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We previously discovered m-carborane-containing estrogen receptor (ER) modulator 4, which exhibits weak ER-agonistic and antagonistic activities in transactivation assays. With the aim of developing novel ER partial agonists, we designed and synthesized various analogues of 4 with a bent-core structure, that is, pseudo cyclic structure (5), tetrahydropyrimidinone (6), m-benzene (7), adamantane (8), and 9,10-dimethyl-m-carborane (9), in place of the m-carborane moiety. Compound 9 showed greater binding affinity than 4 in ER-binding assay using [6,7-3H]-17β-estradiol and was a more effective partial agonist than 4 in MCF-7 cell proliferation assay. It appears to be a promising candidate as a selective ER modulator (SERM).

Genetic variations in cytochrome P450 2D6 (CYP2D6) contribute to interindividual variability in the metabolism of clinically used drugs, e.g., tamoxifen. CYP2D6 is genetically polymorphic and is associated with large interindividual variations in therapeutic efficacy and drug toxicity. In this study, we performed an in vitro analysis of 50 allelic variants of CYP2D6 proteins. Wild-type CYP2D6.1 and 49 variants were transiently expressed in COS-7 cells, and the enzymatic activities of the CYP2D6 variants were characterized using N-desmethyltamoxifen as a substrate. The kinetic parameters K(m), V(max), and intrinsic clearance (V(max)/K(m)) of N-desmethyltamoxifen 4-hydroxylation were determined. Among the 50 CYP2D6 variants, the kinetic parameters for N-desmethyltamoxifen 4-hydroxylation were determined for 20 CYP2D6 variants. On the other hand, the kinetic parameters of 30 CYP2D6 variants could not be determined because the amount of metabolite produced was at or below the detection limit at the lower substrate concentrations. Among them, 8 variants, i.e., CYP2D6.2, .9, .26, .28, .32, .43, .45, and .70, showed decreased intrinsic clearance at

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.

Aromatic nucleophilic substitution (S N Ar) reaction of 1-phenyl- o -carborane with 4-nitrofluorobenzene in the presence of NaH or KO t Bu proceeded smoothly to give 1-(4-nitrophenyl)-2-phenyl- o -carborane; similar reaction affords various 1,2-diaryl- o -carboranes, which are useful precursors for macromolecular construction and drug design.

We previously showed that fluorination of the carborane-containing selective estrogen receptor modulator (SERM) BE360 altered the agonist/antagonist activity balance and the estrogen receptor (ER) α/β subtype selectivity. Here, we designed and synthesized a series of fluorinated carboranyl phenols as candidate ERβ-selective ligands. Introduction of a fluorine atom onto the carborane cage commonly reduced the binding affinity for ERα, to an extent that depended on the other substituents present. The B-fluorinated m-carboranyl phenol 4a showed fourfold more potent ERβ-binding affinity than the parent non-fluorinated compound 7. 1-Iodo-9-fluoro-m-carboranyl phenol 4f showed high ERβ-binding affinity with an ERβ/ERα selectivity ratio of 8.2. Among the compounds tested, 6 showed the highest ERβ selectivity (10.1-fold) and the highest ER-agonistic activity (EC50: 5.1×10(-10) M) in MCF-7 cell proliferation assay.

A potent androgen receptor (AR) antagonist, 3-(12-hydroxymethyl-1,12 dicarba-closo-dodecaboran-1-yl)benzonitrile (3a, BA341), contains a p-carborane cage as a hydrophobic pharmacophore. We elucidated the structural properties of 3a by means of single-crystal X-ray diffraction analysis and conducted a docking study of 3a with hAR LBD. The cyano group of 3a formed hydrogen bonds with Gln711 and Arg752 and the hydroxymethyl group did so with Asn705 and Thr877 in hAR LBD. The bulky p-carborane cage was accommodated in the hydrophobic pocket of hAR LBD. To understand the structure–activity relationship around the hydroxymethyl group of 3a, we designed, synthesized, and evaluated the biological activities of various novel AR ligands. Since the biological activities of carbonyl compounds 8a, 8b, and 8c were similar to or weaker than those of the parent hydroxyl compounds 3a, 7a, and 7b, it seems to be necessary to have not only a hydrogen bonding acceptor, but also a hydrogen bonding donor adjacent to the hydroxymethyl group of 3a for efficient interaction with hAR LBD.

Based on the structures of two potent retinoid X receptor agonists, the novel dibenzodiazepine derivatives (VI), (VIII), and (XIII), containing two diphenylamine substructures, are designed as retinoid X receptor modulator candidates and prepared by means of Pd-catalyzed, cf.

The synthesis and biological evaluation of the dicarba-closo-dodecaborane (carborane) derivatives of retinoids are described. Retinoidal activity was examined in terms of the differentiation-inducing ability toward human promyelocytic leukemia HL-60 cells. High retinoidal activity (agonist or antagonist for the retinoid receptor RAR) requires a carboxylic acid moiety and an appropriate hydrophobic group located at a suitable position on the molecule. 4-[4-(1, 2-Dicarba-closo-dodecaboran-1-yl)phenylamino]benzoic acids and 4-[3-(1, 2-dicarba-closo-dodecaboran-1-yl)phenylamino]benzoic acids showed potent agonistic activity at concentrations of 10-8-10-9 M. The results indicate that carboranes are applicable as the hydrophobic moiety of biologically active molecules.

Pure androgen receptor (AR) full antagonists are candidates to treat anti-androgen refractory prostate cancers. We previously developed a carborane-containing AR antagonist, 3-(12-hydroxymethyl-1,12-dicarba-closo-dodecaborane-1-yl)benzonitrile (BA341), which was more potent than hydroxyflutamide (4) but acted as an agonist toward LNCaP prostate cancer cells expressing T877A AR mutant. Here, we designed and synthesized novel AR full antagonists structurally based upon the clinically used AR full antagonist (R)-bicalutamide (5) to test our hypothesis that the carborane cage is suitable as a hydrophobic pharmacophore for AR ligands. Compounds 7b and 8b showed good biological profiles in AR binding and transactivation assays and dose-dependently inhibited the testosterone-induced proliferation of LNCaP cells, as well as SC-3 cells. The IC(50) values of compounds 7b and 8b were 3.8 x 10(-7) and 4.2 x 10(-7) M, respectively [5, 8.7 x 10(-7) M]. Since compounds 7b and 8b did not show any agonistic activity in functional assays, they seem to be pure AR full antagonists and are therefore candidates for treatment of anti-androgen withdrawal syndrome.

Several tropolone derivatives (4-7) were designed as novel retinoids on the assumption that the tropolone ring may mimic the benzoic acid moiety in retinoid structures, such as Am80 (2). Among the synthesized compounds, 5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethynyl]tropolone (7a) showed moderate potency as a differentiation-inducer of HL-60 cells. The activities of the tropolones were greatly enhanced in the presence of HX630, an RXR agonist (retinoid synergist).

Novel carborane-containing estrogen receptor (ER) modulators, carbamate and thiocarbamate derivatives 5 and 6, were designed and synthesized based upon the m-carborane bisphenol skeleton. Their activities were evaluated by competitive binding assay with recombinant human ERalpha, transcriptional activation assay and cell proliferation assay. All test compounds dose-dependently bound to human ERalpha and showed potent estrogenic activity. The binding affinities of thiocarbamates 6a and 6b are higher than those of the alkyl carbamates 5a-5d and are similar to that of the phenyl carbamate 5e. The binding affinity was well correlated with the acidity of the NH proton, indicating the existence of an interaction between the NH proton and amino acid residue(s) of the ERalpha ligand binding domain. The amino acid residue(s) interacting with the NH proton appears to be different from Asp351, which is known to play an important role in the expression of antiestrogenic activity. The side chain of the m-carborane bisphenol structure strictly controls the balance of estrogenic and antiestrogenic activities, and the (thio)carbamates can be classified as an agonist group.

The effect of the phenyl–alkyl connecting group on mesogenic properties of several series of isostructural compounds containing p-carborane (A and B), bicyclo[2.2.2]octane (C), and benzene (D) was investigated using thermal and optical methods. Results demonstrated that mesophase stability in the series containing A–D follows the order (Alk)CH2CH2– < (Alk)OOC– < (Alk)CH2O– < (Alk)COO–. Surprisingly, the connecting groups (Alk)CH2CH2– and (Alk)OOC– destabilize the mesophase significantly stronger for carboranes (A and B) than for carbocyclic derivatives (C and D). Analysis indicates that this effect may have quadrupolar and conformational origin.

Although the complexation of carborane derivatives with beta-cyclodextrin (beta-CD) is well-known, we present here the first observation of the complexation of carborane derivatives with alpha-CD in aqueous solution. The stoichiometry and association constant (K(a)) of the complexes were estimated from Job's plots and NMR titration studies, respectively. The carborane : alpha-CD stoichiometry was 1 : 1 in all cases. The complexation ability and selectivity of the carborane derivatives for alpha-CD are markedly decreased compared with those for beta-CD. The interaction between the carborane cage and the hydrophobic cavity of alpha-CD appears to be weak, probably because the hydrophobic cavity of alpha-CD is too small to accommodate the carborane cage. The C-H hydrogen and the polar substituents of carborane cage may form hydrogen bonds with secondary alcohol groups at the rim of alpha-CD. The orientation of the carborane cage influences the inclusion process, and o- and m-carborane derivatives showed moderately stronger association constants than p-carborane derivatives.

A novel series of androgen receptor (AR) ligands bearing an acidic heterocycle with hydrogen-bonding ability as the terminal polar group was developed. Since most non-steroidal AR ligands so far known are structurally limited to nitro- or cyanobenzanilide as the polar pharmacophore, development of alternative hydrogen-bonding components is required to obtain novel AR ligands. Various acidic heterocycles were introduced into a hydrophobic phenylcarborane (1-phenyl-1,12-dicarba-closo-dodecaborane) core structure to provide a moiety that could interact effectively with the critical basic arginine residue of the AR ligand binding domain. The most potent compounds, 1,2,4-oxadiazole-5-thione derivatives 21a and 21b, exhibited higher affinity for hAR than did the well-known anti-androgen hydroxyflutamide. The results suggest that this heterocyclic functionality is potential bioisoster of the nitro and cyano groups forming the polar pharmacophores of known non-steroidal AR ligands.

Novel diphenylamine-type estrogen receptor ligands were designed and synthesized, and their biological activities were evaluated by means of binding assays for estrogen receptor-α and -β and cell proliferation assay using MCF-7 cells. Compounds 4f, 11b, 12c, and 8 showed moderate estrogenic activities. We propose that the diphenylamine skeleton may be a privileged structure for various nuclear receptor ligands, including RAR, RXR, and AR ligands.

We previously developed carborane-containing potent AR antagonists, BA321 and BA341, on the basis of our hypothesis that the carborane cage would be an excellent hydrophobic pharmacophore in place of steroidal C and D rings. As an extension of that work, we designed and synthesized carborane-containing AR antagonist candidates with a pyridine ring. Compound 6b, which has a pyridine ring directly bound to the p-carborane cage at the 3-position, exhibited potent AR-antagonistic activity in transcriptional activation assay using NIH3T3 cells transfected with a hAR-expression plasmid. In addition, it showed more potent antiandrogenic activity than that of the well-known antiandrogen flutamide and comparable activity to that of (R)-bicalutamide in SC-3 cell proliferation assay.

To improve the poor pharmacokinetic characteristics of VLA-4 inhibitors, novel piperazinylphenylalanine derivatives were designed. This structure is expected to improve physicochemical properties by increasing overall basicity. By changing components at the 4-position of piperazine and the terminal group of the amido bond, 12t was found to be the most potent of this series of compounds. In addition, dichlorobenzoyl derivative 12aa exhibited better oral availability and showed efficacy in an in vivo model after oral administration.

International audience; Using genetic and pharmacological approaches, we demonstrate that both RARgamma/RXRalpha heterodimers involved in repression events, as well as PPARbeta(delta)/RXRalpha heterodimers involved in activation events, are cell-autonomously required in suprabasal keratinocytes for the generation of lamellar granules (LG), the organelles instrumental to the formation of the skin permeability barrier. In activating PPARbeta(delta)/RXRalpha heterodimers, RXRalpha is transcriptionally active as its AF-2 activation function is required and can be inhibited by an RXR-selective antagonist. Within repressing RARgamma/RXRalpha heterodimers, induction of the transcriptional activity of RXRalpha is subordinated to the addition of an agonistic ligand for RARgamma. Thus, the ligand that possibly binds and activates RXRalpha heterodimerized with PPARbeta(delta) cannot be a retinoic acid, as it would also bind RARgamma and relieve the RARgamma-mediated repression, thereby yielding abnormal LGs. Our data also demonstrate for the first time that subordination of RXR transcriptional activity to that of its RAR partner plays a crucial role in vivo, because it allows RXRs to act concomitantly, within the same cell, as heterodimerization partners for repression, as well as for activation events in which they are transcriptionally active.

1,2-Dicarba-closo-dodecaboranes (o-carboranes) and naphthalenes have potential value as components or building blocks for supramolecular systems. We have efficiently synthesized 1-(1,2-dicarba-closo-dodecaboran-1-yl)naphthalene and 2-(1,2-dicarba-closo-dodecaboran-1-yl)naphthalene derivatives by employing three preparative methods: cyclization of the corresponding acetylenes with decaborane(14), an Ullmann-type coupling reaction of carboranes with aryl halide, and the aromatic nucleophilic substitution (S(N)Ar) reaction of aryl-o-carboranes with nitrophenyl halide. The optimum conditions of each method for synthesis of the title compounds were also investigated.

Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable chemical and thermal stability and hydrophobic character. These features may allow application of carboranes as a new hydrophobic core structure in biologically active molecules that interact hydrophobically with receptors. We report here the design and synthesis of novel androgen antagonists bearing carborane. The most potent compounds, the arylcarborane derivatives 6e and 6i, exhibited antiandrogenic activity greater than that of the well-known antiandrogen hydroxyflutamide in reporter gene assay using NIH3T3 cells transfected with a human AR expression plasmid, as well as in cell growth inhibition assay using androgen-dependent SC-3 cells. Further development of the potent carborane-containing androgen antagonists described here, having a new skeletal structure and unique characteristics, may yield novel therapeutic agents, especially selective androgen receptor modulators.

Candidate estrogen receptor (ER) ligands with two phenolic residues on a three-dimensional hydrophobic core structure (carborane, bicyclo[2.2.2]octene, or adamantane) were synthesized and biologically evaluated. The biological properties of the ligands were markedly dependent on the nature of the hydrophobic core structure. Bis(4-hydroxyphenyl)-o-carborane (6) was a partial agonist/antagonist for ER. 1,2-Bis(4-hydroxyphenyl)bicyclo[2.2.2]octene (10) exhibited potent agonist activity for ER, even though the two phenolic groups are located similarly to those of 6.

Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable chemical and thermal stability, and hydrophobic character. These features may allow application of carboranes as a new hydrophobic core structure in biologically active molecules that interact hydrophobically with receptors. Here, we report the design and synthesis of novel androgen antagonists bearing a carborane moiety. These compounds, particularly 8a, 8c, and 9d, exhibited anti-androgenic activity similar to that of the well-known anti-androgen flutamide in reporter gene assay using NIH3T3 cells transfected with a human AR expression plasmid. The carborane cage seems to be a privileged hydrophobic pharmacophore for the expression of AR-antagonistic activity.

We designed and synthesized novel retinoid X receptor (RXR)-selective antagonists bearing a carborane moiety. Compounds 8a-d or 9a-d themselves have no differentiation-inducing activity toward HL-60 cells and no inhibitory activity towards a retinoic acid receptor (RAR) agonist. However, they inhibit the synergistic activity of an RXR agonist, PA024, in the presence of Am80 on the cell differentiation of HL-60. Transactivation assay using RARs and RXRs suggested that the inhibitory activity of 9b resulted from the selective antagonism at the RXR site of RXR-RAR heterodimers.

Several tropolone derivatives (4-7) were designed as novel retinoids on the assumption that the tropolone ring may mimic the benzoic acid moiety in retinoid structures, such as Am80 (2). Among the synthesized compounds, 5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethynyl]tropolone (7a) showed moderate potency as a differentiation-inducer of HL-60 cells. The activities of the tropolones were greatly enhanced in the presence of HX630, an RXR agonist (retinoid synergist).

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.

Several dibenzodiazepine derivatives were identified as novel retinoid X receptor (RXR) antagonists on the basis of inhibitory activity on retinoid-induced cell differentiation of human promyelocytic leukemia cells HL-60 and transactivation assay using retinoic acid receptors (RARs) and RXRs in COS-1 cells. 4-(5H-2,3-(2,5-Dimethyl-2,5-hexano)-5-n- propyldibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX603, 6c) is an N-n-propyl derivative of an RXR pan-agonist HX600 (6a), and exhibited RXR-selective antagonistic activity. Similar RXR-antagonistic activities were observed with 4-(5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyl- 8-nitrodibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX531, 7a) and 4-(5H-10,11-dihydro-5,10-dimethyl-2,3-(2,5-dimethyl- 2,5-hexano)-dibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX711, 8b), which also inhibited transactivation of RARs induced by an RAR agonist, Am80. These compounds inhibited HL-60 cell differentiation induced by the combination of a low concentration of the retinoid agonist Am80 with an RXR agonist (a retinoid synergist, HX600). These results indicated that HX603 (6c), and the related RXR antagonists inhibit the activation of RAR-RXR heterodimers as well as RXR homodimers, which is a distinct characteristic different from that of the known RXR antagonist, LG100754 (9).

4-[N-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)amino]benzoic acid (5) exhibited weak retinoidal and retinoid synergistic activities in HL-60 cell differentiation assay. N-Alkylation of 5 caused decrease or loss of differentiation-inducing activity, but enhanced the synergistic activity with a synthetic retinoid Am80 (2), as reflected in the potent synergistic EC50 (SEC50) values of DA023 (11, 1.6 x 10(-10) M) and DA113 (14, 1.4 x 10(-10) M) in the presence of 1.0 x 10(-10) M Am80 (2).

We report here the design, synthesis, androgenic activity and anti-androgenic activity of novel derivatives of hexadecahedral 1,10-dicarba-closo-decaborane, which is generally called ten-vertex para-carborane. The synthesized compounds exhibited very high binding affinity for the androgen receptor and showed anti-androgenic activity toward the androgen-dependent SC-3 cell line. Two compounds also exhibited partial agonistic activity in SC-3 assay. The docking studies of carborane derivatives to AR demonstrate that ten-vertex carborane is useful for development of novel bioactive compounds as well as twelve-vertex carboranes that are well known to be versatile pharmacophores. Ten-vertex carborane, which has not previously been applied in the field of medicinal chemistry, appears to have potential as a hydrophobic pharmacophore with characteristic properties.

Development of antagonists for a mutated androgen receptor (AR) is important for treatment of anti-androgen-refractory prostate cancers. We describe here application of the p-carborane cage as a hydrophobic core structure for novel anti-androgens active toward LNCaP human prostate cancer cells with mutated AR. These compounds are expected to be versatile lead compounds not only for development of AR pan-antagonists, but also for discovery of mutant-selective anti-androgens.

Based on the structures of potent RXR agonists 2 and 3, novel dibenzodiazepine derivatives 4 ― 6, containing two diphenylamine substructures, were designed as RXR modulator candidates and synthesized by utilizing Pd-catalyzed and Cu-promoted diphenylamine-generating reactions as key reactions. These compounds showed retinoid-synergistic activity, enhancing the HL-60 cell differentiation-inducing ability of the RAR agonist Am80.

In contrast to conventional syntheses of 3-aryl-o-carborane derivatives, which involve reconstruction of the o-carborane cage or Pd-catalyzed coupling reaction of 3-iodo-o-carborane with Grignard reagents, the Suzuzki-Miyaura coupling reaction of 3-iodo-o-carborane proceeds with a variety of aryl boronic acids, providing a new route to 3-aryl-o-carborane derivatives bearing easily transformable functional groups, including CH 3 O-, NO 2 -, CHO- and CN-. This approach provides easy access to a variety of compounds with a 3-aryl-o-carborane scaffold.

Several members of two homologous series of symmetric bent-shaped compounds with either m-carborane or adamantane (1[n] or 2[n], n = 9–13) in the central position were synthesized and investigated by optical, calorimetric, X-ray diffraction, and electro-optical methods. Results show that the two shortest members of the m-carborane series, 1[9] and 1[10], exhibit an intercalated lamellar B6 phase. The adamantane derivatives 2[9]–2[13] display a monotropic weakly birefringent soft crystalline or crystalline phase with homochiral domains. Neither phase undergoes polarization switching in an electric field.

Two homologous series of carborane-containing dioxanes 1[n] and 2[n] (n = 1–10) were prepared and their mesogenic properties investigated. All compounds exhibit nematic behavior and three members of series 2[n] show an E phase. Numerical analysis of the clearing temperatures gave a limiting value TNI(∞) of 89 °C for series 2[n] and indicated conformational flexibility of the dioxane ring. Investigations of three-ring derivative 1[4] gave Δn = 0.17, S = 0.53, and Δe = +0.4 ± 0.1 at 85 °C. Extrapolation of dielectric data for dilute solutions of 1[4] in 6-CHBT gave Δe = +0.4 ± 0.25 at 24 °C. Modelling of dielectric results with the Maier–Meier equation demonstrated that conformers with a higher β angle are preferred, which is consistent with conformational selection for the most elongated conformers.