WO2024107818A1 - Bis-trifluoromethyl honokiol analogs and their use in treating cardiovascular disorders - Google Patents

Abstract

Methods for treating or preventing cardiovascular disorders, such as hypertension, pulmonary hypertension, vascular rarefaction, endothelial dysfunction, and pulmonary vascular dysfunction. The compounds are hexafluoro-honokiol analogs. Representative hexafluoro-honokiol analogs include hexafluoro-honokiol, analogs in which one or both hydroxy groups are replaced with dichloroacetate esters, and analogs with increased fluorination. The compounds are believed to function, at least, by increasing SIRT3 levels in a patient in need of treatment or prevention thereof.

Description

Bis-Trifluoromethyl Honokiol Analogs and Their Use in Treating Cardiovascular Disorders CROSS-REFERENCE TO RELATED APPLICATIONS This application is an International Application which claims the benefit of U.S. Patent Application Serial No. 63/425,883 filed November 16, 2022, the entire disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to novel methods and compositions for the treatment of cardiovascular disorders, including hypertension. These methods and compositions use hexafluoro-honokiol analogs. These compounds, and pharmaceutical compositions including the compounds, are particularly useful for treating hypertension. The invention also encompasses the varying modes of administration of the therapeutic compounds or compositions. BACKGROUND OF THE INVENTION Hypertension represents a major risk factor for stroke, myocardial infarction, and heart failure which causes one-third of deaths worldwide. Hypertension is a multifactorial disorder involving perturbations of the vasculature, kidney and central nervous system. Despite treatment with multiple drugs, 37% of hypertensive patients remain hypertensive, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Vascular dysfunction is crucial in hypertension pathophysiology and exhibits a bidirectional relationship. Endothelial dysfunction leads to and accelerates the progression of hypertension while hypertension causes vascular dysfunction. Metabolic disorders and oxidative stress contribute to the pathogenesis of vascular dysfunction, and mitochondrial deacetylase Sirt3 is critical in the regulation of metabolic and antioxidant functions, however, the role of Sirt3 has been largely ignored. Clinical studies show that cardiovascular disease risk factors reduce Sirt3 level and Sirt3 declines with age, paralleling the increased incidence of cardiovascular disease and hypertension. Sirt3 depletion in Sirt3−/− mice increases hypertension, which is linked to hyperacetylation of the key mitochondrial antioxidant, superoxide dismutase 2 (SOD2), leading to SOD2 inactivation and mitochondrial oxidative stress. Analysis of human subjects with essential hypertension showed an increase in SOD2 acetylation and decrease in Sirt3 levels in peripheral blood mononuclear cells, supporting the association of Sirt3 depletion and hypertension. The causative role of Sirt3 depletion in vascular alterations remains unclear and the therapeutic potential of targeting Sirt3 expression in vascular dysfunction and hypertension is not known. Mitochondria become dysfunctional in hypertension, however, the precise role of mitochondrial dysfunction remains unclear. Angiotensin II and inflammatory cytokines promote mitochondrial dysfunction. Activation of RAS/AngII/AT1R and inflammation reduce Sirt3 levels, while Sirt3 expression is associated with reduced ventricular hypertrophy, attenuated cardiomyopathy and diminished inflammatory injury. It is conceivable that mitochondria are both the target and the regulator of inflammatory pathways. Indeed, inflammation plays a critical role in the pathogenesis of endothelial dysfunction and hypertension, and overexpression of mitochondrial antioxidant SOD2 protects from cytokine-mediated vascular dysfunction and attenuates hypertension. Sirt3 activates SOD2 by deacetylation of specific lysine residues. Sirt3 overexpression has been shown to protect from doxorubicin-induced cardiomyopathy in mice. Whole-body Sirt3-transgenic mice were generated by crossing loxP-stop-LoxP-SIRT3 transgenic mice with mice expressing Cre under the control of the human β-actin promoter. The whole body Sirt3 overexpressing mice showed significantly reduced expression of fibrotic markers and were found resistant to developing angiotensin-II-mediated cardiac fibrosis. Meanwhile, the protective potential of Sirt3 expression on vascular function and hypertension has not been studied. There remains a need for treatment of cardiovascular disease, particularly for refractory hypertension, where patients do not respond to any of a series of antihypertensive agents. The present invention provides such treatment. SUMMARY OF THE INVENTION Methods of treating or preventing cardiovascular disorders, such as pertension, pulmonary hypertension, vascular rarefaction, including capillary rarefaction, endothelial dysfunction, and pulmonary vascular dysfunction, are disclosed. The methods involve administering an effective treatment or preventative amount of a honokiol hexafluoro analog as described herein, or honokiol itself, to a patient in need of treatment thereof. While not wishing to be bound to a particular theory, it is believed that Increased Sirt3 expression prevents SOD2 hyperacetylation, attenuates mitochondrial oxidative stress and reduces vascular inflammation, which can protect vascular function and reduce hypertension and pulmonary hypertension. In one embodiment, the compounds are bis-trifluoromethyl honokiol analogs (hexafluoro- honokiol analogs), which can be formed by reacting an optionally substituted 4′,4′- hexafluoromethyl-bisphenol A with allyl bromide to convert the phenol groups to allyl ether groups. Reaction with a Lewis acid, such as boron trifluoride etherate, converts the allyl ethers to hydroxy groups, and provides an allyl group at a position ortho to the initial allyl ether. In another embodiment, one or both of the double bonds in these hexafluoro-honokiol analogs are reacted with appropriate reactants to form cyclopropane, epoxide, thiirane, or aziridine rings. A core structure similar to these hexafluoro-honokiol analogs, including those which include cyclopropane, epoxide, thiirane, or aziridine rings, can be formed where one or both of the benzene rings are replaced with a heteroaryl ring. The linker between the aryl/heteroaryl rings and the cyclopropane, epoxide, thiirane, or aziridine rings can be modified from that of honokiol, in that it can be extended from one to three carbons in length, and one of the carbons replaced with an O, S, or amine. Additionally, one or both of the hydroxyl groups on the central aryl/heteroaryl rings can be converted to an alkyl phosphate ester, or a dichloroacetate ester. Representative compounds include those in which one or both of the hydroxy groups in hexafluoro-honokiol is replaced with a dichloroacetate group. Treatment with one or more of these compounds increases SIRT3 levels, and thus provides an effective treatment or preventative regimen for hypertension, particularly among the elderly and in patients with metabolic conditions such as diabetes, hyperlipidemia and metabolic syndrome. In another embodiment, pharmaceutical compositions including an effective amount of the compounds described herein, along with a pharmaceutically acceptable carrier or excipient, are disclosed. When employed in effective amounts, the compounds can act as a therapeutic agent to prevent and/or treat a wide variety of cardiovascular disorders. The foregoing and other aspects of the present invention are explained in detail in the detailed description and examples set forth below. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a chart showing the effect on the blood pressure of a mouse (mm Hg) with angiotensin II-induced hypertension of administration of hexafluoro honokiol (HFH) or vehicle over a period of several days. Figure 2A is a Western blot of aortic Sirt3 in human arterioles treated, ex vivo, with vehicle (Sham) or HFH (3 µM). Figure 2B is a chart showing the effect of ex vivo treatment of human arterioles with vehicle or HFH on mitochondrial O2 (pmol/mg protein) in normotensive and hypertensive arterioles. As shown in the figure, blood pressure was reduced in both normotensive and hypertensive arterioles. Figure 3 is a chart showing the role SIRT3 is believed to play in the risk of various cardiovascular diseases (CVD). DETAILED DESCRIPTION OF THE INVENTION Methods for treating and preventing cardiovascular diseases, including among elderly patients and those with metabolic conditions such as diabetes, hyperlipidemia or metabolic syndrome, using the compounds described herein, and pharmaceutical compositions including the compounds, are disclosed. Endothelial dysfunction plays a key role in the pathogenesis of hypertension and represents a major risk factor for cardiovascular disease. Despite treatment with multiple drugs, only 1 in 4 patients has blood pressure under control. Endothelial dysfunction and hypertension are linked to Sirtuin 3 deficiency; endothelial Sirtuin 3 (i.e., SIRT3) levels are significantly lower, for example, as low as 25 % of normal levels, in patients with hypertension. As discussed in the working examples, the present inventors have discovered a new synergistic control point with the potential to address this problem. We have shown that Sirt3 level is reduced in essential hypertension and endothelial Sirt3 overexpression attenuates endothelial dysfunction and hypertension. We proposed that induction endothelial Sirt3 after onset of hypertension rescues endothelial function and reduces hypertension. To test this hypothesis, we used genetic- and pharmacological Sirt3 induction. To genetically induce the expression of endothelial Sirt3 we used Sirt3 flox/flox mice crossed with VeCad-Cre mice treated with low dose of 4-hydroxytamoxifen (4HOT, i.p.0.3 mg/20 g daily, 5 days) which does not have off-target cardiovascular effects. Mice underwent telemetry placement and ten days later received 4-week osmotic pumps containing vehicle (saline) or angiotensin II (0.7 mg/kg/day). 14-days later half of mice received 4HOT to induce endothelial Sirt3 overexpression. Treatment of mice with 4HOT after onset of hypertension slightly reduced blood pressure but most importantly completely rescued endothelial-dependent relaxation, normalized mitochondrial O2 and restored endothelial nitric oxide. Second, we tested if pharmacological induction of Sirt3 by hexafluoro honokiol (i.p. 8 mg/kg, 4 days) after onset of angiotensin II-induced hypertension improves endothelial function and reduces hypertension. It was found that hexafluoro honokiol substantially reduced systolic blood pressure, significantly diminished vascular mitochondrial O2 and improved endothelial nitric oxide. To test the role of endothelial Sirt3 in pharmacological effect of hexafluoro we used endothelial specific Sirt3 knockout mice and angiotensin II model of hypertension. Interestingly, hexafluoro was not effective in endothelial Sirt3 deficient mice, a fact which supports the critical role of endothelial Sirt3. These in vivo studies demonstrate therapeutic potential of genetic and pharmacological endothelial Sirt3 induction after onset of hypertension for treatment of endothelial dysfunction. Hexafluoro honokiol is effective in an animal model of hypertension after onset of hypertension to i) increase vascular Sirtuin 3 levels; ii) improve vascular metabolism; iii) improve endothelial dependent vasorelaxation; iv) reduce vascular oxidative stress and inflammation; and v) reduce/normalize blood pressure. Hexafluoro honokiol is effective in vascular human tissue isolated from patients with essential hypertension in organoid tissue culture by improving vascular metabolism, reducing vascular oxidative stress and diminishing vascular inflammation. Hexafluoro honokiol increased expression of endothelial Sirtuin 3 and it was effective in wild-type animals but it was not effective in endothelial Sirtuin 3 null animals, indicating that Sirtuin 3 is essential for hexafluoro honokiol’s therapeutic effect. Sirtuin 3 deficiency leads to increased endothelial permeability and microvascular rarefaction. These pathological processes are critical in cardiovascular diseases and end-organ-damage associated with microvascular disease. Sirtuin 3 levels are reduced/deficient in elderly patients, and in patients with metabolic conditions such as diabetes, hyperlipidemia and metabolic syndrome. The hexafluoro honokiol analogs described herein can attenuate end-organ-damage in these metabolic conditions due by improving endothelial and microvascular function. While not wishing to be bound to a particular theory, it is believed that these effects are achieved by increasing/normalizing Sirtuin 3 (SIRT3) levels.

The hexafluoro honokiol analogs described herein can therefore be effective in treatment of pulmonary hypertension and pulmonary vascular dysfunction, since these conditions are also associated with Sirtuin 3 deficiency.

Definitions

The following definitions will be useful in understanding the metes and bounds of the invention as described herein.

As used herein, “alkyl” refers to straight chain or branched alkyl radicals including Ci-Cs, preferably C1-C5, such as methyl, ethyl, or isopropyl; “substituted alkyl” refers to alkyl radicals further bearing one or more substituent groups such as hydroxy, alkoxy, aryloxy, mercapto, aryl, heterocyclo, halo, amino, carboxyl, carbamyl, cyano, and the like; “alkenyl” refers to straight chain or branched hydrocarbon radicals including C₁-C₈, preferably C₁-C₅ and having at least one carbon-carbon double bond; “substituted alkenyl” refers to alkenyl radicals further bearing one or more substituent groups as defined above; “cycloalkyl” refers to saturated or unsaturated, nonaromatic, cyclic ring-containing radicals containing three to eight carbon atoms, preferably three to six carbon atoms; “substituted cycloalkyl” refers to cycloalkyl radicals further bearing one or more substituent groups as defined above; “aryl” refers to aromatic radicals having six to ten carbon atoms; “substituted aryl” refers to aryl radicals further bearing one or more substituent groups as defined above; “alkylaryl” refers to alkyl-substituted aryl radicals; “substituted alkylaryl” refers to alkylaryl radicals further bearing one or more substituent groups as defined above; “arylalkyl” refers to aryl -substituted alkyl radicals; “substituted arylalkyl” refers to arylalkyl radicals further bearing one or more substituent groups as defined above; “heterocyclyl” refers to saturated or unsaturated cyclic radicals containing one or more heteroatoms (e.g., O, N, S) as part of the ring structure and having two to seven carbon atoms in the ring; “substituted heterocyclyl” refers to heterocyclyl radicals further bearing one or more substituent groups as defined above. I. Compounds The compounds are honokiol analogs, prodrugs or metabolites of these compounds, and pharmaceutically acceptable salts thereof, wherein a bis-trifluoromethyl-methylene group is present between the aromatic rings in the parent honokiol compound. In one embodiment, one or both of the double bonds in honokiol has been replaced with a cyclopropane, epoxide, thiirane, or aziridine moiety, optionally along with other structural modifications and optional substitutions. In one embodiment, the compounds have the following formula:

W is (CHR²)n, O—(CHR²)n, S—(CHR²)n, or NR²—(CHR²)n, optionally substituted with halogens, such as fluorine (i.e., (CF2)n and the like), X is O, S, or NR², Y is N or C bonded to a substituent, G, and in one embodiment, at least one Y is CF. R¹ is H, alkyl phosphate, dichloroacetate, trifluoromethyl, or valproate, R² is H, alkyl, aryl, arylalkyl, or alkylaryl, and when bonded to carbon, halo, such as fluoro, n is an integer from 1-4, Representative substituents, G, include C_1-6 alkyl (including cycloalkyl), alkenyl, heterocyclyl, aryl, heteroaryl, halo (e.g., F, Cl, Br, or I), —OR′, —NR³R⁴, —CF3, —CN, —NO2, —C2R³, —S R³, —N3, —C(═O)NR³R⁴, —NR³C(═O)R³, —C(═O)R³, —C(═O)OR³, — OC(═O)R³, —OC(═O)NR³R⁴, —NR³C(═O)OR³, —SO2R³, —SO2NR³R⁴, and —NR³SO2R³, where R³ and R⁴ are individually hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, (such as benzyl); z is an integer of from 0-3, but in any case cannot exceed the number of carbon atoms in the ring, one or both of the aryl rings can be replaced with thiophene, pyrrole, or furan, and one of the three membered rings can be replaced with a double bond (i.e., X represents a bond between the two carbons to which it is attached). In one embodiment, a fluoro moiety is present ortho to one or both OR¹ moieties. In one aspect of this embodiment, each Y is CF. In another embodiment, the compounds have the following formula: where

. In still another embodiment, the compounds have the following formula:

w e e , , a a e as e e above. Representative individual compounds include the following:

and analogs thereof with between one and six additional fluorine atoms. The compounds shown above have, in some embodiments, a double bond that can be present in either cis or trans (E or Z) form, and in other embodiments, a chiral carbon on the epoxide, thiirane, or aziridine rings, which can be in either the R or S configuration, or mixtures thereof. The individual compounds representing the various stereoisomeric forms and isomeric forms of these compounds are within the scope of the invention. In one embodiment, the compound is honokiol. Aqueous extracts of Magnolia grandiflora have been shown to be SIRT3 agonists, and the small molecular weight compound honokiol is the active principle of magnolia extract. Honokiol has the following formula: While honokiol is an active s, can be used, it can be

advantageous to use the hexafluoro-honokiol analogs described herein, as they are believed to be even more active. The compounds of any of the above formulas can be present in the form of racemic mixtures or pure enantiomers, or occur in varying degrees of enantiomeric excess, and racemic mixtures can be purified using known chiral separation techniques. The compounds can be in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts). Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with an acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium; ammonium salt; organic basic salts such as trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, and N,N′-dibenzylethylenediamine; and salts with a basic amino acid such as lysine and arginine. The salts can be in some cases hydrates or ethanol solvates. The stoichiometry of the salt will vary with the nature of the components. II. Methods of Preparing the Compounds In one embodiment, the compounds described above are those in which R¹ and R² = H, X is a double bond, and Y = CH. The synthesis of compounds of this type is described below, followed by the synthesis of analogs of these compounds. These analogs, other than those in which the aromatic ring is replaced with a heteroaromatic ring, can typically be prepared from starting materials of this type. A. General Procedure for Synthesizing the Hexafluoro-Honokiol Analogs The hexafluoro-honokiol analogs compounds described above which contain allyl and hydroxy moieties can be prepared according to the following general procedures. The simplest hexafluoro-honokiol analog, which has the formula of honokiol, but for the bis(trifluoromethyl)methane bridge between the two aromatic rings, has the following formula. following reaction scheme (Scheme I):

, . , igmaAldrich Chemicals) is reacted with allyl bromide in the presence of a base to produce a bis-allyl ether. Hexafluorobisphenol A is also known as 2,2-bis(4-hydroxy-phenyl)-1,1,1,3,3,3-hexafluoropropane; 3,3′- (hexafluoroisopropylidene)diphenol; 4,4′-(2,2,2-trifluoro-1-(trifluoromethyl)ethylidene)bis- pheno; 4,4′-(bis(trifluoromethyl)methylene)di-Phenol; 4,4′-(trifluoro-1- (trifluoromethyl)ethylidene)di-pheno; 4,4′-(trifluoro-1-(trifluoromethyl)ethylidene)diphenol; 4,4′- [2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]bis-pheno; and 4,4′-[2,2,2-Trifluoro-1- (trifluoromethyl)ethylidene]bisphenol). Reaction of the bis-allyl ether with a Lewis acid, such as boron trifluoride etherate, produces the product, 2,2-bis(3-allyl-4-hydroxy-phenyl)-1,1,1,3,3,3-hexafluoropropane. When preparing substituted analogs of this compound, where a desired functional group is present on the allyl moiety, it is important to recognize that the double bond in the allyl moiety switches position during the Lewis acid-catalyzed rearrangement reaction. This rearrangement of the double bond is shown below with respect to an analog where an R² group is present on the allyl ether:

B. Preparation of More Highly Fluorinated Analogs While not wishing to be bound to a particular theory, the presence of the bis(trifluoromethyl)methylene moiety in the compounds is believed to provide the compounds with resistance to metabolic degradation, resulting in longer circulating half-lives. Accordingly, in some cases, it may be desirable to add additional fluorination to the honokiol analogs. The following Schemes II and III show how additional fluorination can be added to the honokiol analogs.

, Chem Compound ID: 10920585) is used instead of allyl bromide. Alternatively, fluoro moieties can be present at different and/or additional positions on the allyl bromide. The chemistry proceeds as in Scheme I, except that a fluoro moiety is present on each of the allyl groups. In the following Scheme III, the hexafluorobisphenol A is replaced with a hexafluorobisphenol in which one or more of the CH groups on the phenol rings is replaced with a CF group.

In the above scheme, each of the aryl rings in the hexafluorobisphenol A can include between one and three fluoro groups on the aromatic rings, so long as there is at least one CH group which can react with the allyl ether when exposed to the Lewis acid. The synthesis then proceeds as in Scheme I, except that one or more fluoro moieties are present on one or more of the aryl rings. C. Replacement of One or Both Phenyl Rings with a Heteroaryl Ring In one embodiment, one or both of the phenyl rings is replaced with a heteroaromatic ring (i.e., one or more Y are N). In one aspect of this embodiment, the chemistry for preparing the hexafluorohonokiol analogs involves first preparing an analog of hexafluoro bisphenol A in which a ring carbon is replaced with one or more ring nitrogens. Generally, methods for producing bi-aryl, aryl-heteroaryl, or bi-heteroaryl core structures including such bis-trifluoromethyl-methylene linkers involve first reacting a aryl organometallic compound, such as an aryl lithium or aryl magnesium bromide, with hexafluoroacetone to produce the corresponding 1,1,1,3,3,3-hexafluoro-propan-2-ol intermediate. This tertiary alcohol can be converted to a suitable leaving group (i.e., halo, tosylate, and the like) using known chemistry, and can be coupled using electrophilic aromatic substitution on a second aromatic ring. Alternatively, the halo or tosylate intermediate can be used to form an organometallic compound, such as an organolithium, organomagnesium halide, or organozinc halide compound, which can be coupled to an appropriately functionalized aryl halide. A representative synthesis, where one ring is pyridine and the other is phenyl, is shown below in Scheme IV.

In Scheme IV above, Pr stands for a protecting group for the hydroxy group. Suitable protecting groups for hydroxy groups, and methods for deprotecting the protected hydroxy groups, are well known, and are described, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^rd Edition, John Wiley & Sons, New York (1999). Other aromatic rings can be substituted for the phenyl and pyridinyl rings shown above. Once the heteroaryl analog of the hexafluorobisphenol A is produced, the remaining steps (i.e., formation of an allyl ether, and the acid catalyzed rearrangement of the ether) proceed as with hexafluorobisphenol A. D. Further Substitution on the Core Molecule The compounds of Formula I can have a bi-aryl, aryl-heteroaryl, or bi-heteroaryl core structure, where each ring includes a hydroxyl group and a side chain. Depending on the definition of W, the side chain also can include an ether, thioether, or amine bridge between the aryl/heteroaryl ring and the three membered ring. Depending on the definition of X, the three membered ring can be a cyclopropane, epoxide, thiirane, or aziridine. Ideally, the aryl/heteroaryl rings either include an appropriate side chain or side chain precursor, or include appropriate functionality to attach the side chain. A double bond can serve as a precursor for a cyclopropane, epoxide, thiirane, or aziridine ring, as discussed in more detail below. Accordingly, using known starting materials, one can couple two appropriately substituted aryl rings, an aryl ring and a heteroaryl ring, or two heteroaryl rings, attach a side chain or side chain precursor, if the side chain or side chain precursor is not already attached, and convert one or more side chain precursors (i.e., double bonds) into cyclopropane, epoxide, thiirane, or aziridine rings. Representative processes for effecting these conversions are described in detail below. Compounds where W is C1-4 Alkyl or Haloalkyl Compounds where W is C1-4 alkyl or haloalkyl, such as perfluoroalkyl or any fluorinated analog with from one fluorine to perfluorination, can be prepared via a number of methods, including either a) having an appropriate C1-4 alkyl moiety, with a double bond attached at the terminal end of the side chain, present during the coupling of the aryl/heteroaryl rings to form the biaryl, aryl-heteroaryl, or bi-heteroaryl rings, or b) including a functional group on the aryl/heteroaryl rings that can be converted to a C1-4 alkyl moiety, with a double bond attached at the terminal end of the side chain. For example, if a halide is present on one of the aryl/heteroaryl rings, it can be reacted, for example, using conventional coupling chemistry, with a halo-alkene (such as an allyl halide (also known as a 3-halo-prop-1-ene, for example, allyl bromide), 4-halo-but-1-ene, 5-halo-pent-1-ene, or 6-halo-hex-1-ene), to form an aryl-alkene or heteroaryl-alkene intermediate. Following the coupling reaction, the double bond can be converted to a suitable three membered ring, such as a cyclopropane, epoxide, thiirane, or aziridine. The double bond-containing moieties listed above would produce a three membered ring with a (CH2) moiety, but if other functionalization is desired, one of the hydrogens on the ═CH2 terminus of the halo-alkene could be replaced with an alkyl, aryl, alkylaryl, or arylalkyl group. Such double bond-containing materials are either well known to those of skill in the art, or can be easily prepared using conventional chemistry. If one or more double bond-containing moieties are present during the coupling of the aryl/heteroaryl rings, they will not interfere with nor be destroyed during the coupling chemistry. Similarly, if a cyclopropane ring-containing side chain is present on the aryl/heteroaryl ring during the coupling chemistry, the ring will not be adversely affected during the coupling chemistry. However, if a side chain when X O, S, or NR² were present during the coupling chemistry, these groups might be adversely affected, so it is preferred to first provide the double bond moiety, and then to convert it to the desired cyclopropane, thiirane, or aziridine moiety. Compounds where W is O—(CHR²)n, S—(CHR²)n, or NR²—(CHR²)n Compounds where W is O—(CHR²)n, S—(CHR²)n, or NR²—(CHR²)n can be prepared via a number of methods, including either a) having an appropriate O—(CHR²)n, S—(CHR²)n, or NR²—(CHR²)n alkyl moiety, with a double bond attached at the terminal end of the side chain, present during the coupling of the aryl/heteroaryl rings to form the biaryl, aryl-heteroaryl, or bi- heteroaryl rings, or b) including a protected hydroxyl, thiol, or amine group on the aryl/heteroaryl rings that can be deprotected and subsequently converted to an O—(CHR²)n, S—(CHR²)n, or NR²—(CHR²)n moiety, with a double bond attached at the terminal end of the side chain. The latter can be accomplished, for example, by reaction of a hydroxyl, thiol, or amine with an alkenyl bromide (as above) to form an ether, thioether, or amine linkage. In some embodiments, it is desired to incorporate halogens, such as flourines, into the alkyl group (i.e., (CF2)n). Such fluorinated moieties can readily be incorporated, using techniques known to those of skill in the art. Conversion of Double Bonds to Cyclopropane Rings Following the attachment of double bond-containing side chains, one or both of the double bonds can be converted to cyclopropane rings. The cyclopropane rings can include a CH2 moiety, or can be substituted with one or two methyl groups. The derivatives described herein include derivatives in which one or both of the double bonds is replaced with a (unsubstituted, monoalkyl or dialkyl, where alkyl can be substituted or unsubstituted, and is preferably methyl)cyclopropyl group. The synthesis of alkyl, such as methyl, dialkyl, such as dimethyl and unsubstituted cyclopropane derivatives is well known to those of skill in the art, and involves, for example, bromoform reaction to form the dibromocyclopropane derivative, followed by stoichiometric reaction with a hydride or an alkyl-lithium. An aryl-lithium will provide aryl substitution on the cyclopropane ring. If fluoro-substitution is desired on the cyclopropane ring, it can be provided, for example, by displacing the bromines with fluorines using known chemistry. Conversion of Double Bonds to Epoxide Rings Following the attachment of double bond-containing side chains, one or both of the double bonds can be converted to epoxide rings. The epoxide rings can be formed, for example, by reaction of the double bond with m-chloroperbenzoic acid. Alternatively, the epoxide rings can be formed by halohydrogenation of the double bond to form halohydrins, followed by the addition of base. Halohydrins are typically prepared by adding aqueous hypochlorous acid (HOCl) or hypobromous acid (HOBr) to alkenes, often by using aqueous solutions of the halogen, where the reaction proceeds by formation of the intermediate halonium ion. The base deprotonates the hydroxyl group, which then nucleophilically displaces the halide to form the epoxide ring. The choice of reaction conditions can be made depending on the susceptibility of the other substituents on the intermediate to such reaction conditions. Conversion of Double Bonds to Thiirane Rings Following the attachment of double bond-containing side chains, one or both of the double bonds can be converted to thiirane rings. The thiirane rings can be formed, for example, by bromination of the double bond, followed by S′-substitution in sodium sulfides (see for example, Choi J et al (1995) Bull. Korean. Chem. Soc., 16, 189-190, Convenient Synthesis of Symmetrical Sulfides from Alkyl Halides and Epoxides). Conversion of Double Bonds to Aziridine Rings Following the attachment of double bond-containing side chains, one or both of the double bonds can be converted to aziridine rings. The aziridine rings can be formed, for example, by selective aziridination of olefins with p-toluenesulfonamide catalyzed by dirhodium(II) caprolactamate. Aziridine formation occurs through aminobromination and subsequent base- induced ring closure. See, for example, A. J. Catino, J. M. Nichols, R. E. Forslund, M. P. Doyle, Org. Lett., 2005, 7, 2787-2790. Protection and Deprotection of Hydroxy Groups As discussed herein, hydroxyl groups present on the aryl/heteroaryl rings may need to be protected during portions of the synthesis, and deprotected at a later time. Protecting groups, and methods for their removal, are well known to those of skill in the art, and are described for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^rd Edition, John Wiley & Sons, New York (1999). Conversion of Hydroxy Groups to Trifluoromethyl Ethers Starting with honokiol or the analogs thereof, one can readily convert one or both of the hydroxyl groups to a trifluoromethyl ether, using techniques known to those of skill in the art. For example, an alkoxide salt of the hexafluoro-honokiol compounds where R¹ is H can be reacted with trifluoroiodomethane to form the trifluoromethyl ether. The starting materials used to make the hexafluoro-honokiol analogs described herein are either commercially available, or can be prepared from commercially available starting materials. Those that are not commercially available can be made by a variety of synthetic methodologies, related to the particular moieties and the particular substitution desired. The variation in synthetic methodology will be readily apparent to those of skill in the art of organic synthesis. Those skilled in the art will readily understand that incorporation of other substituents onto the aromatic or heteroaromatic rings used as a starting material to prepare the hexafluoro-honokiol analogs, and other positions in the hexafluoro-honokiol framework, can be readily realized. Such substituents can provide useful properties in and of themselves or serve as a handle for further synthetic elaboration. Substituents typically can be added to a phenyl and/or heteroaryl ring before adding the side chains. A number of other analogs, bearing substituents in the diazotized position of the aryl/heteroaryl rings, can be synthesized from the corresponding amino compounds, via diazonium salt intermediates. The diazonium salt intermediates can be prepared using known chemistry, for example, as described above. Nitration of an aryl or heteroaryl results, followed by reaction with a nitrite salt, typically in the presence of an acid, produces an amine functionality on the aryl/heteroaryl ring. Other substituted analogs can be produced from diazonium salt intermediates, including, but are not limited to, hydroxy, alkoxy, fluoro, chloro, iodo, cyano, and mercapto, using general techniques known to those of skill in the art. For example, hydroxy-aryl/heteroaryl analogs can be prepared by reacting the diazonium salt intermediate with water. Likewise, alkoxy hexafluoro-honokiol analogs can be made by reacting the diazonium salt with alcohols. The diazonium salt intermediates can also be used to synthesize cyano or halo compounds, as will be known to those skilled in the art. In one embodiment, where the halo compounds are fluoro compounds, a diazonium group can be converted into a diazonium-fluoro-borate group, and the fluorine substituent can be formed via the latter group using known chemistry (see, for example, U.S. Pat. No. 4,960,797). Mercapto substitutions can be obtained using techniques described in Hoffman et al., J. Med. Chem. 36: 953 (1993). The mercaptan so generated can, in turn, be converted to an alkylthio substitutuent by reaction with sodium hydride and an appropriate alkyl bromide. Subsequent oxidation would then provide a sulfone. Acylamido analogs of the aforementioned compounds can be prepared by reacting the corresponding amino compounds with an appropriate acid anhydride or acid chloride using techniques known to those skilled in the art of organic synthesis. Hydroxy-substituted analogs can be used to prepare corresponding alkanoyloxy- substituted compounds by reaction with the appropriate acid, acid chloride, or acid anhydride. Likewise, the hydroxy compounds are precursors of both the aryloxy and heteroaryloxy via nucleophilic aromatic substitution at electron deficient aromatic rings. Such chemistry is well known to those skilled in the art of organic synthesis. Ether derivatives can also be prepared from the hydroxy compounds by alkylation with alkyl halides and a suitable base or via Mitsunobu chemistry, in which a trialkyl- or triarylphosphine and diethyl azodicarboxylate are typically used. See Hughes, Org. React. (N.Y.) 42: 335 (1992) and Hughes, Org. Prep. Proced. Int. 28: 127 (1996) for typical Mitsunobu conditions. Cyano-substituted analogs can be hydrolyzed to afford the corresponding carboxamido- substituted compounds. Further hydrolysis results in formation of the corresponding carboxylic acid-substituted analogs. Reduction of the cyano-substituted analogs with lithium aluminum hydride yields the corresponding aminomethyl analogs. Acyl-substituted analogs can be prepared from corresponding carboxylic acid-substituted analogs by reaction with an appropriate alkyllithium using techniques known to those skilled in the art of organic synthesis. Carboxylic acid-substituted analogs can be converted to the corresponding esters by reaction with an appropriate alcohol and acid catalyst. Compounds with an ester group can be reduced with sodium borohydride or lithium aluminum hydride to produce the corresponding hydroxymethyl-substituted analogs. These analogs in turn can be converted to compounds bearing an ether moiety by reaction with sodium hydride and an appropriate alkyl halide, using conventional techniques. Alternatively, the hydroxymethyl-substituted analogs can be reacted with tosyl chloride to provide the corresponding tosyloxymethyl analogs, which can be converted to the corresponding alkylaminoacyl analogs by sequential treatment with thionyl chloride and an appropriate alkylamine. Certain of these amides are known to readily undergo nucleophilic acyl substitution to produce ketones. Hydroxy-substituted analogs can be used to prepare N-alkyl- or N-arylcarbamoyloxy- substituted compounds by reaction with N-alkyl- or N-arylisocyanates. Amino-substituted analogs can be used to prepare alkoxycarboxamido-substituted compounds and urea derivatives by reaction with alkyl chloroformate esters and N-alkyl- or N-arylisocyanates, respectively, using techniques known to those skilled in the art of organic synthesis. Similarly, benzene rings (and pyridine, pyrimidine, pyrazine, and other heteroaryl rings) can be substituted using known chemistry, including the reactions discussed above. For example, the nitro group on nitrobenzene can be reacted with sodium nitrite to form the diazonium salt, and the diazonium salt manipulated as discussed above to form the various substituents on a benzene ring. III. Pharmaceutical Compositions The compounds described herein can be incorporated into pharmaceutical compositions and used to prevent a condition or disorder in a subject susceptible to such a condition or disorder, and/or to treat a subject suffering from the condition or disorder. The pharmaceutical compositions described herein include one or more of the hexafluoro-honokiol analogs described herein, and/or pharmaceutically acceptable salts thereof. Optically active compounds can be employed as racemic mixtures, as pure enantiomers, or as compounds of varying enantiomeric purity. The manner in which the compounds are administered can vary. The compositions are preferably administered orally (e.g., in liquid form within a solvent such as an aqueous or non- aqueous liquid, or within a solid carrier). Preferred compositions for oral administration include pills, tablets, capsules, caplets, syrups, and solutions, including hard gelatin capsules and time- release capsules. Compositions may be formulated in unit dose form, or in multiple or subunit doses. Preferred compositions are in liquid or semisolid form. Compositions including a liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids may be used. The use of such liquids and semisolids is well known to those of skill in the art. The compositions can also be administered via injection, i.e., intraveneously, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally; and intracerebroventricularly. Intravenous administration is a preferred method of injection. Suitable carriers for injection are well known to those of skill in the art, and include 5% dextrose solutions, saline, and phosphate buffered saline. The compounds can also be administered as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids). The formulations may also be administered using other means, for example, rectal administration. Formulations useful for rectal administration, such as suppositories, are well known to those of skill in the art. The compounds can also be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Pat. No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety); topically (e.g., in lotion form); or transdermally (e.g., using a transdermal patch, using technology that is commercially available from Novartis and Alza Corporation). Although it is possible to administer the compounds in the form of a bulk active chemical, it is preferred to present each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration. The compounds can be incorporated into drug delivery devices such as nanoparticles, microparticles, microcapsules, and the like. Representative microparticles/nanoparticles include those prepared with cyclodextrins, such as pegylated cyclodextrins, liposomes, including small unilamellar vesicles, and liposomes of a size designed to lodge in capillary beds around the heart, particularly when a patient has ischemia, or in the brain following an ischemic stroke. Suitable drug delivery devices are described, for example, in Heidel J D, et al., Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA, Proc Natl Acad Sci USA. 2007 Apr. 3; 104(14):5715-21; Wongmekiat et al., Preparation of drug nanoparticles by co-grinding with cyclodextrin: formation mechanism and factors affecting nanoparticle formation, Chem Pharm Bull (Tokyo). 2007 March; 55(3):359-63; Bartlett and Davis, Physicochemical and biological characterization of targeted, nucleic acid-containing nanoparticles, Bioconjug Chem.2007 March- April; 18(2):456-68; Villalonga et al., Amperometric biosensor for xanthine with supramolecular architecture, Chem Commun (Camb). 2007 Mar. 7; (9):942-4; Defaye et al., Pharmaceutical use of cyclodextrines: perspectives for drug targeting and control of membrane interactions, Ann Pharm Fr. 2007 January; 65(1):33-49; Wang et al., Synthesis of Oligo(ethylenediamino)-beta- Cyclodextrin Modified Gold Nanoparticle as a DNA Concentrator; Mol. Pharm. 2007 March- April; 4(2):189-98; Xia et al., Controlled synthesis of Y-junction polyaniline nanorods and nanotubes using in situ self-assembly of magnetic nanoparticles, J Nanosci Nanotechnol., 2006 December; 6(12):3950-4; and Nijhuis et al., Room-temperature single-electron tunneling in dendrimer-stabilized gold nanoparticles anchored at a molecular printboard, Small. 2006 December; 2(12):1422-6. Exemplary methods for administering such compounds will be apparent to the skilled artisan. The usefulness of these formulations may depend on the particular composition used and the particular subject receiving the treatment. These formulations may contain a liquid carrier that may be oily, aqueous, emulsified or contain certain solvents suitable to the mode of administration. The compositions can be administered intermittently or at a gradual, continuous, constant or controlled rate to a warm-blooded animal (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey), but advantageously are administered to a human being. In addition, the time of day and the number of times per day that the pharmaceutical formulation is administered can vary. In certain circumstances, the compounds described herein can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular cardiovascular disorder, i.e., combination therapy. In addition to effective amounts of the compounds described herein, the pharmaceutical compositions can also include various other components as additives or adjuncts. Combination Therapy The combination therapy may be administered as (a) a single pharmaceutical composition which comprises a hexafluoro-honokiol analog as described herein, at least one additional pharmaceutical agent described herein, and a pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a hexafluoro-honokiol analog as described herein and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical compositions can be administered simultaneously or sequentially and in any order. In use in treating or preventing cardiovascular disorders, the hexafluoro-honokiol analogs described herein can be administered together with at least one other therapeutic agent as part of a unitary pharmaceutical composition. Alternatively, the hexafluoro-honokiol analogs can be administered apart from the other therapeutic agent. In this embodiment, the hexafluoro-honokiol analogs and the at least one other therapeutic agent are administered substantially simultaneously, i.e. the compounds are administered at the same time or one after the other, so long as the compounds reach therapeutic levels for a period of time in the blood. Combination therapy involves administering a hexafluoro-honokiol analog, as described herein, or a pharmaceutically acceptable salt or prodrug of a compound described herein, in combination with at least one therapeutic agent useful for treating cardiovascular disorders, ideally one which functions by a different mechanism. When used to treat hypertension, the type of anti-hypertensive agents which can be used for combination therapy will typically vary, depending on the patient, and the stage of hypertension. Several classes of known medications, collectively referred to as antihypertensive medications, are available for treating hypertension. First-line medications for hypertension include thiazide-diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), and angiotensin receptor blockers (ARBs). Beta-blockers, such as atenolol, can also be used. These medications may be used alone or in combination, though ACE inhibitors and ARBs are not recommended for use in combination. Medications for blood pressure control can be implemented using a stepped care approach when target levels are not reached. Resistant hypertension is defined as high blood pressure that remains above a target level, in spite of being prescribed three or more antihypertensive drugs simultaneously with different mechanisms of action. Resistant hypertension may also result from chronically high activity of the autonomic nervous system, an effect known as neurogenic hypertension. Electrical therapies that stimulate the baroreflex are an option for lowering blood pressure in people in this situation. Some common secondary causes of resistant hypertension include obstructive sleep apnea, pheochromocytoma, renal artery stenosis, coarctation of the aorta, and primary aldosteronism. Refractory hypertension is characterized by uncontrolled elevated blood pressure unmitigated by five or more antihypertensive agents of different classes, including a long-acting thiazide-like diuretic, a calcium channel blocker, and a blocker of the renin-angiotensin system. Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the arteries of the lungs. A patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 25mmHg at rest, or greater than 30mmHg during exercise. When used to treat pulmonary hypertension, the hexafluoro honokiol analogs described herein can be co-administered with oxygen therapy, diuretics, and medications to inhibit blood clotting. Specific agents used to treat pulmonary hypertension include epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, and sildenafil. The appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers. By “effective amount”, “therapeutic amount” or “effective dose” is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder. When treating cardiovascular disorders, an effective amount of the hexafluoro-honokiol analog is an amount sufficient to increase SIRT3 levels by at least 10%, preferably at least 20%, more preferably, at least 30%, and still more preferably at least 40% or more, relative to levels prior to administration of the hexafluoro honokiol analogs. Preferably, the effective amount is sufficient to obtain the desired result, but insufficient to cause appreciable side effects. The effective dose can vary, depending upon factors such as the condition of the patient, the severity of the cardiovascular disorder, and the manner in which the pharmaceutical composition is administered. The effective dose of compounds will of course differ from patient to patient, but in general includes amounts starting where desired therapeutic effects occur but below the amount where significant side effects are observed. For human patients, the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1, often at least about 10, and frequently at least about 25 μg/24 hr/patient. The effective dose generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 μg/24 hr/patient. In addition, administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/mL and frequently does not exceed 100 ng/mL. IV. Methods of Using the Compounds and/or Pharmaceutical Compositions In one embodiment, the compounds described herein, and pharmaceutical compositions including the compounds, can be used to treat or prevent cardiovascular disorders. Representative disorders that can be treated include hypertension, endothelial dysfunction, vascular rarefaction, including capillary rarefaction, pulmonary hypertension and pulmonary vascular dysfunction. The compounds described herein are SIRT3 agonists, and as such, can be used to treat these disorders. The role of SIRT3 in cardiovascular disease is illustrated in Figure 3. In some embodiments, the patient already has a cardiovascular disorder, and is undergoing treatment for the disorder, and in other embodiments, the patient does not already show symptoms of a cardiovascular disorder, but has relatively low SIRT3 levels, and the administration of the hexafluoro honokiol analogs described herein can prevent the development of the disorders by normalizing, or at least increasing, the patient’s SIRT3 levels. The compounds can also be used as adjunct therapy in combination with existing therapies in the management of the aforementioned types of cardiovascular disorders. In another embodiment, the compounds described herein can be used to treat or prevent ischemic strokes. The following examples are provided to illustrate the present invention, and should not be construed as limiting thereof. In these examples, all parts and percentages are by weight, unless otherwise noted. Reaction yields are reported in mole percentages. EXAMPLES The following examples are provided to illustrate the present invention and should not be construed as limiting the scope thereof. In these examples, all parts and percentages are by weight, unless otherwise noted. Reaction yields are reported in mole percentage. Example 1: Effectiveness of Hexafluoro Honokiol in Treating Hypertension – In Vivo Assay Endothelial dysfunction plays a key role in the pathogenesis of hypertension and represents a major risk factor for cardiovascular disease. Despite treatment with multiple drugs, only 1 in 4 patients has blood pressure under control. We discovered a new synergistic control point with the potential to address this problem. We have shown that Sirt3 level is reduced in essential hypertension and endothelial Sirt3 overexpression attenuates endothelial dysfunction and hypertension. We proposed that induction endothelial Sirt3 after onset of hypertension rescues endothelial function and reduces hypertension. To test this hypothesis, we used genetic- and pharmacological Sirt3 induction. To genetically induce the expression of endothelial Sirt3 we used Sirt3 flox/flox mice crossed with VeCad-Cre mice treated with low dose of 4-hydroxytamoxifen (4HOT, i.p.0.3 mg/20 g daily, 5 days) which does not have off-target cardiovascular effects. Mice underwent telemetry placement and ten days later received 4-week osmotic pumps containing vehicle (saline) or angiotensin II (0.7 mg/kg/day). 14-days later half of mice received 4HOT to induce endothelial Sirt3 overexpression. Treatment of mice with 4HOT after onset of hypertension slightly reduced blood pressure but most importantly completely rescued endothelial-dependent relaxation, normalized mitochondrial O 2 . - and restored endothelial nitric oxide. Second, we tested if pharmacological induction of Sirt3 by hexafluoro (i.p. 8 mg/kg, 4 days) after onset of angiotensin II-induced hypertension improves endothelial function and reduces hypertension. It was found that hexafluoro substantially reduced systolic blood pressure, significantly diminished vascular mitochondrial O2 - and improved endothelial nitric oxide. To test the role of endothelial Sirt3 in pharmacological effect of hexafluoro we used endothelial specific Sirt3 knockout mice and angiotensin II model of hypertension. Interestingly, hexafluoro was not effective in endothelial Sirt3 deficient mice supporting critical role of endothelial Sirt3. These in vivo studies demonstrate therapeutic potential of genetic and pharmacological endothelial Sirt3 induction after onset of hypertension for treatment of endothelial dysfunction. The data shown in Figure 1 support the hypothesis that treatment of hypertensive mice (after onset of hypertension) with Sirt3 agonist hexafluoro honokiol (HFH) increases Sirt3 expression and reduces blood pressure (systolic blood pressure, mm Hg, was reduced when a mouse with angiotensin II-induced hypertension was administered hexafluoro honokiol (HFH), and increased when administered vehicle alone. As shown in Figures 2A and 2B, ex vivo treatment of human arterioles from hypertensive patients with Sirt3 agonist HFH, after onset of hypertension, reduces blood pressure. Figure 2A shows a typical Western blot of aortic Sirt3 in human arterioles treated, ex vivo, with vehicle (Sham) or HFH (3 µM). Results are mean ± SEM. *P<0.01 vs Ang II. These figures show the treatment of human arterioles with HFH (3 µM). (A) Western blots; (B) Mitochondrial O2^· in human arterioles isolated from mediastinal fat. Results are mean ± SEM (n=6). *P<0.01, *

P<0.01. Figure 2B is a chart showing the effect of ex vivo treatment of human arterioles with vehicle or HFH on mitochondrial O2 (pmol/mg protein) in normotensive and hypertensive arterioles. As shown in the figure, blood pressure was reduced in both normotensive and hypertensive arterioles. While not wishing to be bound to a particular theory, it is believed that ex vivo HFH treatment of arterioles from hypertensive patients improves Sirt3 expression and Sirt3 activity by deacetylation of SOD2 and LCAD proteins promoting the recovery of mitochondrial function and inhibiting vascular oxidative stress. Hexafluoro honokiol increases Sirt3 expression inducing deacetylation of mitochondrial proteins which results in reduced vascular inflammation markers (p65, ICAM) and reduction of cell-senescence marker (p21). Furthermore, by functioning as a Sirt3 agonist, treatment with hexafluoro honokiol reduces mitochondrial superoxide in human tissue and in animal experiments after onset of hypertension, and reduces blood pressure. The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.

Claims

Claims 1. A method for treating or preventing cardiovascular disorders, comprising administering a therapeutically-effective or prophylactically-effective amount of a compound of the following formula:

R¹ is H, alkyl phosphate, dichloroacetate, trifluoromethyl, or valproate, R^{2 is H, alkyl, aryl, arylalkyl, or alkylaryl, and when bonded to carbon, halo, such as fluoro,} Y is N or C bonded to a substituent, G, G is a substituent selected from the group consisting of C1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR³R⁴, —CF3, —CN, —NO2, —C2R³, —S R³, —N3, — C(═O)NR³R⁴, —NR³C(═O)R³, —C(═O)R³, —C(═O)OR³, —OC(═O)R³, —OC(═O)NR³R⁴, — NR³C(═O)OR³, —SO2R³, —SO2NR³R⁴, and —NR³SO2R³, where R³ and R⁴ are individually hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and z is an integer of from 0-3, but in any case cannot exceed the number of carbon atoms in the ring, optionally along with a pharmaceutically-acceptable carrier or excipient, to a patient in need of treatment or prevention thereof. 2. The method of Claim 1, wherein the therapeutic amount of the compound is that which provides a dosage of between about 1 and about 500 micrograms (μg) per patient per day. 3. The method of Claim 1, wherein the disorder is cardiovascular disorder is hypertension, endothelial dysfunction, vascular rarefaction, pulmonary hypertension or pulmonary vascular dysfunction.

4. The method of claim 1, wherein the compound has the formula:

R¹ is H, alkyl phosphate, dichloroacetate, trifluoromethyl, or valproate, R² is H, alkyl, aryl, arylalkyl, or alkylaryl, and when bonded to carbon, halo, such as fluoro, G is a substituent selected from the group consisting of C1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR³R⁴, —CF3, —CN, —NO2, —C2R³, —S R³, —N3, — C(═O)NR³R⁴, —NR³C(═O)R³, —C(═O)R³, —C(═O)OR³, —OC(═O)R³, —OC(═O)NR³R⁴, — NR³C(═O)OR³, —SO2R³, —SO2NR³R⁴, and —NR³SO2R³, where R³ and R⁴ are individually hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and z is an integer of from 0-3, but in any case cannot exceed the number of carbon atoms in the ring. 5. The method of claim 1, wherein the compound has one of the formulas:

dditional fluorine atoms. 6. The method of claim 1, wherein both of X are O. 7. The method of claim 1, wherein one of X is O, and the other represents a bond between the two carbons to which it is attached. 8. The method of claim 1, wherein all Y are C bonded to H or a substituent, G. 9. The method of claim 1, wherein one of Y is N. 10. The method of claim 1, wherein two of Y are N. 11. the method of claim 1, wherein each R² is H. 12. The method of claim 1, wherein each W is CH2. 13. The method of claim 1, wherein one or two of R¹ represent an alkyl phosphate ester, or a dichloroacetate. 14. The method of claim 1, wherein the compound has the formula:

selected from the group consisting of

valproate mono and diesters of hexafluoro-honokiol, dichloroacetate mono and diesters of hexafluoro-honokiol, and C1-6 alkyl phosphate mono and di-esters of hexafluoro-honokiol. 16. The method of any of Claims 1-15, wherein the compound is administered with a second active agent selected from the group consisting of thiazide-diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs) and beta-blockers. 17. The method of Claim 1, wherein the patient is elderly and/or suffers from one or more metabolic conditions. 18. The method of Claim 17, wherein the metabolic conditions are diabetes, hyperlipidemia or metabolic syndrome. 19. The use of a compound of the following formula:

R¹ is H, alkyl phosphate, dichloroacetate, trifluoromethyl, or valproate, R² is H, alkyl, aryl, arylalkyl, or alkylaryl, and when bonded to carbon, halo, such as fluoro, Y is N or C bonded to a substituent, G, G is a substituent selected from the group consisting of C1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR³R⁴, —CF3, —CN, —NO2, —C2R³, —S R³, —N3, — C(═O)NR³R⁴, —NR³C(═O)R³, —C(═O)R³, —C(═O)OR³, —OC(═O)R³, —OC(═O)NR³R⁴, — NR³C(═O)OR³, —SO2R³, —SO2NR³R⁴, and —NR³SO2R³, where R³ and R⁴ are individually hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and z is an integer of from 0-3, but in any case cannot exceed the number of carbon atoms in the ring, in the preparation of a medicament for use in treating or preventing cardiovascular disorders. 20. The use of Claim 19, wherein the medicament provides a dosage of between about 1 and about 500 micrograms (μg) per patient per day. 21. The use of Claim 19, wherein the disorder is cardiovascular disorder is hypertension, endothelial dysfunction, vascular rarefaction, pulmonary hypertension or pulmonary vascular dysfunction. 22. The use of Claim 19, wherein the compound has the formula:

R¹ is H, alkyl phosphate, dichloroacetate, trifluoromethyl, or valproate, R² is H, alkyl, aryl, arylalkyl, or alkylaryl, and when bonded to carbon, halo, such as fluoro, G is a substituent selected from the group consisting of C1-6 alkyl, alkenyl, heterocyclyl, aryl, heteroaryl, halo, —OR′, —NR³R⁴, —CF3, —CN, —NO2, —C2R³, —S R³, —N3, — C(═O)NR³R⁴, —NR³C(═O)R³, —C(═O)R³, —C(═O)OR³, —OC(═O)R³, —OC(═O)NR³R⁴, — NR³C(═O)OR³, —SO2R³, —SO2NR³R⁴, and —NR³SO2R³, where R³ and R⁴ are individually hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl, and z is an integer of from 0-3, but in any case cannot exceed the number of carbon atoms in the ring. 23. The use of Claim 19, wherein the compound has one of the formulas:

dditional fluorine atoms. 24. The use of Claim 19, wherein both of X are O. 25. The use of Claim 19, wherein one of X is O, and the other represents a bond between the two carbons to which it is attached. 26. The use of Claim 19, wherein all Y are C bonded to H or a substituent, G. 27. The use of Claim 19, wherein one of Y is N. 28. The use of Claim 19, wherein two of Y are N. 2^{9. The use of Claim 19, wherein each R2 is H.}

30. The use of Claim 19, wherein each W is CH2. 31. The use of Claim 19, wherein one or two of R¹ represent an alkyl phosphate ester, or a dichloroacetate. 32. The use of Claim 19, wherein the compound has the formula: elected from the group consisting of

valproate mono and diesters of hexafluoro-honokiol, dichloroacetate mono and diesters of hexafluoro-honokiol, and C1-6 alkyl phosphate mono and di-esters of hexafluoro-honokiol. 34. The use of any of Claims 19-34, wherein the compound is administered with a second active agent selected from the group consisting of thiazide-diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs) and beta-blockers. 35. The use of Claim 19, wherein the metabolic conditions are diabetes, hyperlipidemia or metabolic syndrome.