Yuqing Hou

Antioxidant effects of phyto-and synthetic-estrogens on cupric ion-induced oxidation of human low-density lipoproteins in vitro

Oxidation of low-density lipoproteins (LDL) promotes the formation of atherosclerotic plaques. Estrogenic compounds (EC) from foods and other natural products, and synthetic estrogenic compounds (SECs) may prevent heart disease by inhibiting LDL oxidation. In the present study, we tested the antioxidant capacities of two phytoestrogens, daidzein (DAI) and genistein (GEN), and four SECs, (+)- and (-)-Z-bisdehydrodoisynolic acid (ZBDDA), and (+)- and (-)-hydroxy-allenoic acid (HAA), on isolated human LDL subjected to oxidation by cupric sulfate. The effects of these estrogenic compounds on the kinetics of conjugated diene formation in LDL undergoing oxidation were evaluated with a lag-time assay with continuous monitoring of absorbance at 234 nm. Lag-time data revealed that (+)-HAA, (-)-HAA, (+)-ZBDDA, and (-)-ZBDDA had similarly stronger antioxidant activities than either GEN or DAI. We also found that (+)-HAA, (-)-HAA, (+)-ZBDDA, and (-)-ZBDDA strongly inhibited the formation of Cu+-induced thiobarbituric acid reactive substances (TBARS) in LDL, and that GEN and DAI were less effective for inhibiting LDL lipid peroxidation. Finally, electrophoretic evaluation suggested that (+)-HAA, (-)-HAA, (+)-ZBDDA, and (-)-ZBDDA protected the apolipoprotein B-100 of LDL against oxidation better than did GEN or DAI. In summary, the four SECs, (+)-HAA, (-)-HAA, (+)-ZBDDA, and (-)-ZBDDA, were more potent antioxidants than the phytoestrogens, DAI and GEN.

Nitromethane with IBX/TBAF as a nitrosating agent: synthesis of nitrosamines from secondary or tertiary amines under mild conditions.

Aliphatic or aromatic N,N-disubstituted nitrosamine was generated in fair to excellent yield from the reaction of a secondary or tertiary amine with o-iodoxybenzoic acid (IBX) or o-iodosylbenzoic acid (IBA)/R(4)NX (X = halide) and nitromethane. The product yield was strongly influenced by both the halide of R(4)NX and iodanes. IBX gave a higher yield than IBA, while the halides follow F(-) > Cl(-) > Br(-) ∼ I(-). Nitrous acid formed in situ from nitromethane and IBX (or IBA)/halides is likely responsible for the observed reaction.

A short, economical synthesis of 2-methoxyestradiol, an anticancer agent in clinical trials.

2-Methoxyestradiol, a natural metabolite of estradiol and potential therapeutic agent for many types of cancers, has been synthesized successfully in three steps, starting from estradiol and cumyl methyl peroxide.

Absolute Structure Determination of the Highly Biologically Active Bisdehydrodoisynolic Acids

In a project designed to relate the unexpected in vivo and in vitro properties exhibited by (+)- and (-)-bisdehydrodoisynolic acid with their absolute stereochemical structure, an X-ray crystal-structure analysis was undertaken of the highly estrogenic, poorly binding (-) enantiomer. (1) and (13)C NMR spectra are also reported for the first time. The crystal structure shows the cis juxtaposition of the carboxyl and ethyl groups, which are separated by a large torsion angle, and that only the carbon atom holding the carboxyl group is out of the plane in which the remainder of the fused three-ring moiety lies. The crystal structure, which unequivocally characterizes the (-) enantiomer as cis-13(S),14(R) and, implicitly, the (+) enantiomer as cis-13(R),14(S), will be useful in continued studies aimed at explaining the selective estrogen receptor modulation (SERM) of these enantiomers which, in some cases, produces significantly different end-organ effects compared to those of estradiol, in both males and females, affording the promise of a variety of therapeutic and pharmacologic applications.

Potential Clinical Applications of (-), (+) and (±)-Z-Bisdehydrodoisynolic Acids in Metabolic Disorders

Doisynolic acids (DAs), such as (±)-Z-bisdehydrodoisynolic acid [(±)-Z-BDDA], are a group of synthetically produced compounds with structural similarity to 17β-estradiol (E2), which exhibit significant estrogenic activity. They regulate estrogen receptor-α and -β (ERα/β) reporter gene activation, as well mediate significant uterotropic effects in vivo. Despite these estrogen-specific effects, (±)-Z-BDDA and related compounds exhibit low ER binding activity in vitro. This may reflect changes in chemical structure or cellular environment necessary for optimum binding of DAs. are possible explanations for the binding/activity paradox. Selective estrogen receptor modulators (SERMs), such as tamoxifen, provide estrogenic activity without undesired adverse effects of E2. The strong SERM activity and limited side effects of (±)-Z-BDDA make it an ideal alternative to hormone replacement therapy. Recent investigation of (±)-Z-BDDA has revealed a marked protection against obesity, diabetes, cardiovascular disease, and prostate cancer. The underlying mechanisms involved in attenuation of these degenerative diseases are not fully elucidated but may relate to the compounds significant estrogenic and anti-inflammatory properties. This review summarizes some of the proposed mechanisms for different therapeutic applications of DAs, including obesity and diabetes, as well as some patents on (±)- Z-BDDA protection against prostate cancer.

Racemic 1,2,4-Trimethylurazole

The structural and stereochemical parameters of 1,2,4-trimethyl-1,2,4-triazolidine-3,5-dione, C5H9N3O2, (1), were examined in view of the contrast between its physical properties and those of urazoles having one or more unsubstituted NH groups. The X-ray structure shows that (1) is devoid of intermolecular hydrogen bonding but retains the structural features of strongly hydrogen-bonded urazoles. Its trans H3C—N—N—CH3 torsion angle, 72.3 (5)°, is slightly larger than the corresponding angle in urazoles having an unsubstituted or monomethylated N—N function, but smaller than that in urazoles monosubstituted with bulkier groups. Like other crystalline urazoles, (1) is racemic by virtue of N1 and N2 chirality. In its packing pattern of parallel molecular sheets, two pass through the unit cell; within a sheet, each molecule is surrounded by two of its own chirality and four of opposite chirality. While physical properties of crystalline urazoles can be associated with their degree of intermolecular hydrogen bonding, this study shows that their chirality is an intrinsic molecular phenomena.

(+)-z-bisdehydrodoisynolic Acid enhances Basal metabolism and Fatty Acid oxidation in female obese zucker rats.

We have previously reported that the synthetic estrogen, (+)-Z-bisdehydrodoisynolic Acid [(+)-Z-BDDA], attenuated weight gain and cardiovascular risk in obese rodents. To determine if these antiobesity effects were attributed to changes in basal metabolism, we assessed indirect calorimetry and metabolic profile in female obese Zucker (OZR) rats provided (+)-Z-BDDA (0.0002% food admixture) for 11 weeks. Similar to our previous findings, (+)-Z-BDDA reduced weight gain and improved lipid and glucose homeostasis in OZR rats. Furthermore, resting energy expenditure was increased by (+)-Z-BDDA, as evident by heat production and oxygen consumption. We also observed a marked reduction in respiratory quotient (RQ) along with a corresponding induction of hepatic AMPK in rodents provided (+)-Z-BDDA. Collectively, these findings indicate that (+)-Z-BDDA partially attenuated obesity and associated pathologies through increased resting energy expenditure and fatty acid utilization. Further investigation is required to fully elucidate the mechanisms involved as well as to determine the potential therapeutic implications for (+)-Z-BDDA on obesity and its related pathologies.

trans-3-Ethyl-cis-2,6,6-trimethyl-4-oxocyclohexanecarboxylic acid: an intermediate in the synthesis of a highly potent estrogen.

The title compound, C(12)H(20)O(3), (IV), the ethyl ester of which is an intermediate in the synthesis of a compound reported to be highly estrogenic, has been prepared. After the initial steps reported for the synthesis of this ester intermediate were followed, it was converted into the crystalline acid, (IV), for X-ray analysis. It was verified that (IV) was racemic when prepared. X-ray analysis showed that anti-hydrogenation of the double bond had occurred in the synthesis, making the orientation of the carboxyl group cis to the 2-methyl group and trans to the 3-ethyl group. NMR spectroscopy showed that the stereochemistry of (IV) was identical with that of its ester precursor. While the earlier report did not note the stereochemistry of this ester, it pointed out that the estrogenic product derived from it possessed the opposite carboxyl-2-methyl orientation, i.e. trans, although no X-ray analysis was performed. In the light of these results and the importance of correlating biological activity with compound structure, the unequivocal characterization of the highly estrogenic compound is warranted.

The surprising sp rotameric structure of 9-methyl-9-pivaloylfluorene

Methylation of 9-lithiated ap-9-pivaloylfluorene, (I), as well as pivaloylation of 9-lithiated 9-methylfluorene provided rotationally stable sp-9-methyl-9-pivaloylfluorene, (III), C(19)H(20)O, which lies about a crystallographic mirror plane. Fluorene (I) exists exclusively in the ap configuration in solution (NMR) as well as in the crystalline state, reflecting the unfavorable interaction between the tert-butyl and fluorene-ring pi electrons in the sp configuration. The existence of (III) exclusively in the sp configuration indicates that, in this case, the interaction between the tert-butyl group and the fluorene-ring pi electrons provides relatively more thermodynamic stability than the steric interaction between the tert-butyl and 9-methyl groups (ap configuration).

ap-9-(o-tert-Butylphenyl)-9-methylthiofluorene, the first isolated ap rotamer of a 9-substituted 9-(o-tert-butylphenyl)fluorene

Treatment of sp-9-(o-tert-butylphenyl)-9-fluorenol with HBr and methanethiol provided ap-9-(o-tert-butylphenyl)-9-methylthiofluorene, C 24 H 24 S, exclusively, the first isolated ap rotamer of a 9-substituted 9-(o-tert-butylphenyl)fluorene. The ap configuration in this series, generally the thermodynamically less favored, is preferred in the case of the title compound because the even larger interaction between the tert-butyl group and S in the sp configuration is energetically forbidden. The extensive distortion in the title compound is obvious from its X-ray structure and the associated geometric parameters.