Acetic Acid Side Chain Research Articles

An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors.

Allosteric HIV-1 integrase inhibitors (ALLINIs) are a new class of potential antiretroviral therapies with a unique mechanism of action and drug resistance profile. To further extend this class of inhibitors via a scaffold hopping approach, we have synthesized a series of analogues possessing an isoquinoline ring system. Lead compound 6l binds in the v-shaped pocket at the IN dimer interface and is highly selective for promoting higher-order multimerization of inactive IN over inhibiting IN-LEDGF/p75 binding. Importantly, 6l potently inhibited HIV-1NL4-3 (A128T IN), which confers marked resistance to archetypal quinoline-based ALLINIs. Thermal degradation studies indicated that at elevated temperatures the acetic acid side chain of specific isoquinoline derivatives undergo decarboxylation reactions. This reactivity has implications for the synthesis of various ALLINI analogues.

Synthesis, Characterization and Antimicrobial Screening of Substituted Indanone Derivatives

Indanone acetic acid is a non-heterocyclic fused ring of benzene attached to cyclopentananone moiety with acetic acid side chain at 1-position. A simple and efficient method has been developed for the synthesis by condensation of indanone acetic acid with various substituents like aniline, o-toludine, 2-chloroaniline, 3chloroaniline, o-anisidine, and p-fluoroaniline to obtain substituted indanone acetic acid (5a-f) derivatives. The newly synthesized compounds were structurally confirmed by analytical and spectral data and evaluated for their antimicrobial activities. Antimicrobial activity of synthesized compounds were screened by using gram positive Staphylococcus aureus, Bacillus subtilis and gram negative Escherichia coli and Salmonella typhi microbial cultures and fungal strains Candida albicans and Aspergillus niger with reference to standard drug. The results showed that para-fluorophenyl substituted indanone acetic acid (5f) derivative exhibited marked potency as antimicrobial agents and ortho-methoxyphenyl (5d) derivative exhibited better antifungal activity.

Jasmonoyl-L-Tryptophan Disrupts IAA Activity through the AUX1 Auxin Permease.

Amide-linked conjugates between tryptophan (Trp) and jasmonic (JA) or indole-3-acetic (IAA) acids interfered with gravitropism and other auxin-dependent activities in Arabidopsis, but the mechanism was unclear. To identify structural features necessary for activity several additional Trp conjugates were synthesized. The phenylacetic acid (PAA) conjugate was active, while several others were not. Common features of active conjugates is that they have ring structures that are linked to Trp through an acetic acid side chain, while longer or shorter linkages are inactive or less active. A dominant mutant, called tryptophan conjugate response1-D that is insensitive to JA-Trp, but still sensitive to other active conjugates, was identified and the defect was found to be a substitution of Asn for Asp456 in the C-terminal domain of the IAA cellular permease AUX1. Mutant seedling primary root growth in the absence of added conjugate was 15% less than WT, but otherwise plant phenotype appeared normal. These results suggest that JA-Trp disrupts AUX1 activity, but that endogenous JA-Trp has only a minor role in regulating plant growth. In contrast with IAA- and JA-Trp, which are present at <2 pmole g-1 FW, PAA-Trp was found at about 30 pmole g-1 FW. The latter, or other undiscovered Trp conjugates, may still have important endogenous roles, possibly helping to coordinate other pathways with auxin response.

Discovery of α-Substituted Imidazole-4-acetic Acid Analogues as a Novel Class of ρ1 γ-Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone.

The ρ-containing γ-aminobutyric acid type A receptors (GABAA Rs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAA Rs are of interest. In this study, we demonstrate that the partial GABAA R agonist imidazole-4-acetic acid (IAA) is able to penetrate the blood-brain barrier in vivo; we prepared a series of α- and N-alkylated, as well as bicyclic analogues of IAA to explore the structure-activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l-histidine by an efficient minimal-step synthesis, and their pharmacological properties were characterized at native rat GABAA Rs in a [3 H]muscimol binding assay and at recombinant human α1 β2 γ2S and ρ1 GABAA Rs using the FLIPR™ membrane potential assay. The (+)-α-methyl- and α-cyclopropyl-substituted IAA analogues ((+)-6 a and 6 c, respectively) were identified as fairly potent antagonists of the ρ1 GABAA R that also displayed significant selectivity for this receptor over the α1 β2 γ2S GABAA R. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.

Conformational preferences of 3,4-dihydroxyphenylacetic acid (DOPAC)

The conformational space of 3,4-dihydroxyphenylacetic acid (DOPAC), an important dopamine metabolite, has been investigated by quantum chemical methods (B3LYP and MP2, with the 6-311++G(d,p) basis set) and matrix-isolation infrared spectroscopy. Detailed analysis of the calculated potential energy surfaces of the molecule led to identification of thirteen unique conformers, all of them showing the acetic acid side chain out of the aromatic ring plane by 60–95°. According to the calculated Gibbs energies, the five lowest energy conformers make up 99.7% of the conformational mixture at 298.15K, exhibiting individual populations falling between 16% and 24%. The main conformational trends of this molecule were interpreted on the grounds of a thorough analysis of the structural parameters and by the application of the Natural Bond Orbital theory. The role of the intramolecular interactions on the relative stability and structure of the conformers was also investigated. The infrared spectrum of DOPAC was registered after isolation of its monomers in argon and xenon matrices. Only one of DOPAC forms populated in the gas phase could be trapped in both matrix gases. This result is in agreement with the predicted low energy barriers for conformational isomerization and is also supported by annealing experiments. The spectra of matrix-isolated model compounds, phenylacetic acid and catechol, were studied under the same experimental conditions. These data were used as references and assisted in the interpretation of the results obtained for DOPAC.

The structure, function and properties of sirohaem decarboxylase--an enzyme with structural homology to a transcription factor family that is part of the alternative haem biosynthesis pathway.

Some bacteria and archaea synthesize haem by an alternative pathway, which involves the sequestration of sirohaem as a metabolic intermediate rather than as a prosthetic group. Along this pathway the two acetic acid side-chains attached to C12 and C18 are decarboxylated by sirohaem decarboxylase, a heterodimeric enzyme composed of AhbA and AhbB, to give didecarboxysirohaem. Further modifications catalysed by two related radical SAM enzymes, AhbC and AhbD, transform didecarboxysirohaem into Fe-coproporphyrin III and haem respectively. The characterization of sirohaem decarboxylase is reported in molecular detail. Recombinant versions of Desulfovibrio desulfuricans, Desulfovibrio vulgaris and Methanosarcina barkeri AhbA/B have been produced and their physical properties compared. The D. vulgaris and M. barkeri enzyme complexes both copurify with haem, whose redox state influences the activity of the latter. The kinetic parameters of the D. desulfuricans enzyme have been determined, the enzyme crystallized and its structure has been elucidated. The topology of the enzyme reveals that it shares a structural similarity to the AsnC/Lrp family of transcription factors. The active site is formed in the cavity between the two subunits and a AhbA/B-product complex with didecarboxysirohaem has been obtained. A mechanism for the decarboxylation of the kinetically stable carboxyl groups is proposed.

Molecular hijacking of siroheme for the synthesis of heme and d 1 heme

Modified tetrapyrroles such as chlorophyll, heme, siroheme, vitamin B(12), coenzyme F(430), and heme d(1) underpin a wide range of essential biological functions in all domains of life, and it is therefore surprising that the syntheses of many of these life pigments remain poorly understood. It is known that the construction of the central molecular framework of modified tetrapyrroles is mediated via a common, core pathway. Herein a further branch of the modified tetrapyrrole biosynthesis pathway is described in denitrifying and sulfate-reducing bacteria as well as the Archaea. This process entails the hijacking of siroheme, the prosthetic group of sulfite and nitrite reductase, and its processing into heme and d(1) heme. The initial step in these transformations involves the decarboxylation of siroheme to give didecarboxysiroheme. For d(1) heme synthesis this intermediate has to undergo the replacement of two propionate side chains with oxygen functionalities and the introduction of a double bond into a further peripheral side chain. For heme synthesis didecarboxysiroheme is converted into Fe-coproporphyrin by oxidative loss of two acetic acid side chains. Fe-coproporphyrin is then transformed into heme by the oxidative decarboxylation of two propionate side chains. The mechanisms of these reactions are discussed and the evolutionary significance of another role for siroheme is examined.

Demonstration That CobG, the Monooxygenase Associated with the Ring Contraction Process of the Aerobic Cobalamin (Vitamin B12) Biosynthetic Pathway, Contains an Fe-S Center and a Mononuclear Non-heme Iron Center

The ring contraction process that occurs during cobalamin (vitamin B(12)) biosynthesis is mediated via the action of two enzymes, CobG and CobJ. The first of these generates a tertiary alcohol at the C-20 position of precorrin-3A by functioning as a monooxygenase, a reaction that also forms a gamma lactone with the acetic acid side chain on ring A. The product, precorrin-3B, is then acted upon by CobJ, which methylates at the C-17 position and promotes ring contraction of the macrocycle by catalyzing a masked pinacol rearrangement. Here, we report the characterization of CobG enzymes from Pseudomonas denitrificans and Brucella melitensis. We show that both contain a [4Fe-4S] center as well as a mononuclear non-heme iron. Although both enzymes are active in vivo, the P. denitrificans enzyme was found to be inactive in vitro. Further analysis of this enzyme revealed that the mononuclear non-heme iron was not reducible, and it was concluded that it is rapidly inactivated once it is released from the bacterial cell. In contrast, the B. melitensis enzyme was found to be fully active in vitro and the mononuclear non-heme iron was reducible by dithionite. The reduced mononuclear non-heme was able to react with the oxygen analogue NO, but only in the presence of the substrate precorrin-3A. The cysteine residues responsible for binding the Fe-S center were identified by site-directed mutagenesis. A mechanism for CobG is presented.

Screening and evaluation of rat kidney aldose reductase inhibitory activity of some pyridazine derivatives

Aldose reductase (AR) is an enzyme that catalyzes the conversion of glucose to sorbitol, which is in turn converted to fructose by sorbitol dehydrogenase. The increased glucose flux through this metabolic pathway has been linked to the development of diabetic complications such as neuropathy, nephropathy, retinopathy, and cataract. Inhibitors of AR thus seem to have the potential to prevent or treat diabetic complications. AR inhibitors belong to different chemical classes, one of which comprises pyridazinone analogues. At present, however, side effects and/or insufficient pharmacokinetic profiles have made most of the drug candidates undesirable. We evaluated a series of 2H-pyridazine-3-one and 6-chloropyridazine analogues via an in vitro spectrophotometric assay for their ability to inhibit rat kidney AR. The study showed that the introduction of a pyrazole ring on pyridazinone led to a marked decrease in AR inhibitory potency. Moreover, introduction of an acetic acid side chain on 2H-pyridazine-3-one and 6-chloropyridazine did not improve the AR inhibitory activity, which was an unexpected result. On the basis of preliminary AR inhibitory screening results on 2H-pyridazine-3-one and 6-chloropyridazine derivatives, we embarked on the synthesis of more derivatives to discover more active molecules.

First total synthesis of tuberonic acid

A vinyl group as an acetic acid side chain was attached to the optically active monoacetate of 4-cyclopentene-1,3-diol with CH 2 CHMgBr, LiCl, and a CuCN catalyst to produce the S N2-type product, from which the full carbon skeleton of tuberonic acid was constructed through Mitsunobu inversion, Claisen rearrangement, and Wittig reaction. At the last stage, the THP protective group was removed with MgBr 2 in Et 2O. The diastereomeric ratio of tuberonic acid and the trans isomer was 92:8 by 1H NMR spectroscopy.

Stereoselective Mannich-Like Reactions of Ester Enolates Generated on Sugar Templates: A Novel Access to a Key Intermediate for 1β-Methylcarbapenem Synthesis

The Mannich-like reactions of the enolates generated from 2,3-di-O-protected 6-deoxy-4-O-propionyl-α-D-glucopyranosides with (3R,4R)-4-acetoxy-3-1(R)-1 -(t-buiyldimethylsilyloxy)ethyl ]azetidin-2-one were investigated. The corresponding 2,3-di-O-methyl derivative provided the Mannich adduct in good to excellent stereoselectivity. From the major adduct, the azetidin-2-one incorporating an α-methyl acetic acid side chain at the Opposition with β-configuration was obtained by alkaline hydrolysis. This product, (35,45)-3-[(R)-1 (t-butyldimethylsilyloxy)ethyl [-4-](R)-1 -carboxyethyl |azetidin-2-one, is a useful intermediate for the 1 β-methylcarbapenem synthesis.

Practical Syntheses of the Adhesion Molecule Inhibitor ER-49890 and Its Stereoisomer

Practical synthetic routes to anti-[3-(10H-pyrazino[2,3-b][1,4]-benzothiazin-8-ylmethyl)-3-azabicyclo[3.3.1]non-9-yl]acetic acid (ER-49890, 1) and its syn-isomer are reported. The anti-(3-azabicyclo[3.3.1]non-9-yl)acetic acid side chain (anti-12) was synthesized stereoselectively using Pd/C hydrogenation in the presence of HCl. The syn-isomer (syn-12) was concisely obtained by crystallization as its oxalic acid salt from a 1:1 mixture of anti- and syn-isomers. The 10H-pyrazino[2,3-b][1,4]benzothiazine core (7) was prepared from commercially available 4-chloro-3-nitrobenzyl alcohol (13) in four steps and good yield.

N-functionalization of poly(ethylene glycol)-linked mono- and bis-dioxocyclams as potential ligands for Gd3+.

A number of highly functionalized dioxocyclams with acetic acid side chains on the secondary amine sites and ethylene glycol side chains on 6 and 13-positions (12a, 12b) or a tetra(ethylene glycol) side chain linking the 6 and 13 positions (15) were synthesized and characterized, as was a bis-dioxocyclam bridged across the 6 and 13 positions by tetra(ethylene glycol) groups (16). These were screened for their ability to complex Gd3+. Only ligands 15 and 16, having tetra(ethylene glycol) groups, formed such complexes.

Synthesis and analgesic and anti-inflammatory activity of some new (6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid residues.

In this study for developing potent analgesic and anti-inflammatory compounds, we synthesized 6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid side chain, and performed preliminary screening of their in vivo analgesic and anti-inflammatory activities at a single dose of 100 mg/kg inmice by a p-benzoquinone-induced writhing test and a Carrageenaninduced hind paw edema model, respectively. We also determined their gastric ulceration effects in the tested animals. Propanoic acid derivatives were generally found to have higher analgesic and anti-inflammatory activities, and among them, 3-(6-benzoyl-2-benzothiazolinon-3-yl)propanoic acid (Compound 4 a) exhibited the highest analgesic and anti-inflammatory activity. However, all compounds showed lower anti-inflammatory effects than we observed for indomethacin at 10 mg/kg dose. Consequently, 6-acyl-2-benzoxazolinone/2-benzothiazolinones having propanoic acid side chain might lead to further studies for developing better candidates with potent analgesic and anti-inflammatory effects while acetic acid derivatives do not exhibit comparable satisfactory features.

Comparison of two assay methods for activities of uroporphyrinogen decarboxylase and coproporphyrinogen oxidase

Uroporphyrinogen decarboxylase (UROD) and coproporphyrinogen oxidase (copro'gen oxidase) are two of the least well understood enzymes in the heme biosynthetic pathway. In the fifth step of the pathway, UROD converts uroporphyrinogen III to coproporphyrinogen III by the decarboxylation of the four acetic acid side chains. Copro'gen oxidase then converts coproporphyrinogen III to protoporphyrinogen IX via two sequential oxidative decarboxylations. Studies of these two enzymes are important to increase our understanding of their mechanisms. Assay comparisons of UROD and copro'gen oxidase from chicken blood hemolysates (CBH), using a newly developed micro-assay, showed that the specific activity of both enzymes is increased in the micro-assay relative to the large-scale assay. The micro-assay has distinct advantages in terms of cost, labor intensity, amount of enzyme required, and sensitivity.

5,6-dimethylxanthenone-4-acetic acid (DMXAA): a new biological response modifier for cancer therapy.

The investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was developed by the Auckland Cancer Society Research Centre (ACSRC). It has recently completed Phase I trials in New Zealand and UK under the direction of the Cancer Research Campaign's Phase I/II Clinical Trials Committee. As a biological response modifier, pharmacological and toxicological properties of DMXAA are remarkably different from most conventional chemotherapeutic agents. Induction of cytokines (particularly tumour necrosis factor (TNF-alpha), serotonin and nitric oxide (NO)), anti-vascular and anti-angiogenic effects are considered to be major mechanisms of action based on in vitro and animal studies. In cancer patients of Phase I study, DMXAA also exhibited various biological effects, including induction of TNF-alpha, serotonin and NO, which are consistent with those effects observed in in vitro and animal studies. Preclinical studies indicated that DMXAA had more potent anti-tumour activity compared to flavone-8-acetic acid (FAA). In contrast to FAA that did not show anti-tumour activity in cancer patients, DMXAA (22 mg/kg by intravenous infusion over 20 min) resulted in partial response in one patient with metastatic cervical squamous carcinoma in a Phase I study where 65 cancer patients were enrolled in New Zealand. The maximum tolerated dose (MTD) in mouse, rabbit, rat and human was 30, 99, 330, and 99 mg/kg respectively. The dose-limiting toxicity of DMXAA in cancer patients included acute reversible tremor, cognitive impairment, visual disturbance, dyspnoea and anxiety. The plasma protein binding and distribution into blood cells of DMXAA are dependent on species and drug concentration. DMXAA is extensively metabolised, mainly by glucuronidation of its acetic acid side chain and 6-methylhydroxylation, giving rise to DMXAA acyl glucuronide (DMXAA-G), and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA), which are excreted into bile and urine. DMXAA-G has been shown to be chemically reactive, undergoing hydrolysis, intramolecular migration and covalent binding. Studies have indicated that DMXAA glucuronidation is catalysed by uridine diphosphate glucuronosyltransferases (UGT1A9 and UGT2B7), and 6-methylhydroxylation by cytochrome P450 (CYP1A2). Non-linear plasma pharmacokinetics of DMXAA has been observed in animals and patients, presumably due to saturation of the elimination process and plasma protein binding. Species differences in DMXAA plasma pharmacokinetics have been observed, with the rabbit having the greatest plasma clearance, followed by the human, rat and mouse. In vivo disposition studies in these species did not provide an explanation for the differences in MTD. Co-administration of DMXAA with other drugs has been shown to result in enhanced anti-tumour activity and alterations in pharmacokinetics, as reported for the combination of DMXAA with melphalan, thalidomide, cyproheptadine, and the bioreductive agent tirapazamine, in mouse models. Species-dependent DMXAA-thalidomide pharmacokinetic interactions have been observed. Co-administration of thalidomide significantly increased the plasma area of the plasma concentration-time curve (AUC) of DMXAA in mice, but had no effect on DMXAA's pharmacokinetics in the rat. It appears that the pharmacological and toxicological properties of DMXAA as a new biological response modifier are unlikely to be predicted based on preclinical studies. Similar to many biological response modifiers, DMXAA alone did not show striking anti-tumour activity in patients. However, preclinical studies of DMXAA-drug combinations indicate that DMXAA may have a potential role in cancer treatment when co-administered with other drugs. Further studies are required to explore the molecular targets of DMXAA and mechanisms for the interactions with other drugs co-administered during combination treatment, which may allow for the optimisation of DMXAA-based chemotherapy.

PREDICTING PHARMACOKINETICS AND DRUG INTERACTIONS IN PATIENTS FROM IN VITRO AND IN VIVO MODELS: THE EXPERIENCE WITH 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID (DMXAA), AN ANTI-CANCER DRUG ELIMINATED MAINLY BY CONJUGATION

The novel anti-tumor agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was developed in the Auckland Cancer Society Research Center. Its pharmacokinetic properties have been investigated using both in vitro and in vivo models, and the resulting data extrapolated to patients. The metabolism of DMXAA has been extensively studied mainly using hepatic microsomes, which indicated that UGT1A9 and UGT2B7-catalyzed glucuronidation on its acetic acid side chain and to a lesser extent CYP1A2-catalyzed hydroxylation of the 6-methyl group are the major metabolic pathways, resulting in DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid. The predominant metabolite in human urine (up to 60% of total dose) was identified as DMXAA-G, which was chemically reactive, undergoing hydrolysis, intramolecular rearrangement, and covalent binding to plasma proteins. In vivo formation of DMXAA–protein adducts were also observed in cancer patients receiving DMXAA treatment. The comparison of the in vitro human hepatic microsomal metabolism and inhibition of DMXAA by UGT and/or CYP substrates with animal species indicated species differences. Renal microsomes from all animal species examined had glucuronidation activity for DMXAA, but lower than the liver. In vitro–in vivo extrapolations based on human microsomal data indicated a 7-fold underestimation of plasma clearance in patients. In contrast, allometric scaling using in vivo data from the mouse, rat, and rabbit predicted a plasma clearance of 3.5 mL/min/kg, similar to that observed in patients (3.7 mL/min/kg). Based on in vitro metabolic inhibition studies, it appears possible to predict the effects on the plasma kinetic profile of DMXAA of drugs such as diclofenac, which are mainly metabolized by UGT2B7. However, it did not appear possible to predict the effect of thalidomide on the pharmacokinetics of DMXAA in patients based on in vitro inhibition and animal studies. These data indicate that preclincial pharmacokinetic studies using both in vitro and in vivo models play an important but different role in predicting pharmacokinetics and drug interactions in patients.

Miscibility of poly(thiophene-3-acetic acid) and poly(ethylene oxide)

Poly(thiophene-3-acetic acid) (PTAA), prepared from polymerization of ethyl-thiophene-3-acetate followed by hydrolysis, was blended with poly(ethylene oxide) (PEO). The 1.5% aqueous ammonia solution was used as a solvent in the blending process and a base for the neutralization of acetic acid side chain of PTAA, which also results in the dissolution of PTAA in the solvent. Thermal analysis by DSC thermograms of PTAA/PEO blends shows that the melting points of PTAA/PEO blends are slightly lower than that of the neat PEO when re-crystallized from molten state. This specific interaction of the blends was analyzed by FT-IR spectra and characterized by shifting of characteristic absorption peaks of COO − and NH 4 +. This specific interaction was due to the combination effect of the ionic and H-bonding. The X-ray diffraction patterns show no change of both PEO and PTAA lattice after blending. The degradation temperatures of the blends, as measured by the thermogravimetric analysis (TGA), are higher than the pure PTAA. According to the pictures of PTAA/PEO film taken from the optical microscopy (OM), the melting point ( T m), phase equilibrium curve, and degradation temperature ( T d) of blend samples can be roughly measured. Combined the T m obtained from the DSC data and the cloud point defined as the temperature when a sharp increase of the exposure time of the OM camera, a phase diagram (PD) can be constructed. The conductivity of PTAA in PTAA/PEO is slightly affected by the existence of this specific interaction and different compositions with different morphology.

3,4-Dihydroxyphenylacetic acid

In the title compound, C8H8O4, the acetic acid side chain adopts a roughly perpendicular orientation with respect to the phenyl ring. Hydro­gen bonding between carboxyl groups results in the formation of a centrosymmetric dimer. An intramolecular hydrogen bond is formed in the catechol part of the mol­ecule. Molecules are linked together through hydrogen bonds between hydroxyl and carboxyl­ic acid O atoms.

Identification of new triarylethylene oxyalkanoic acid analogues as bone selective estrogen mimetics

Previously, the estrogen receptor (ER) ligand 4-[1-( p-hydroxyphenyl)-2-phenylethyl]phenoxyacetic acid ( 5) was found to have differential bone loss suppressive effects in the ovariectomized (OVX) rat approaching those of selective ER modulators (SERMs) such as tamoxifen. In an effort to improve efficacy, analogues of this compound were prepared which incorporated features designed to reduce polarity/ionizability. Thus, the acetic acid side chain of 5 was replaced by n-butanoic acid and 1 H-tetrazol-4-ylmethyl moieties, to give 8 and 10, respectively. Also, the phenolic hydroxyl of 5 was replaced, giving deoxy analogue 9. We also developed new methods for the synthesis of triarylethylene variants of 5 and 9, namely 4-{[1-( p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxy}- n-butanoic acid ( 6) and its des-hydroxy counterpart ( 7), because the former of these had in vitro antiestrogenic effects characteristic of known SERMs. In the OVX rat, 6 and 7 were as effective as 17β-estradiol in suppressing serum markers of bone resorption/turnover, namely osteocalcin and deoxypyridinoline, but had only 30% of the uterotrophic efficacy of 17β-estradiol. This study has thus identified two triarylethylene oxybutyric acids, 6 and 7, that have differential bone/uterus effects like those of known SERMs.