocyte maturation and fibroblast proliferation. In cells deprived of insulin or serum, the rate of proteolysis nearly doubles. Inhibition of the proteasome reduces proteolysis, thereby decreasing the loss of muscle proteins and the nitrogen load on the kidneys or liver. The inhibitors of the invention are useful for treating conditions such as cancer, chronic infectious diseases, fever, muscle inactivity (atrophy) and denervation, nerve damage, fasting, renal failure associated with acidosis, diabetes, and liver failure. See, for example, Goldberg, U.S. Patent No. 5,340,736.The embodiments of the invention therefore comprise compounds for use in reducing the rate of intracellular protein degradation in a cell; reducing the rate of intracellular protein degradation; reducing the rate of p53 protein degradation in a cell; and inhibiting the growth of p53-related cancers. Each of these uses includes contacting a cell (in vivo or in vitro, e.g., a muscle in a subject) with an effective amount of a compound (e.g., pharmaceutical composition) disclosed herein. Fibrosis is the excessive and persistent formation of scar tissue resulting from the hyperproliferative growth of fibroblasts and is associated with activation of the TGF-β signaling pathway. Fibrosis involves deposition Extensive extracellular matrix activity can occur virtually within any tissue or across several different tissues. Normally, the level of intracellular signaling protein (Smad) that activates transcription of target genes following TGF-β stimulation is regulated by proteasome activity (Xu et al., 2000). However, accelerated degradation of TGF-β signaling components has been observed in cancers and other hyperproliferative conditions. Thus, certain embodiments of the invention relate to compounds for use in treating hyperproliferative conditions such as diabetic retinopathy, macular degeneration, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, cirrhosis, biliary atresia, congenital heart failure, scleroderma, radiation-induced fibrosis, and pulmonary fibrosis (idiopathic pulmonary fibrosis, collagen vascular disease, sarcoidosis, interstitial lung diseases, and extrinsic lung disorders).The treatment of burn victims is often hampered by fibrosis; thus, a further embodiment of the invention is the topical and systemic administration of inhibitors for treating burns. Wound closure is often associated with disfiguring scarring, which can be avoided by inhibiting fibrosis. Thus, in certain embodiments, the invention relates to compounds for use in preventing or reducing scar formation. Another protein processed by the proteasome is NF-κB, a member of the Rel family of proteins. The Rel family of transcriptional activator proteins can be divided into two groups. The first group requires proteolytic processing and includes p50 (NF-κB1, 105 kDa) and p52 (NF-κB2, 100 kDa). The second group does not require proteolytic processing and includes p65 (RelA, Rel(c-Rel), and RelB). Both homo- and heterodimers can be formed by members of the Rel family; NF-κB, for example, is an ap50-p65 heterodimer. After phosphorylation and ubiquitination of IκB and p105, the two proteins are degraded and processed, respectively, to produce active NF-κB, which translocates from the cytoplasm to the nucleus. Ubiquitinated p105 is also processed by purified proteasomes (Palombella et al., Cell (1994) 78: 773-785).Active NF-KB forms a stereospecific enhancer complex with other transcriptional activators and, for example, HMG l (Y), which induces selective expression of a particular gene. NF-κB regulates genes involved in the immune and inflammatory response and in mitotic events. For example, NF-κB is required for the expression of the immunoglobulin light chain K gene, the IL-2 receptor alpha chain gene, the major histocompatibility complex class I gene, and a number of cytokine genes encoding, for example, IL-2, IL-6, granulocyte colony-stimulating factor, and IFN-κ (Palombella et al., Cell (1994) 78: 773-785). Some embodiments of the invention include compounds for use in affecting the expression level of IL-2, MHC-I, IL-6, TNF-α, IFN-κ, or any of the other proteins mentioned above, each use including administering to a subject an effective amount of a compound described herein. Complexes that include p50 are rapid mediators of acute inflammatory and immune responses (Thanos, D. and Maniatis, T., Cell (1995) 80: 529-532). NF-KB also participates in the expression of cell adhesion genes encoding E-selectin, P-selectin, ICAM, and VCAM-1 (Collins, T., Lab. Invest. (1993) 68: 499-508). One embodiment of the invention relates to compounds for use in inhibiting cell adhesion (e.g., E-selectin, P-selectin, ICAM, or VCAM-1-mediated cell adhesion), including contacting a cell with (or administering to a subject) an effective amount of a compound (or pharmaceutical composition) disclosed herein. Ischemia and reperfusion injury result in hypoxia, a condition characterized by a deficiency of oxygen reaching the body's tissues. This condition causes increased degradation of IK-B, thereby resulting in the activation of NF-κB (Koong et al., 1994). It has been shown that the severity of the resulting hypoxia can be reduced by administering a proteasome inhibitor (Gao et al., 2000; Bao et al., 2001; Pye et al., 2003). Therefore, certain embodiments of the invention relate to compounds for use in treating an ischemic condition or reperfusion injury, comprising administering an effective amount of a compound disclosed herein to a subject in need of such treatment.Examples of such conditions or damage include, but are not limited to, acute coronary syndrome (vulnerable plaques), occlusive arterial disease (cardiac, cerebral, peripheral arterial and vascular occlusions), atherosclerosis (coronary sclerosis, coronary artery disease), heart attacks, heart failure, pancreatitis, myocardial hypertrophy, stenosis and restenosis. NF-κB is also specifically added to the HIV promoter / enhancer. When compared to the Nef of mac239, the HIV regulatory protein Nef of pbjl 4 differs by two amino acids in the control protein kinase-binding region. The protein kinase is thought to signal phosphorylation of IκB, activating IκB degradation via the ubiquitin-proteasome pathway. After degradation, NF-κB is released into the nucleus, thereby enhancing HIV transcription (Cohen, J., Science, (1995) 267: 960). Two embodiments of the invention are compounds for use in inhibiting or reducing HIV infection in a subject and for use in decreasing the level of viral gene expression, each use including administering to the subject an effective amount of a compound described herein. The overproduction of lipopolysaccharide (LPS)-induced cytokines such as TNFα is considered central to processes associated with septic shock. Furthermore, it is generally accepted that the first step in LPS-induced cell activation is the binding of LPS to specific membrane receptors. The α- and β-subunits of the 20S proteasome complex have been identified as LPS-binding proteins, suggesting that LPS-induced signal transduction may be an important therapeutic target in the prevention and treatment of sepsis (Qureshi, N. et al., J. Immun. (2003) 171: 1515-1525). Therefore, in certain embodiments, the compounds of the invention can be used for TNFα inhibition to prevent and / or treat septic shock. Intracellular proteolysis generates small peptides for presentation to T lymphocytes to induce MHC class I-mediated immune responses. The immune system searches for autologous cells that are virally infected or have undergone oncogenic transformation. One embodiment relates to compounds for use in inhibiting antigen presentation on a cell, including exposing the cell to a compound described herein. A compound of the invention can be used to treat immune-related conditions such as allergies, asthma, organ / tissue rejection (graft-versus-host disease), and autoimmune diseases, including, but not limited to, lupus, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease).Thus, a further embodiment is a compound for use in suppressing a subject's immune system (e.g., inhibiting transplant rejection, allergies, autoimmune diseases, and asthma), including administering to the subject an effective amount of a compound described herein. Another embodiment is a procedure for altering the repertoire of antigenic peptides produced by the proteasome or other multicatalytic Ntns. For example, if the PGPH activity of the 20S proteasome is selectively inhibited, a different group of antigenic peptides will be produced by the proteasome and presented on MHC molecules on the cell surface. These peptides would be produced and presented either without any enzymatic inhibition or with, for example, selective inhibition of chymotrypsin-like activity of the proteasome. Certain proteasome inhibitors block both the degradation and processing of ubiquitinated NF-κB in vitro and in vivo. Proteasome inhibitors also block the degradation of IκBα and the activation of NF-κB (Palombella et al., Cell (1994) 78: 773-785; and Traenckner et al., EMBO J. (1994) 13: 5433-5441). One embodiment of the invention is a compound for use in inhibiting the degradation of IκBα, including contacting the cell with a compound described herein. A further embodiment is a compound for use in reducing the cellular content of NF-κB in a cell, muscle, organ, or subject, including contacting the cell, muscle, organ, or subject with a compound described herein. Other eukaryotic transcription factors that require proteolytic processing include general transcription factor TFIIA, herpes simplex virus accessory protein (host cell factor), virus-inducible IFN regulator factor 2 protein, and membrane-bound sterol regulatory element-binding protein 1. Other embodiments of the invention are compounds for use in affecting cyclin-dependent eukaryotic cell cycles, including exposing a cell (in vitro or in vivo) to a compound described herein. Cyclins are proteins involved in cell cycle control. The proteasome participates in cyclin degradation. Examples of cyclins include mitotic cells, G1 cyclins, and cyclin B. Cyclin degradation allows a cell to exit one phase of the cell cycle (e.g., mitosis) and enter another (e.g., division). All cyclins are believed to be associated with protein kinase p34.sup.cdc2 or related kinases. The signal that designates them as a target for proteolysis is located at amino acids 42-RAALGNISEN-50 (destruction box). There is evidence that the cyclic form is converted into a form vulnerable to ubiquitin ligase. A specific cyclin ligase is activated during mitosis (Ciechanover, A., Cell, (1994) 79: 13-21). Inhibition of the proteasome inhibits cyclin degradation and thus inhibits cell proliferation, for example, in cyclin-related cancers (Kumatori et al., Proc. Natl. Acad. Sci. U.S.A. (1990) 87: 7071-7075). One embodiment of the invention is a compound for use in treating a proliferative disease in a subject (for example, cancer, psoriasis, or restenosis), including administering to the subject an effective amount of a compound disclosed herein. The invention also comprises a compound for use in treating cyclin-related inflammation in a subject, including administering a therapeutically effective amount of a compound described herein. These are additional embodiments of compounds for use in affecting proteasome-dependent regulation of oncoproteins and procedures for treating or inhibiting cancer growth, each embodiment including exposing a cell (in vivo, for example, in a subject, or in vitro) to a compound described herein. E6 proteins derived from HPV-16 and HPV-18 stimulate ATP- and ubiquitin-dependent conjugation and degradation of p53 in raw reticulocyte lysates. The recessive oncogene p53 has been shown to accumulate at non-admissible temperatures in a cell line with a thermolabile mutated E1. Elevated levels of p53 can lead to apoptosis. Examples of proto-oncoproteins degraded by the ubiquitin system include c-Mos, c-Fos, and c-Jun. One embodiment is a compound for use in treating p53-related apoptosis, including administering an effective amount of a compound described herein to a subject. In another embodiment, the disclosed compounds are useful for the treatment of a parasitic infection, such as infections caused by parasitic protozoa. The proteasome of these parasites is considered to be primarily involved in cell differentiation and replication activities (Paugam et al., Trends Parasitol. 2003, 19(2): 5559). Furthermore, Entamoeba species have been shown to lose encystment ability when exposed to proteasome inhibitors (Gonzales et al., Arch. Med. Res. 1997, 28, Issue No.: 139-140). In certain such embodiments, the disclosed compounds are useful for the treatment of parasitic infections in humans caused by a selected parasitic protozoan of Plasmodium spp. (including P. falciparum, P. vivax, P. malariae and P. ovale, which cause malaria), Tr and panosoma spp. (including T. cruzi, which causes Chagas disease and T. brucei which causes African sleeping sickness), Leishmania spp. (including L.amazonensis, L. donovani, L. infantum, L. mexicana, etc.), Pneumocystis carinii (a protozoan known to cause pneumonia in AIDS patients and other immunocompromised patients), Toxoplasma gondii, Entamoeba histolytica, Entamoeba invadens, and Giardia lamblia. In certain embodiments, the described compounds are useful for the treatment of parasitic infections in animals and livestock caused by a selected parasitic protozoan from Plasmodium hermani, Cr and Ptosporidium spp., Echinococcus granulosus, Eimeria tenella, Sarcocystis neurona, and Neurospora crassa. Other useful compounds such as proteasome inhibitors in the treatment of parasitic diseases are described in WO 98 / 10779. In certain embodiments, the revealed compounds irreversibly inhibit proteasome activity in a parasite. Such irreversible inhibition has been shown to induce complete cessation of enzymatic activity without recovery in red and white blood cells. In certain embodiments, the long half-life of the blood cells may provide protection with regard to therapy against recurrent parasite exposures. In certain embodiments, the long half-life of the blood cells may provide prolonged protection with regard to chemoprophylaxis against future infection. It has also been shown that inhibitors that bind to the 20S proteasome stimulate bone formation in bone organ cultures. Furthermore, when such inhibitors were administered systemically to mice, certain proteasome inhibitors increased bone volume and bone formation by over 70% (Garrett, IR et al., J. Clin. Invest. (2003) 111: 1771-1782), thus suggesting that the ubiquitin-proteasome machinery regulates osteoblast differentiation and bone formation. Therefore, the compounds described may be useful in the treatment and / or prevention of diseases associated with bone loss, such as osteoporosis. Bone tissue is an excellent source of factors that can stimulate bone cells. Thus, bovine bone tissue extracts contain not only structural proteins responsible for maintaining bone integrity, but also biologically active bone growth factors that can stimulate bone cells to proliferate. Among these latter factors is a recently discovered family of proteins called bone morphogenetic proteins (BMPs). All of these growth factors have effects on other cell types as well as bone cells. Hardy, MH, et al., Trans Genet (1992) 8: 55-61, describes evidence that bone morphogenetic proteins (BMPs) are differentially expressed in hair follicles during development. Harris, SE, et al., J Bone Miner Res (1994) 9: 855-863, describes the effects of TGF-β on the expression of BMP-2 and other substances in bone cells.BMP-2 expression in mature follicles also occurs during maturation and after the cell proliferation period (Hardy et al. (1992) supra). Thus, the compounds of the invention may also be useful for stimulating hair follicle cell growth. Finally, the revealed compounds are also useful as diagnostic agents (e.g., in diagnostic kits or for use in clinical laboratories) to screen for proteins (e.g., enzymes, transcription factors) processed by Ntn hydrolases, including the proteasome. The revealed compounds are also useful as research agents for specifically binding to the X / MB1 subunit or the α chain and for inhibiting the proteolytic activities associated with it. For example, the activity of (and specific inhibitors of) other proteasome subunits can be determined. Most cellular proteins undergo proteolytic processing during maturation or activation. The enzyme inhibitors disclosed herein can be used to determine whether a cellular, developmental, or physiological process or yield is regulated by the proteolytic activity of a particular Ntn hydrolase. Such a procedure includes obtaining an organism, an intact cell preparation, or a cell extract; exposing the organism, cell preparation, or cell extract to a compound disclosed herein; exposing the compound-exposed organism, cell preparation, or cell extract to a signal; and monitoring the process or yield. The high selectivity of the compounds disclosed herein allows for the rapid and safe elimination of the Ntn (e.g., the 20S proteasome) in a given cellular, developmental, or physiological process. Administration The compounds prepared as described herein may be administered in various forms, depending on the disorder being treated and the patient's age, condition, and body weight, as is well known in the practice. For example, where the compounds are for oral administration, they may be formulated as tablets, capsules, granules, powders, and syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular, or subcutaneous), drip infusion preparations, or suppositories. For application via the ophthalmic mucous membrane, they may be formulated as eye drops or eye ointments.These formulations can be prepared by conventional means, and if desired, the active ingredient can be mixed with any conventional additive or excipient, such as a binder, disintegrant, lubricant, corrective, solubilizing agent, suspending aid, emulsifying agent, coating agent, cyclodextrin, and / or buffer. Although the dosage will vary depending on the symptoms, the patient's age and body weight, the nature and severity of the injury to be treated or prevented, the route of administration, and the drug form, a daily dosage of 0.01 to 2000 mg of the compound is generally recommended for an adult human patient, and this can be administered as a single dose or in divided doses. The amount of active ingredient that can be combined with a vehicle material to produce an individual pharmaceutical form will generally be the amount of the compound that produces a therapeutic effect. The precise timing and / or quantity of the compound that will provide the most effective results in terms of efficacy or treatment for a given patient will depend on the activity, pharmacokinetic properties, and bioavailability of a particular compound, the patient's physiological condition (including age, sex, type and stage of disease, general physical condition, responsiveness to a given dose, and type of medication), route of administration, and other factors. However, the above guidelines can be used as a basis for adjusting treatment, for example, to determine the optimal timing and / or quantity of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and / or timing. The phrase "pharmaceutically acceptable" is used in this document to refer to those compounds, materials, compositions, and / or pharmaceutical forms that are, according to sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and that correspond to a reasonable benefit-risk ratio. The phrase "pharmaceutically acceptable vehicle" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a solid or liquid filler, diluent, excipient, solvent, or encapsulating material. Each vehicle may be "acceptable" in the sense that it is compatible with the other ingredients and not harmful to the patient. Examples of materials that may serve as pharmaceutically acceptable vehicles include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes;(9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl acetate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other compatible non-toxic substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., they do not induce significant temperature increases when administered to a patient. The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of the inhibitor(s). These salts can be prepared in situ during the final isolation and purification of the inhibitor(s), or by separately reacting a purified inhibitor(s) in its free-base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and amino acid salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.) In other cases, the inhibitors useful in the present invention may contain one or more acid functional groups and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these cases refers to relatively non-toxic inorganic and organic base addition salts of the inhibitor(s). These salts may also be prepared in situ during the final isolation and purification of the inhibitor(s), or by separately reacting the purified inhibitor(s) in their free acid form with a suitable base, such as hydroxide or carbonate. or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali or alkaline earth salts include the salts of lithium, sodium, potassium, calcium, magnesium, and aluminum, and the like. Representative organic amines useful for the formation of addition salts of bases include ethylamine, diethylamine, ethylanediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and perfumes, preservatives and antioxidants may be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents such as nitric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Suitable oral formulations may be in the form of capsules, lozenges, pills, tablets, pastilles (using a flavored base, usually sucrose and gum arabic or tragacanth gum), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as lozenges (using an inert matrix, such as gelatin or glycerin, or sucrose and gum arabic), and / or as mouthwashes, and the like, each containing a predetermined amount of an inhibitor(s) as an active ingredient. A composition may also be administered as a rapid intravenous injection, an electuary, or a paste. In solid dosage forms for oral administration (capsules, tablets, pills, coated tablets, powders, granules and the like), the active ingredients are mixed with one or more pharmaceutically acceptable vehicles, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or expanders, such as starches, cyclidextrins, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolving retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate;(8) absorbents, such as kaolin clay and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. A tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate or crosslinked sodium carboxymethylcellulose), surfactant, or dispersing agent. Molded tablets can be manufactured by molding a powdered inhibitor(s) mixture moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as coated tablets, capsules, pills, and granules, may optionally be evaluated or prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation. They may also be formulated to provide slow or controlled release of the active ingredient using, for example, hydroxypropyl cellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes, and / or microspheres. They may be sterilized by, for example, filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or other sterile injectable media immediately before use.These compositions may optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferably, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of inclusion compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, wheat germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, colorings, perfumes, and preservatives. Suspensions, in addition to the active inhibitor(s), may contain suspending agents such as, for example, isostearyl ethoxylated alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof. Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more inhibitor(s) with one or more suitable non-irritating excipients or vehicles that They include, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active agent. Formulations that are suitable for vaginal administration also include formulations of pessaries, tampons, creams, gels, pastes, foams, or sprays containing such vehicles as are known in the art to be appropriate. Topical or transdermal pharmaceutical forms of an inhibitor(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable vehicle and any preservatives or buffers. or propulsion systems that may be required. Ointments, pastes, creams and gels may contain, in addition to inhibitor(s), excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to inhibitor(s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamine powder, or mixtures of these substances. Sprays may contain common propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane. The inhibitor(s) can alternatively be administered by aerosol. This is achieved by preparing an aqueous aerosol, a liposomal preparation, or solid or liquid particles containing the composition. A non-aqueous suspension (e.g., fluorocarbon propellant) can also be used. Sonic nebulizers are preferred because they minimize the agent's exposure to shear, which can result in degradation of the compound. Typically, an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional, pharmaceutically acceptable vehicles and stabilizers. The vehicles and stabilizers vary with the requirements of the particular composition, but typically include nonionic surfactants (Tweens, Pluronics, sorbitan esters, lecithin, Cremophores), pharmaceutically acceptable cosolvents such as polyethylene glycol, harmless proteins such as serum albumin, oleic acid, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions. Transdermal patches have the added advantage of providing controlled delivery of an inhibitor(s) to the body. Such dosage forms can be prepared by dissolving or dispersing the agent in an appropriate medium. Absorption enhancers can also be used to increase the flow of the inhibitor(s) through the skin. The rate of this flow can be controlled either by providing a rate-controlling membrane or by dispersing the inhibitor(s) in a polymeric matrix or gel. The pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more inhibitor(s) in combination with one or more pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, which may contain antioxidants, buffers, bacteriostatics, solutes that make the formulation isotonic with the blood of the desired recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous vehicles that may be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate flowability may be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The prevention of microbial activity can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and similar substances. It may also be desirable to include agents that adjust the tonicity, such as sugars, sodium chloride, and similar substances, in the compositions. Furthermore, prolonged absorption of the injectable dosage form can be achieved by the inclusion of absorption-retarding agents such as aluminum monostearate and gelatin. In some cases, to prolong the effect of a drug, it is desirable to slow its absorption from subcutaneous or intramuscular injection. For example, delayed absorption of a parenterally administered drug is achieved by dissolving or suspending the drug in an oily vehicle. Slow-release injectable formulations are prepared by forming microencapsulated matrices of inhibitor(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug-to-polymer ratio and the specific polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Stock injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissue. Antibiotic preparations can be administered orally, parenterally, topically, or rectally. They are, of course, given in forms appropriate for each route of administration. For example, they are administered as tablets or capsules; by injection, inhalation, eye lotion, ointment, suppository, or infusion; topically as a lotion or ointment; and rectally as suppositories. Oral administration is preferred. The phrases “parenteral administration” and “administer parenterally” as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. The phrases "systemic administration", "systemically administered", "peripheral administration", and "peripherally administered" as used herein mean the administration of a ligand, drug, or other distinct material directly into the central nervous system, such that it enters the patient's system and is thus subjected to metabolism and other similar processes, e.g., subcutaneous administration. This inhibitor / these inhibitors can be administered to humans and other animals by therapy by any suitable route of administration, including orally, nasally, such as by a spray, rectally, intravaginally, parenterally, intracisternally and topically, such as by powders, ointments or drops, including buccally and sublingually. Regardless of the route of administration selected, the inhibitor(s), which can be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated in pharmaceutically acceptable forms by conventional procedures for those skilled in the art. The actual dosage levels of the active ingredients in the pharmaceutical compositions of the invention can be varied in such a way as to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, a particular composition, and a particular mode of administration, without being toxic to the patient. The concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) used, and the route of administration. In general, the compositions of this invention can be provided in an aqueous solution containing approximately 0.1–10% w / v of a compound described herein, among other substances, for parenteral administration. Typical dosage ranges are from approximately 0.01 to approximately 50 mg / kg of body weight per day, given in 1–4 divided doses. Each of the divided doses may contain the same or different compounds of the invention. The effective dosage will depend on several factors, including the patient's general health, and the formulation and route of administration of the desired compound(s). Another aspect of the invention provides a combination therapy in which one or more therapeutic agents are administered with the proteasome inhibitor. Such combination therapy can be achieved by simultaneous, sequential, or separate dosing of the individual treatment components. In certain embodiments, a compound of the invention is administered together with one or more different proteasome inhibitor(s). In certain embodiments, a compound of the invention is administered concurrently with a chemotherapeutic agent. Suitable chemotherapeutic agents may include natural products such as vinca alkaloids (i.e., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (i.e., etoposide, teniposide), antibiotics (dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithracin), and mitomycin, enzymes (L-asparaginase, which systemically metabolizes L-asparagine and deprives cells that lack the ability to synthesize their own asparagine of it); and antiplatelet agents.antiproliferative / antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogues, melphalan, chlorambucil), ethyleneimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates (busulfan), nitrosoureas (carmustine (BCNU) and analogues, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogues (methotrexate), pyrimidine analogues (fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine); aromatase inhibitors (anastrozole, exemestane and letrozole); and platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; histone deacetylase (HDAC) inhibitors (trichostatin, sodium butyrate, apicidan, hydroamic acid suberoyl anilide);Hormones (i.e., estrogen) and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (goserelin, leuprolide, and triptorelin). Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbin, or any analogue or variant derivative thereof. In certain embodiments, a compound of the invention is co-administered with a cytokine. Cytokines include, but are not limited to, interferon-α, -α, and -β, interleukins 1-8, 10, and 12, granulocyte colony-stimulating factor (GM-CSF), TNF-α and -β, and TGF-β. In certain embodiments, a compound of the invention is administered together with a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclometasone, betamethasone, budesonide, chlorprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidenum acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, parametasone, prednicarbate, prednisolone,Prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednilide, rimexolone, tixocortol, triamcinolone, triamcinolone acetonite, triamcinolone benetonide, triamcinolone hexacetonide and salts and / or derivatives thereof. In certain embodiments, a compound of the invention is administered concurrently with an immunotherapeutic agent. Suitable immunotherapeutic agents may include, but are not limited to, MDR modulators (verapamil, valsporid, biricodar, tariquidar, laniquidar), cyclosporine, thalidomide, and monoclonal antibodies. Monoclonal antibodies may be either bare or conjugated, such as rituximab, tositumomab, alemtuzumab, epratuzumab, ibritumomab, tiuxethane, gemtuzumab, ozogamicin, bevacizumab, cetuximab, erlotinib, and trastuzumab. Example Scheme 1: Summary of Example 1 (Reference) ** (See formula) ** Summary of (A) To a solution of N-Boc leucine (19.81 g, 85.67 mmol, 1.0 eq.) and benzyl phenylalanine ester (25.0 g, 85.67 mmol, 1.0 eq.) in 900 mL of MeCN, DIEA (44.29 g, 60 mL, 342.68 mmol, 4.0 eq.) was added, and the mixture was cooled to 0°C in an ice bath. HOBT (18.52 g, 137.08 mmol, 1.6 eq) was added to this mixture, followed by PyBOP (71.33 g, 137.08 mmol, 1.6 eq), which was added in several parts over five minutes. The reaction was carried out under an argon atmosphere and stirred overnight. The volatile products were removed under reduced pressure, and the remaining material was carried in 500 mL of EtOAc and washed with saturated NaHCO3, H2O, and brine, then dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. To a cooled solution of 70% TFA / DCM (150 mL), BocNHLeuPheOBz (25.0 g, 53.35 mmol, 1.0 eq.) was added.The solution was stirred and allowed to warm to room temperature for 2 hours, during which time the mixture was concentrated and placed under high pressure for 2 hours, yielding the TFA salt of the dipeptide amine. BocNHhPheCO2H (14.68 g, 53.35 mmol, 1.0 eq.), 550 ml of MeCN, and DIEA (27.58 g, 37.2 ml, 213.4 mmol, 4.0 eq.) were added to the resulting oil, and the mixture was cooled to 0°C in an ice bath. HOBT (11.53 g, 85.36 mmol, 1.6 eq.) was added to the cooled mixture, followed by PyBOP (44.42 g, 85.36 mmol, 1.6 eq.), which was added in several parts over five minutes. The reaction was carried out under argon and heated at room temperature overnight, at which time a white precipitate had formed. The reaction mixture was cooled and the solids were collected and then washed with cold MeCN, giving (A) (24, 86 g). Summary of (B) The intermediate (A) (23.0 mmol, 14.5 g) was mixed with TFA / DCM (80%) and stirred at room temperature for one hour, at which time the mixture was concentrated and placed under high vacuum for 2 hours, giving (B) Synthesis of (C) To a solution of (B) (1.6 mmol, 1 eq.) in MeCN (100 mL) were added 5-chlorovaleryl chloride (1.9 mmol, 0.24 mL, 1.2 eq.) and DIEA (6.4 mmol, 1.2 m, 4 eq.). The mixture was stirred at room temperature overnight and then concentrated to give a solid. The solid was collected and washed with ether to give the alkyl chloride. To a solution of the alkyl chloride (0.21 mmol, 0.134 g) in dry acetone (100 mL) were added NaI (2.5 mmol, 0.387 g) and the reaction was refluxed overnight. The reaction mixture was then concentrated under vacuum and the residue was dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration and the volatile products were removed under reduced pressure giving (C). Summary of (D) Piperidine (0.048 mmol, 5.0 mg) and DIEA (0.040 mmol, 0.5 mg) were added to a solution of (C) (0.040 mmol, 30.0 mg) in THF (2 mL). After stirring for 2 hours at room temperature, the contents were concentrated and dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The crude ester was dissolved in EtOAc 1:1 / MeOH (10 mL), Pd 5% / C (30.0 mg) was added, and the mixture was placed under 1 atmosphere of hydrogen for 2 hours. The reaction was filtered through Celite, and the volatile products were removed under reduced pressure, yielding (D) (11.0 mg). Synthesis of Compound I To a stirred solution of (E) [see: Bioorg. Med Chem. Lett, 1999, 9, 2283-2288] (0.098 mmol, 5.2 eq.) in DMF (3 ml) were added (D) (0.019 mmol, 0.014 g, 1 eq.), DIEA (0.50 mmol, 0.88 µl, 20 eq.) and HOBT (0.20 mmol, 0.0272 g, 10.5 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.20 mmol, 0.105 g, 10.5 eq.) was added in several parts. The mixture was then stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil, which was purified by ultrafast chromatography to yield compound 1 (5.1 mg). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 2: Summary of Example 2 (Reference) Summary of (F) ** (See formula) ** To a solution of (C) (0.040 mmol, 0.030 g) in THF (2 mL), morpholine (0.050 mmol, 5.0 mg) and DIEA (0.040 mmol, 0.5 mg) were added. After stirring for 2 hours at room temperature, the contents were concentrated and dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The crude ester was dissolved in EtOAc 1:1 / MeOH (10 mL), Pd 5% / C (30.0 mg) was added, and the mixture was placed under 1 atmosphere of hydrogen for 2 hours. The reaction was filtered through Celite, and the volatile products were removed under reduced pressure, yielding (F) (19.0 mg). Synthesis of Compound 2 To a stirred solution of (E) [see: Bioorg. Med Chem. Lett, 1999, 9, 2283-2288] (0.098 mmol, 3.2 eq.) in DMF (3 ml) were added (D) (0.030 mmol, 0.018 g, 1 eq.), DIEA (0.50 mmol, 0.88 µl, 17 eq.) and HOBT (0.20 mmol, 27.2 mg, 6.7 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.20 mmol, 0.105 g, 6.7 eq.) was added in several parts. The mixture was then stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil, which was purified by ultrafast chromatography, yielding compound 2 (6.0 mg). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 3: Summary of Example 3 (Reference) ** (See formula) ** Synthesis of (G) To a solution of (C) (0.040 mmol, 30.0 mg) in THF (2 mL), N-methylpiperazine (0.050 mmol, 5.0 mg) and DIEA (0.040 mmol, 0.5 mg) were added. After stirring for 2 hours at room temperature, the contents were concentrated and dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The crude ester was dissolved in EtOAc 1:1 / MeOH (10 mL), Pd at 5% / C (30.0 mg) was added, and the mixture was placed under 1 atmosphere of hydrogen for 2 hours. The reaction was filtered through Celite, and the volatile products were removed under reduced pressure, yielding (G) (31.0 mg). Synthesis of Compound 3 To a stirred solution of (E) [see: Bioorg Med Chem. Lett, 1999, 9, 2283-2288] (0.098 mmol, 3.2 eq.) in DMF (3 ml) were added (G) (0.030 mmol, 18.0 mg, 1 eq.), DIEA (0.50 mmol, 88 µl, 17 eq.) and HOBT (0.20 mmol, 27.2 mg, 6.7 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.20 mmol, 0.105 g, 6.7 eq.) was added in several parts. The mixture was then stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil, which was purified by ultrafast chromatography, yielding compound 3 (3.9 mg). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 4: Summary of Example 5 (Reference) ** (See formula) ** Summary of (I) To a solution of (B) (2.0 mmol, 1 eq.) in MeCN (120 mL) were added 4-Chlorobutyryl chloride (2.8 mmol, 0.32 mL, 1.2 eq.) and DIEA (8 mmol, 1.4 m, 4 eq.). The mixture was stirred at room temperature overnight and then concentrated to give a solid. The solid was collected and washed with ether to give alkyl chloride (0.008 g). To a solution of the alkyl chloride (0.09 mmol, 0.060 g) in dry acetone (10 mL) was added NaI (0.86 mmol, 0.130 g) and the reaction was refluxed overnight. The contents were concentrated under vacuum and the residue was dissolved in DCM, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration and the volatile products were removed under reduced pressure. Purification by ultrafast chromatography yielded (I) (0.050 g). Synthesis of (J): To a solution of (1) (0.040 mmol, 30.0 mg) in THF (2 mL), piperidine (0.050 mmol, 4.0 mg) and DIEA (0.040 mmol, 0.5 mg) were added. After stirring overnight at room temperature, the contents were concentrated and dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The crude ester was dissolved in EtOAc 1:1 / MeOH (10 mL), 5% Pd / C (0.020 g) was added, and the mixture was placed under 1 atmosphere of hydrogen for 2 hours. The reaction was filtered through Celite, and the volatile products were removed under reduced pressure, yielding (J). Synthesis of Compound 5 To a stirred solution of (E) [see: Lett, 1999, 9, 2283-2288] (0.098 mmol, 4.9 eq.) in DMF (3 mL) were added (D) (0.020 mmol, 1 eq.), DIEA (0.18 mmol, 31 mL, 9 eq.), and HOBT (0.074 mmol, 10.0 mg, 3.7 eq.). The mixture was cooled to 0°C in an ice bath, and PyBOP (0.07 mmol, 36.0 mg, 3.7 eq.) was added in several parts. The mixture was then stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil that was purified by ultrafast chromatography, yielding the compound (18.2 mg). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 5: Summary of Example 6 (Reference) Summary of (K) ** (See formula) ** To a solution of (I) (0.040 mmol, 30.0 mg) in THF (2 mL) morpholine (0.050 mmol, 5.0 mg) and DIEA (0.040 mmol, 0.5 mg) were added. After stirring overnight at room temperature, the contents were concentrated, dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The crude ester was dissolved in EtOAc 1:1 / MeOH (10 mL), 5% Pd / C (20.0 mg) was added, and the mixture was placed under 1 atmosphere of hydrogen for 2 hours. The reaction was filtered through Celite, and the volatile products were removed under reduced pressure by providing (K). Synthesis of Compound 6. To a stirred solution of (E) [see: Bioorg. Med Chem. Lett, 1999, 9, 2283-2288] (0.151 mmol, 1.2 eq.) in DMF (3 ml) were added (K) (0.126 mmol, 0.075 g, 1 eq.), DIEA (0.50 mmol, 0.88 µl, 4 eq.) and HOBT (0.20 mmol, 0.27.0 mg, 1.6 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.202 mmol, 0.105 g, 1.6 eq.) was added in several parts. The mixture was then stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil, which was purified by ultrafast chromatography, yielding compound 6 (46.6 mg). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 6: Summary of Example 7 (Reference) ** (See formula) ** Synthesis of (L) To a solution of (I) (0.040 mmol, 30.0 mg) in THF (2 mL) were added N-methylpiperazine (0.050 mmol, 5.0 mg) and DIEA (0.040 mmol, 0.5 mg). After stirring overnight at room temperature, the contents were concentrated and dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The crude ester was dissolved in EtOAc 1:1 / MeOH (10 mL), 5% Pd / C (20.0 mg) was added, and the mixture was placed under 1 atmosphere of hydrogen for 2 hours. The reaction was filtered through Celite, and the volatile products were removed under reduced pressure, yielding (L). Synthesis of Compound 7 To a stirred solution of (E) [see: Bioorg. Med Chem. Lett, 1999, 9, 2283-2288] (0.098 mmol, 1.5 eq.) in DMF (3 ml) were added (L) (0.065 mmol, 0.075 g, 1 eq.), DIEA (0.50 mmol, 88 µl, 8 eq.) and HOBT (0.20 mmol, 27.0 mg, 3.1 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.20 mmol, 0.105 g, 3.1 eq.) was added in several parts. The mixture was then stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil, which was purified by ultrafast chromatography, yielding compound 7 (4, 8 mg). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 7: Summary of Example 8 ** (See formula) ** Synthesis of (N) Compound (B) (0.39 mmol) was dissolved in DMF (6 mL) and 4-morpholinoacetic acid (0.507 mmol, 0.074 g) was added, followed by DIEA (3.90 mmol, 0.504 g, 0.68 mL). The mixture was cooled to 0°C in an ice bath and PyBOP (0.62 mmol, 0.32 g) was added. The mixture was stirred under an argon atmosphere while being heated to room temperature overnight. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (5 x 20 mL). The organic layers were combined, washed with saturated NaHCO3 (5 x 15 mL) and brine (1 x 25 mL), and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were... They were withdrawn under reduced pressure giving the intermediate ester (M) (0.195 g). To (M) (0.150 g, 0.23 mmol) 10% / C Pd (0.05 g) was added followed by 5 ml of 1:1 mixture of MeOH and EtOAc and the mixture was placed under a hydrogen atmosphere.After 2 hours, the contents were filtered through a short bed of Celite and concentrated under vacuum giving (N) (0, 12 g) . Synthesis of Compound 8 To a stirred solution of (E) [see: Lett, 1999, 9, 2283-2288] (0.27 mmol, 0.083 mg, 1.3 eq.) in DMF (3 ml) were added (D) (0.17 mmol, 1 eq.), DIEA (1.73 mmol, 0.30 l, 10 eq.) and HOBT (0.27 mmol, 0.037 mg, 1.6 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.27 mmol, 0.14 g, 1.6 eq.) was added in several parts. The mixture was stirred at 5°C under an argon atmosphere overnight, after which the reaction was diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, and concentrated to a paste. The raw material was dissolved in a minimal amount of MeOH and slowly added to rapidly stirred water, frozen at 0°C (100 mL). Compound 8 was then isolated by filtration (0.080 g). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 8: Summary of Example 9 (Reference) Summary of (P) ** (See formula) ** To a 0°C solution of (O) [prepared following the same procedure as for the synthesis of (B) except substituting phenylalanine benzyl ester for phenylalanine methyl ester] (1.8 mmol, 1 eq.) in DMF (10 mL) chloroacetyl chloride (2.7 mmol, 0.22 mL, 1.5 eq.) and DIEA (3.5 mmol, 1.4 mL, 3 eq.) were added. The mixture was heated and stirred at room temperature overnight. The reaction was concentrated to vacuum and dissolved in EtOAc, washed with water and brine, and dried over Na₂SO₄. The Na₂SO₄ was removed by filtration, and the volatile products were removed under reduced pressure, yielding (P) (0.64 g). Synthesis of (Q) To a solution of (P) (0.188 mmol, 0.10 g) in THF (20 mL) were added N-methylpiperazine (0.226 mmol, 22.0 mg) and KI (0.04 mmol, 6.4 mg). After stirring overnight at room temperature, the contents were concentrated and dissolved in EtOAc, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure, yielding the crude ester (0.095 g). The crude ester (0.095 g) was dissolved in MeOH 3:1 / H2O (8 mL), cooled to 0°C, and LiOH (1.6 mmol, 39.0 mg) was added. The mixture was stirred at 5°C overnight, deactivated with saturated NH4Cl, diluted with water (20 mL), and the pH was adjusted to 3 with 1N HCl. The mixture was extracted with chloroform, and the organic phases were combined and dried over Na2SO4. The Na2SO4 was removed by filtration, and the volatile products were removed under reduced pressure, yielding (P) (20.0 mg). Synthesis of Compound 9 To a stirred solution of (E) [see: Bioorg. Med. Chem. Lett, 1999, 9, 2283-2288] (0.082 mmol, 2.4 eq.) in DMF (3 ml) were added (Q) (0.034 mmol, 0.075 g, 1 eq.), DIEA (0.29 mmol, 50 µl, 8.5 eq.) and HOBT (0.13 mmol, 18.0 mg, 3.8 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.13 mmol, 0.058 g, 3.8 eq.) was added in several parts. The mixture was then stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to an oil, which was purified by ultrafast chromatography, yielding compound 9. IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. Scheme 9: Summary of Example 10 (Reference) ** (See formula) ** Synthesis of (R) To a solution of benzyl 2-bromoacetate (4.56 mmol, 0.715 mL) and 4-(2-hydroxyethyl)morpholine (3.8 mmol, 0.466 mL) in DMF (4 mL), NaH (5.7 mmol, 0.136 g) was added, and the mixture was stirred overnight under a nitrogen atmosphere. The reaction was diluted with brine and extracted with EtOAc. The organic phases were combined, washed with water and brine, and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The crude ester was purified by ultrafast chromatography. The purified ester was dissolved in EtOAc 1:1 / MeOH (10 ml), 5% Pd / C (0.100 g) was added, and the mixture was placed under an atmosphere of hydrogen overnight. The reaction was purged, filtered through Celite and concentrated under vacuum yielding (R) (0.107 g). Synthesis of (S) To a solution of (B) (0.56 mmol) in DMF (15 mL), (R) (0.56 mmol, 0.107 g) was added, followed by DIEA (2.24 mmol, 0.391 mL). The mixture was cooled to 0°C in an ice bath, and HOBT (0.90 mmol, 0.121 g) and PyBOP (0.90 mmol, 0.466 g) were added. The reaction was stirred under an argon atmosphere while heating at room temperature overnight. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (5 x 20 mL). The organic layers were combined, washed with saturated NaHCO3 (5 x 15 ml) and brine (1 x 25 ml) and dried over MgSO4. The MgSO4 was removed by filtration and the volatile products were removed under reduced pressure giving (S). Synthesis of (T) To a solution of (S) (0.56 mmol) in 1:1 MeOH / EtOAc (10 mL) Pd at 5% / C (0.1 g) was added, and the mixture was placed under a hydrogen atmosphere overnight. The reaction was purged, filtered through Celite, and concentrated under vacuum, yielding (T). Synthesis of Compound 10 To a stirred solution of (E) [see: Bioorg. Med Chem. Lett, 1999, 9, 2283-2288] (0.164 mmol, 1.0 eq.) in DMF (10 ml) were added (T) (0.16 mmol, 0.100 g, 1 eq.), DIEA (0.64 mmol, 112 µl, 4.0 eq.) and HOBT (0.25 mmol, 0.25 mg, 1.6 eq.). The mixture was cooled to 0°C in an ice bath and PyBOP (0.25 mmol, 0.133 g, 1.6 eq.) was added in several parts. The mixture was stirred at 5°C under a nitrogen atmosphere overnight. The reaction was then diluted with saturated NaCl and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous MgSO4, and concentrated to an oil, which was purified by ultrafast chromatography, yielding compound 10 (19.0 mg). IC50 of 20S CT-L < 50 nM, IC50 of cell-based CT-L < 50 nM. ** (See formula) ** Synthesis of (W) To a solution of Fmoc-Phe(4-CF3)-OH (2.2 mmol, 1.0 g) in DCM (20 mL) was added 1-methylimidizol (6.7 mmol, 0.370 mL). When the solution was homogeneous, 1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole (MSNQ) (2.9 mmol, 0.870 g) was added. Once the MSNQ was dissolved, the reaction mixture was added to Wang resin (0.8 mmol, 1.0 g) and the resulting solution was stirred for 45 minutes. The resin was filtered and washed with DMF (50 mL), MeOH (50 mL), and DCM (50 mL). The resulting resin was allowed to air dry, yielding (W). Synthesis of (X) Piperidine 20% / DMF (10 mL) was added to (W) (0.40 mmol, 0.5 g), and the resulting heterogeneous solution was stirred for 20 minutes. The mixture was filtered, and the resin was washed with DMF (20 mL), MeOH (20 mL), and DCM (20 mL) and allowed to air dry. The resin was subjected to the above reaction conditions a second time, providing (X). Summary of (Y) To (X) (0.40 mmol) DMF (20 ml), Fmoc-Leu-OH (0.40 mmol, 0.143 g), DIEA (1.6 mmol, 0.12 ml), HOBT (0.64 mmol, 0.086 g) and BOP (0.64 mmol, 0.178 g) were added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the resin was washed with DMF (40 ml), MeOH (40 ml) and DCM (40 ml) and allowed to air dry, yielding (Y). Synthesis of (Z): Piperidine 20% / DMF (2 ml) was added to (Y) (0.08 mmol, 0.1 g) and the resulting heterogeneous solution was stirred for 20 minutes. The mixture was filtered and the resin was washed with DMF (10 ml), MeOH (10 ml) and DCM (10 ml) and allowed to air dry. The resin was subjected to the above reaction condition a second time, yielding (Z). Summary of (AA) To (Z) (0.08 mmol, 0.10 g) DMF (20 ml), Fmoc-hPhe-OH (0.40 mmol, 0.143 g), DIEA (1.6 mmol, 0.12 ml), HOBT (0.64 mmol, 0.062 mg) and BOP (0.64 mmol, 0.178 g) were added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the resin was washed with DMF (40 ml), MeOH (40 ml) and DCM (40 ml) and allowed to air dry, yielding (AA). Summary of (BB) Piperidine 20% / DMF (2 ml) was added to (AA) (0.08 mmol, 0.10 g) and the resulting heterogeneous solution was stirred for 20 minutes. The mixture was filtered and the resin was washed with DMF (10 ml), MeOH (10 ml) and DCM (10 ml) and allowed to air dry. The resin was subjected to the above reaction conditions a second time providing (BB). Summary of (CC) To (BB) (0.08 mmol, 0.10 g) DMF (12 ml), 4-morpholinoacetic acid (0.10 mmol, 0.015 g), DIEA (0.17 mmol, 0.029 ml), HOBT (0.11 mmol, 0.016 g) and BOP (0.11 mmol, 0.051 g) were added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the resin was washed with DMF (15 ml), MeOH (15 ml) and DCM (15 ml) and allowed to air dry, providing (CC). Summary of (DD) To (CC) (0.08 mmol, 0.10 g) 50% TFA / DCM (2 ml) was added and the mixture was stirred for 20 minutes (the resin turned purple). The reaction was filtered and the resin was washed with DCM (10 ml). The volatile products were removed under reduced pressure and the resulting oil was diluted with DCM (10 ml) and evaporated a total of three times, providing (DD). Synthesis of Compound 13 To a stirred solution of (E) [see: Bioorg. Med Chem. Lett., 1999, 9, 2283-2288] (0.11 mmol, 0.019 g) in MeCN (2 mL) were added (DD) (0.1 mmol), DIEA (2.9 mmol, 0.5 mL), HOBT (0.2 mmol, 0.032 g), and BOP (0.23 mmol, 0.103 g), and the mixture was stirred at room temperature overnight. The reaction was diluted with brine (15 mL) and extracted with EtOAc. The organic phase was washed with water, saturated NaHCO3, H2O, and brine and dried over MgSO4. The MgSO4 was removed by filtration, and the volatile products were removed under reduced pressure. The raw material was purified by flash chromatography to provide 13 (12.6 mg). 20S CT-L IC50 < 500 nM, cell-based CT-L IC50 < 50 nM.

Claims

1. A compound having a structure of formula III or a pharmaceutically acceptable salt thereof, ** (See formula) ** wherein X is O; R1, R2, R3 and R4 are all hydrogen; R5 and R7 are independently C1-6 aralkyl optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxylic ester, thiol and thioether; and R6 and R8 are independently C1-6 alkyl substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxylic ester, thiol and thioether; where the term "C1-6 alkyl" refers to saturated hydrocarbon groups, including straight-chain alkyl groups and branched-chain alkyl groups containing 1 to 6 carbon atoms in the chain, including haloalkyl groups, the term "C1-6 aralkyl" refers to a C1-6 alkyl group substituted with an aryl group, and the term "aryl" includes ring systemsPolycyclic compounds having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of which rings is aromatic.

2. A compound according to claim 1, having a structure of formula IV or a pharmaceutically acceptable salt thereof, **(See formula)** wherein X is O; R1, R2, R3, and R4 are all hydrogen; R6 and R8 are independently selected from C1-6 alkyl optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxylic ester, thiol, and thioether.

3. A compound of claim 2, wherein R6 and R8 are both isobutyl.

4. A compound of claim 2, having the following structure.

5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

6. A compound of any one of claims 1 to 4 for use in7. A compound of any one of claims 1 to 4 for use in inhibiting or reducing HIV infection.

8. A compound of any one of claims 1 to 4 for use in the treatment of neurodegenerative disease.

9. A compound of any one of claims 1 to 4 for use in the treatment of amyotrophic diseases. (See formula) 10. A compound of any one of claims 1 to 4 for use in the treatment of cancer.

11. A compound of any one of claims 1 to 4 for use in the treatment of chronic infectious diseases.

12. A compound of any one of claims 1 to 4 for use in the treatment of a hyperproliferative condition.

13. A compound of any one of claims 1 to 4 for use in the treatment of muscle wasting.

14. A compound of any one of claims 1 to 4 for use in the treatment of conditionsrelated to the immune system.

15. A compound of any one of claims 1 to 4 for use in affecting the level of viral gene expression in a subject.

16. A compound of any one of claims 1 to 4 for use in altering the diversity of antigenic peptides produced by the proteasome in an organism.