WO2021042080A1

WO2021042080A1 - N-aryl arylsulfonamides that function as mitochondrial uncouplers for the treatment of metabolic disease and cancer

Info

Publication number: WO2021042080A1
Application number: PCT/US2020/048852
Authority: WO
Inventors: Chunming LIU; David S WATT; Roberto GEDALY; Wen Zhang; Brett T. SPEAR; Yang YANG-HARTWICH; Francesc Marti
Original assignee: University Of Kentucky Research Foundation; Yale University
Priority date: 2019-08-30
Filing date: 2020-08-31
Publication date: 2021-03-04

Abstract

A mitochondrial uncoupler and method of treating a disorder using the same are provided. The mitochondrial uncoupler includes any compound having a structure according to Formula I, where R1 includes a dihalophenyl, R2 includes a substituted or unsubstituted aromatic group, and when R1 specifically includes 2,5-dichlorobenzyl R2 does not include N-(2-methyl-4-nitrophenyl). The method of treating a disorder includes administering the compound according to Formula I to a subject in need thereof.

Description

/V-Aryl Arylsulfonamides That Function as Mitochondrial Uncouplers for the Treatment of

Metabolic Disease and Cancer

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 62/894,511, filed August 30, 2019, the entire disclosure of which is incorporated herein by this reference.

TECHNICAL FIELD

[0002] The present disclosure is directed to a articles and methods for proton uncoupling. In particular, the disclosure is directed to A-aryl aryl sulfonamides that act as eukaryotic proton uncouplers and methods of use thereof.

BACKGROUND

[0003] Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third most common cause of cancer-related deaths worldwide. The prevalence of HCC differs greatly by geographical location, reflecting variations in the main risk factors. A majority of HCC cases arise in the Asian Pacific and sub-Saharan African regions, where the dominant risk factor is chronic infection with hepatitis B virus. However, the incidence of HCC is increasing in Western countries, including the United States, and reflects increasing infection with hepatitis C virus (HCV) and alcohol use. Additionally, obesity-related non-alcoholic fatty liver disease (NAFLD) is becoming an important risk factor in developed countries. The relative five-year survival rate for patients with liver cancer is about 15% overall. As such, hepatocellular carcinoma is a major health care problem for which traditional solutions, such as surgery and radiation, cannot provide a complete solution.

[0004] A number of signaling pathways are deregulated in hepatocellular carcinoma: RAS/RAF/MAPK, PI3K/Akt/mTOR, HGF/c-MET, IGF, VEGF, PDGF and Wnt/p-catenin. The latter signaling pathway represents a particular challenge in the case of hepatocellular carcinoma where aberrant Wnt/p-catenin appears in approximately one-third of cases. In a normal situation and in the absence of a Wnt signal, b-catenin undergoes degradation via ubiquination and proteolysis in the 26S proteasome. In the presence of a Wnt signal, degradation of the cytosolic b-catenin wanes, and cytosolic levels of b-catenin increase. Entry of b-catenin into the nucleus then triggers transcription of numerous target genes, including cyclin D1 and other cell-cycle regulators. In abnormal situations such as hepatocellular carcinoma, mutations in either b-catenin or an associated factor, APC, block the normal degradation pathway and elevate levels of b- catenin which in turn activates genes leading to abnormal cell proliferation and tumor progression.

[0005] In 2008, screening of a ChemBridge small-molecule library identified 2,5-dichloro-A- (2-methyl-4-nitrophenyl)benzenesulfonamide (1), which is also known as FH535 (FIG. 1), as a suppressor of both the Wnt^-catenin and the peroxisome proliferator-activated receptor (PPAR) signaling. This report gave no indication of structure-activity relationships surrounding FH535 and did not identify a precise molecular target or targets for FH535. Subsequent reports utilized FH535 as a Wnt/^-catenin inhibitor, also without exploring other sulfonamides.

[0006] More recently, the inventors described a series of A-arylbenzenesulfonamides that were synthesized as potential antineoplastic agents for the treatment of hepatocellular carcinoma (HCC)³. However, previous attempts to define the precise biological target of these agents using biotinylated analogs failed.

[0007] Accordingly, there remains a need for a need to identify a precise molecular target or targets for FH535 and additional antineoplastic agents directed towards these targets.

SUMMARY

[0008] The presently-disclosed subject matter meets some or all of the above-identified needs, as will become evident to those of ordinary skill in the art after a study of information provided in this document.

[0009] This summary describes several embodiments of the presently-disclosed subject matter, and in many cases lists variations and permutations of these embodiments. This summary is merely exemplary of the numerous and varied embodiments. Mention of one or more representative features of a given embodiment is likewise exemplary. Such an embodiment can typically exist with or without the feature(s) mentioned; likewise, those features can be applied to other embodiments of the presently-disclosed subject matter, whether listed in this summary or not. To avoid excessive repetition, this summary does not list or suggest all possible combinations of such features.

[0010] In some embodiments, the presently-disclosed subject matter includes a mitochondrial uncoupler comprising a compound according to Formula I:

H

1

R' _/N I;

R²

O 0 wherein R¹ includes a dihalophenyl; wherein R² includes a substituted or unsubstituted aromatic group; and wherein, when R¹ specifically includes 2,5-dichlorobenzyl R² does not include N-( 2- methyl-4-nitrophenyl). In some embodiments, R¹ is a phenyl group according to Formula II:

wherein each R³ independently includes a halogen. In some embodiments, each halogen is independently selected from Cl, Br, and F. In some embodiments, the halogen substitutes are at C2 and C5 or G„ according to Formula III:

[0011] In some embodiments, R² is a phenyl group according to Formula IV:

wherein each R³ independently includes a each R⁴ independently includes an alkyl, aryl, nitro, or combination thereof. In some embodiments, R² includes a methyl and nitro substituted phenyl having a structure according to Formula V:

In some embodiments, R² is a biaryl group. In some embodiments, R² is a naphthyl group according to Formula VI:

wherein R⁵ includes an alkyl, aryl, nitro, or combination thereof. In some embodiments, the mitochondrial uncoupler includes the structure according to Formula VII:

[0012] Also provided herein, in some embodiments is a method of treating a disorder, the method comprising administering a pharmaceutically effective amount of one or more of the compounds of Formula I to a subject in need thereof. In some embodiments, the subject has been diagnosed with a disorder of uncontrolled cellular proliferation.

[0013] Further features and advantages of the presently-disclosed subject matter will become evident to those of ordinary skill in the art after a study of the description, figures, and non limiting examples in this document.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The presently-disclosed subject matter will be better understood, and features, aspects and advantages other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such detailed description makes reference to the following drawings, wherein: [0015] FIG. 1 shows the structure of FH535 (1).

[0016] FIG. 2 shows the structure of 2,5-dichloro-A-(4-nitronaphthalen-l- yl)benzenesulfonamide (2), a representative example of an A-arylbenzenesulfonamide.

[0017] FIG. 3 shows the structure of inactive analogs (3) and (4) of compounds (1) and (2), respectively, in which N-H has been replaced by A-methyl.

[0018] FIG. 4 shows a schematic illustrating proton transport across the inner mitochondrial membrane.

[0019] FIG. 5 shows a schematic illustrating the overall mechanism of N- arylbenzenesulfonamides.

[0020] FIG. 6 shows a graph illustrating the disruption of the suppressive activity of Treg cells by FH535 and SK-293, a derivative of SK-293.

DEFINITIONS

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure belongs. Any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present disclosure, including the methods and materials are described below.

[0022] Following long-standing patent law convention, the terms “a,” “an,” and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a cell” includes a plurality of cells, and so forth.

[0023] The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0024] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter. [0025] As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration, percentage, or the like is meant to encompass variations of in some embodiments ±50%, in some embodiments ±40%, in some embodiments ±30%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

[0026] As used herein, ranges can be expressed as from “about” one particular value, and/or to “about” another particular value. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed.

For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0027] All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

[0028] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E/Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation,

U.S.A.).

[0029] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0030] As used herein, the term "patient" refers to a subject afflicted with a disease or disorder. A patient includes human and veterinary subjects. [0031] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.

[0032] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N- oxides of a parent compound.

[0033] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (z^'.c., further substituted or unsubstituted).

[0034] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds.

Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0035] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized p electrons above and below the plane of the molecule, where the p clouds contain (4n+2) p electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups, as well as polyaromatic rings.

[0036] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0037] The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where A-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, V-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, 1,2- oxazol-4-yl, l,2-oxazol-5-yl, 1,3- oxazolyl, 1 ,2,4-oxadiazol-5-yl, 1,2,3-triazolyl, 1,3-thiazol- 4-yl, pyridinyl, and pyrimidin-5-yl.

[0038] The terms “halo,” “halogen,” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0039] The term “nitro” as used herein is represented by the formula — NO2.

DETAILED DESCRIPTION

[0040] The details of one or more embodiments of the presently-disclosed subject matter are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. In case of conflict, the specification of this document, including definitions, will control.

[0041] Provided herein are articles and methods for mitochondrial proton-uncoupling. In some embodiments, the mitochondrial proton-uncouplers include A-aryl arylsulfonamides. In one embodiment, for example, the A-aryl arylsulfonamides include compounds having a structure according to Formula I:

where R¹ and R² each independently includes an aromatic group. The aromatic group of R¹ and/or R² may be substituted or unsubstituted.

[0042] In some embodiments, the/V-aryl arylsulfonamides include N- arylbenzenesulfonamides, where R¹ is a phenyl group. For example, in one embodiment, the N- arylbenzenesulfonamides include compounds having a structure according to Formula II:

where R² is defined according to any of the embodiments disclosed herein, and each R³ independently includes a halogen. In another embodiment, the phenyl group of R¹ is dihalogenated. In a further embodiment, the dihalogenated phenyl group includes a halogen substitution at C2 and C5 or Ce, according to Formula III:

The halogen of each R³ may be the same ( e.g ., di chlorinated, difluorinated, dibrominated) or different (e.g., Cl/F, Cl/Br, Br/F).

[0043] In some embodiments, R² is a phenyl group and the V-aryl arylsulfonamides include compounds having a structure according to Formula IV:

where R¹ is defined according to any of the embodiments disclosed herein, and each R⁴ independently includes an alkyl, aryl, nitro, or combination thereof. For example, in one embodiment, R² includes a methyl and nitro substituted phenyl having a structure according to Formula V:

[0044] In some embodiments, R² is a biaryl group, such as a naphthyl group, and the V-aryl arylsulfonamides include compounds having a structure according to Formula VI:

where R¹ is defined according to any of the embodiments disclosed herein, and R⁵ includes an alkyl, aryl, nitro, or combination thereof. For example, in one embodiment, R² includes a nitro substituted naphthyl having a stmcture according to Formula VII:

[0045] As will be appreciated by those skilled in the art, the compounds according to Formula I are not limited to the structures recited in Formulas II- VII and may include any other suitable structure encompassed by the general structure of Formula I. As will also be appreciated by those skilled in the art, the compounds according to Formulas II and III are expressly intended to include, but are not limited to, the R² groups defined in Formulas IV- VII. Similarly, the compounds according to Formulas IV- VII are expressly intended to include, but are not limited to, the R¹ groups defined in Formulas II- III.

[0046] In some embodiments, the compounds include any suitable structure according to a combination of R¹ as defined in any of Formulas II-III and R² as defined in any of Formulas IV- VII, excluding the specific combination resulting in the structure of FIG. 1. Stated another way, in some embodiments, when R¹ includes 2,5-dichlorobenzyl, R² includes any group according to Formulas IV, VI, or VII other than the V-(2-methyl-4-nitrophenyl) group shown in Formula V. Similarly, when R² includes the A-(2-methyl-4-nitrophenyl) group shown in Formula V, R¹ includes any group according to Formulas II and III other than 2,5-dichlorobenzyl. For example, in some embodiments, the compound includes any 2,6-dihalobenzyl (i.e., Cl/Cl, F/F, Br/Br, Cl/F, Cl/Br, or Br/F) in the R¹ position with any R² according to Formulas IV-VII. In some embodiments, the compound includes any 2,5-dihalobenzyl other than 2,5-dichlorobenzyl (i.e., F/F, Br/Br, Cl/F, Cl/Br, or Br/F) in the R¹ position with any R² according to Formulas IV-VII. In some embodiments, the compound includes 2,5-dichlorobenzyl in the R¹ position with any R² group according to Formulas IV, VI, or VII, other than the V-(2-methyl-4-nitrophenyl) group shown in Formula V.

[0047] In some embodiments, the compound includes any 2,6-dihalobenzyl in the R¹ position, where the halo is selected from Cl, F, or a combination thereof (i.e., Cl/Cl, F/F, or Cl/F), with any R² according to Formulas IV-VII. In some embodiments, the compound includes any 2,5-dihalobenzyl in the R¹ position, where the halo is selected from F/F or Cl/F, with any R² according to Formulas IV-VII. In some embodiments, the compound includes 2,5- dichlorobenzyle in the R¹ position with any R² group according to Formulas IV, VI, or VII, other than the V-(2-methyl-4-nitrophenyl) group shown in Formula V. In some embodiments, the compound includes any 2,5- or 2,6-dihalobenzyl in the R¹ position with R² including N-(4- nitronaphthyl), V-(4-hydroxymethyl-2-methylphenyl), A-(2-carbomethoxy-4-fluorophenyl), N- (2-carbomethoxy-4-chlorophenyl), V-(2-carboxaldehyde-4-chlorophenyl), N-( 1- benzyloxyphenyl), V-(3 -benzyl oxyphenyl), or V-(4-benzoylphenyl) groups. In some embodiments, the compound includes any 2,5- or 2,6-dihalobenzyl in the R¹ position, where the halo is selected from Cl, F, or a combination thereof (i.e., Cl/Cl, F/F, or Cl/F), with R² including V-(4-nitronaphthyl), /V-(4-hydroxym ethyl -2-methyl phenyl), A-(2-carbomethoxy-4-fluorophenyl), /V-(2-carbomethoxy-4-chlorophenyl), V-(2-carboxaldehyde-4-chlorophenyl), N-( 2- benzyloxyphenyl), V-(3 -benzyl oxyphenyl), or V-(4-benzoylphenyl) groups. Although not recited separately, each of the specific combinations disclosed herein are explicitly contemplated on their own, as are each group and sub-group above.

[0048] In some embodiments, the compounds disclosed herein target the micro-environment of a tumor and/or tumor infiltrating lymphocytes. Without wishing to be bound by theory, it is believed that the targeting of the micro-environment of a tumor and/or the tumor infiltrating lymphocytes by the compounds disclosed herein disrupts the function of suppressive/regulatory T cells without significantly affecting effector T cells. This previously unknown immunomodulatory mechanism of action is believed to contribute, at least in part, to the anti cancer properties of the compounds disclosed herein. Additionally, in some embodiments, the compounds disclosed herein reduce or eliminate cancer cell proliferation/progression. This reduction or elimination of cancer cell proliferation is also believed to contribute, at least in part, to the anti-cancer properties of the compounds disclosed herein. Accordingly, in some embodiments, the anti-cancer properties of the compounds disclosed herein are the result of a dual mechanism of action.

[0049] Also provided herein, in some embodiments, are methods of treating one or more disorders with one or more of the mitochondrial proton-uncouplers disclosed herein. For example, in some embodiments, the method includes administering one or more of the mitochondrial proton-uncouplers disclosed herein to a subject in need thereof. In some embodiments, the subject is a mammal. In some embodiments of the disclosed methods, prior to the administering step, the subject has been diagnosed with a need for treatment of one or more disorders. In some embodiments of the disclosed method, prior to the administering step, the subject has been diagnosed with a disorder of uncontrolled cellular proliferation (e.g., cancer). In some embodiments of the disclosed method, prior to the administering step, the subject has been diagnosed with a metabolic disease (e.g., obesity). In some embodiments of the disclosed method, prior to the administering step, the subject has been diagnosed with a need for mitochondrial uncoupling. In some embodiments of the disclosed method, prior to the administering step, the subject has been identified with a disorder treatable by mitochondrial uncoupling.

[0050] The presently-disclosed subject matter is further illustrated by the following specific but non-limiting examples. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the presently-disclosed subject matter. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein.

EXAMPLES

[0051] EXAMPLE 1

[0052] This Example describes evaluation of the structure-activity relationships (SAR) of certain A-arylbenzenesulfonamides. Referring to FIG. 1, the structure-activity relationships (SAR) within the FH535 were explored to identify compounds with increased potency relative to FH535 in assays used to assess antineoplastic activity. [0053] The effect of these SAR modifications were analyzed using the following assay: ³H- thymidine incorporation in human hepatocellular carcinoma Huh7 cells as a percentage of control; percent inhibition in a luciferase-based assay for b-catenin activity relative to control in HEK293T cells and in Huh7 cells; and percent inhibition in LS174T cell proliferation assay. The following modifications were reported as being consistent with activity greater than or equipotent to FH535 as follows: (1) fluoro or chloro groups in a 2,5- or 2,6-substitution pattern in the benzenesulfonyl portion of these A'-arylbenzenesulfonamides; and (2) replacement of the A -(2-methyl -4-nitrophenyl) group with A'-(4-nitronaphthyl ), A-(4-hydroxymethyl-2- methylphenyl), A^r-(2-carbomethoxy-4-fluorophenyl), A^f-(2-carbomethoxy-4-chlorophenyl), N-( 2- carboxaldehyde-4-chlorophenyl), V-(2-benzyloxy phenyl). A^f-(3-benzyloxyphenyl), or A^f-(4- benzoylphenyl) groups.

[0054] Following the analysis of FH535, a series of AAarylbenzenesulfonamides were synthesized as potential antineoplastic agents for the treatment of hepatocellular carcinoma (HCC). The compounds in this series possess an aromatic group attached to the nitrogen of the sulfonamide and a second, halogenated aromatic group attached to the sulfonyl group of the sulfonamide. In addition to the inventors’ previously disclosed work, it was also discovered that certain compounds in this series increase oxidative stress and provide a potential treatment for ovarian cancer.

[0055] In view thereof, it was hypothesized that specific compounds in this series, a representative of which is illustrated in FIG. 2, functioned as mitochondrial proton uncouplers. More specifically, it was hypothesized that the hydrogen substituent identified by the dashed circle in FIG. 2 provides the biological activity in these A-arylbenzenesulfonamides. To test this hypothesis, the hydrogen in compounds (1) and (2) was replaced with a methyl group. As predicted, these methyl-substituted compounds, which are shown as compounds (3) and (4) in FIG. 3, respectively, were completely inactive.

[0056] The inactivity of the methyl substituted compounds led to a clear understanding that the hydrogen containing compounds function as mitochondrial proton-uncouplers which transport protons across the inner mitochondrial membrane (FIG. 4), depress the biosynthesis of ATP dependent on this differential proton concentration, activate an energy sensor called 5'- adenosine monophosphate-activated protein kinase (AMPK), and inhibit the Wnt-signaling pathway upregulated in various cancers including colorectal cancer and HCC. The pK_a value of A-phenylbenzenesulfonamide is 9.1⁴ and the presence of halogen and nitro substituents would be expected to lower this value closer to 7. Lipophilic compounds with pK_a values in the 6-8 range are best suited to function as uncouplers.

[0057] In summary, the W-arylbenzenesulfonamides disclosed herein act as proton uncouplers with the overall mechanism shown in FIG. 5. These uncouplers have applicability for treatment of metabolic diseases (e.g., obesity) and cancer.

[0058] EXAMPLE 2

[0059] This Example describes the discovery of the anti-cancer effect of the A-aryl arylsulfonamides disclosed herein. The effect of FH535 and SK-293, a derivative of FH535, on the suppressive activity of Treg cells was evaluated. As illustrated in FIG. 6, the suppressive activity of the Treg cells was suppressed or eliminated after treatment with the compounds. Without wishing to be bound by theory, it is believed that this disruption of the suppressive activity of the Treg cells provides an anti-cancer effect.

[0060] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, including the references set forth in the following list:

REFERENCES

1. Aravalli, R.N., E.N. Cressman, and C.J. Steer, Cellular and molectdar mechanisms of hepatocellular carcinoma: an update. Arch Toxicol, 2013. 87(2):227-47.

2. Larsson, S.C. and A. Wolk, Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer, 2007. 97(7): 1005-8.

3. Kril, L; Vilchez, V; Jiang, J; Turcios, L; Chen, C; Sviripa VM; Zhang W; Liu C; Spear B; Watt DS; Gedaly R (2015) N-Aryl Benzenesulfonamide Inhibitors of [³H]-Thymidine Incorporation and b-Catenin Signaling in Human Hepatocyte-derived Huh-7 Carcinoma Cells Bioorg Med Chem Lett 25081:3897-3899. PMID: 26243371.

4 Williams, A. Free Energy Relationships in Organic and Bio-Organic Chemistry, Royal Society of Chemistry, 2003, p. 99. [0061] While the disclosure is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described below in detail. It should be understood, however, that the description of specific embodiments is not intended to limit the disclosure to cover all modifications, equivalents and alternatives falling within the spirit and scope of the disclosure as defined by the appended claims.

Claims

What is claimed is:

1 A mitochondrial uncoupler comprising a compound according to Formula I:

wherein R¹ includes a dihalophenyl; wherein R² includes a substituted or unsubstituted aromatic group; wherein, when R¹ specifically includes 2,5-dichlorobenzyl R² does not include N-(2- methyl-4-nitrophenyl).

2. The mitochondrial uncoupler of claim 1, wherein R¹ is a phenyl group according to Formula II:

wherein each R³ independently includes a halogen.

3. The mitochondrial uncoupler of claim 2, wherein each halogen is independently selected from Cl, Br, and F.

4. The mitochondrial uncoupler of claim 2, wherein the halogen substitutes are at C2 and C5 or C6, according to Formula III:

5. The mitochondrial uncoupler of any of claims 1-4, wherein R² is a phenyl group according to Formula IV:

wherein each R³ independently includes a each R⁴ independently includes an alkyl, aryl, nitro, or combination thereof.

6. The mitochondrial uncoupler of claim 5, wherein R² includes a methyl and nitro substituted phenyl having a structure according to Formula V:

7. The mitochondrial uncoupler of claim 5, wherein R² is a biaryl group.

8. The mitochondrial uncoupler of claim 5, wherein R² is a naphthyl group according to Formula VI:

wherein R⁵ includes an alkyl, aryl, nitro, or combination thereof.

9. The mitochondrial uncoupler of claim 8, comprising the structure according to Formula

VII:

10. A method of treating a disorder, the method comprising administering a pharmaceutically effective amount of one or more of the compounds of claim 1 to a subject in need thereof.

11. The method of claim 10, wherein the subject has been diagnosed with a disorder of uncontrolled cellular proliferation.