Cal Y. Meyers

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.

Doisynolic-type acids—Uterotropically potent estrogens which compete poorly with estradiol for cytosolic estradiol receptors

Doisynolic acids, a class of seco-steroid acids some of which exhibit greater uterotropic estrogenicity than estradiol-17 beta, are D-ring cleavage products of steroidal estrogens formed by fusion with KOH above 200 degrees C. We have found that electron-transfer reactions between estrone or estradiol and CCl4 or CBrCl3 in KOH-t-BuOH at 25 degrees C rapidly provide 16,16-dichloro- or -dibromodoisynolic acid, respectively, the former approaching estradiol in uterotropic potency. Simple esters from these highly hindered tertiary carboxylic acids, easily prepared via phase-transfer-catalyzed alkylations, also rival estradiol in uterotropic activity. Unlike natural steroidal estrogens or their commonly used artificial equivalents (DES, hexoestrol, ethynylestradiol, etc.) whose uterotropic activity is accompanied by substantial binding affinity for cytosolic estradiol receptors, these highly uterotropic doisynolic-type acids and esters exhibit binding affinities for this receptor of only about 1% that of estradiol-17 beta as determined by the usual competitive binding-inhibition studies with [3H]estradiol. Other highly uterotropic carboxylic acids may exhibit similar characteristics. These unusual results leave open the possibilities that uterotropic seco-steroid and related carboxylic acids undergo some unknown metabolic activation, are exceptionally persistent estrogens, bind to a cytosolic receptor site other than the conventional (type I) estradiol site, or bind directly to type I or type II nuclear receptor sites. At dosages of 1000 times those required for a uterotropic effect, the doisynolic-type acids (24 doses over an 8-week period) were neither toxic nor carcinogenic.

Transcriptional regulation of estrogen-responsive genes by non-steroidal estrogens: Doisynolic and allenolic acids

Estrogen receptor (ER), a member of the nuclear receptor superfamily, exerts prominent physiological roles in both humans and other species by acting directly as a transcription factor, altering nuclear gene expression. One peculiarity of estrogenic regulation is that it is affected by a wide variety of non-steroidal compounds in addition to the natural hormone, estradiol. Doisynolic and allenolic acid compounds are non-steroidal compounds that act as potent estrogens in animal studies, yet bind to ER extremely poorly in competitive binding assays, raising the possibility of alternative molecular mechanisms for the observed estrogenic effects. In this work we demonstrate that (+/-)-Z-bisdehydrodoisynolic acid, (+/-)-Z-bisdehydrodoisynolic acid 3-methyl ether, and (-) allenolic acid can interact directly with ER. These compounds all serve as ligands for ER in mechanism-specific tissue culture-based reporter gene assays for both positive and negative gene regulation. We have also used a novel assay based on electromobility shift by ER for directly determining relative binding affinities for ER. In addition, we show cell-type-specific activity differences for (+/-)-Z-bisdehydrodoisynolic acid 3-methyl ether, supporting clinical observations indicating a higher potency of this compound in female animals than in humans.

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.

6,7,8,9-Tetrahydro-3-methyl-1H-pyrano-[4,3-b]quinolin-1-one

The condensation reaction of 4-amino-6-methyl-2-pyrone with 1-cyclohexenecarboxaldehyde and a catalytic amount of (S)-(+)-10-camphorsulfonic acid in toluene at 358 K gave a 1:2.5 ratio of the title compound, (1) (C13H13NO2), and 7,8,9,10-tetrahydro-1H-pyrano[4,3-c]isoquinoline-1-one, (2). The formation of (2) presumably proceeds through an intermediate imine. Both (1) and (2) show inhibitory activities against acetylcholinesterase and human aldose reductase. Of the three linear-fused rings of (1), both ring A and ring B are planar and the angle between these planes is 0.46 (13) degrees. While the two C atoms of cyclohexane ring C attached to its common atoms with ring B are in the plane of the latter, as expected, the remaining two C atoms of ring C are out of this plane, by 0.342 (4) and -0.402 (3) A, respectively.

NEW SYNTHESES AND REACTIONS OF ORGANIC COMPOUNDS: REACTIONS WITH CARBON TETRACHLORIDE AND OTHER PERHALOMETHANES IN POWDERED POTASSIUM HYDROXIDE – t -BUTYL ALCOHOL

Ketones, sulfones, alcohols, and “acidic” hydrocarbons are readily halogenated with perhalomethanes—CCl 4 , CBr 4 , CBrCl 3 , CCl 2 Br 2 , etc,—in t-butyl alcohol-powdered potassium hydroxide. Depending upon the structure of the substrate, the halogenated derivative may be isolated or other, specific products formed from it in situ in this medium are obtained, generally in high yields. For the most part the halogenations with these reagents are selective and do not affect other sites of the substrate or other compounds that are usually sensitive to halogenating agents. Powdered potassium hydroxide suspended in t-butyl alcohol plays a special role in these halogenations as well as the subsequent reactions, which are all base-induced (“catalyzed”). The reactions occur rapidly apparently on the surface of the potassium hydroxide which is essentially insoluble in t-butyl alcohol. This phenomenon readily lends itself to commercial adaptation and high yields of products have been obtained merely by passing a solution of substrate in perhalomethane – t-butyl alcohol through a column packed with powdered potassium hydroxide on an inert support; the effluent is simply collected and evaporated, leaving the product. Evidence suggests that a finite concentration of potassium t-butoxide is maintained virtually on the surface of the potassium hydroxide (from commercial pellets, 15% H 2 O) in equilibrium with the KOH, H 2 O, and t-BuOH, and is responsible for the formation of substrate anion. In turn, these poorly solvated anions—in these studies mainly enolates or other varieties of carbanions —readily share an electron with perhalomethanes, and in the resulting caged radical/anion-radical pair (RARP) halogen-atom transfer is effected. Anions which cannot easily share an electron with the perhalomethanes are unreactive under these conditions; anions which actually transfer an electron to perhalomethanes are not halogenated either, but are responsible for the formation of free-radical related products. This chapter summarizes and categorizes the variety of new syntheses made available with these reactions. While the reaction pathways responsible for these syntheses are discussed in the respective sections, mechanistic details associated with the important halogenation step are described in the final section. The fact that CCl 4 , KOH, and t-BuOH are readily available, inexpensive, easily and safely handled and stored in any laboratory, and readily removed from the reaction products, contributes to the attractiveness of these new syntheses.

Improving the floatability and cleanability of ultrafine coal by the use of anionic surfactants; I. Correlation of surfactant structure with efficiency

Abstract A series of 10 reagents of known chemical structure, synthesized or obtained commercially, were evaluated for their ability to remove pyritic sulfur and ash from ultrafine coal by flotation processes. A correlation was made between the structure of these reagents and their coal cleaning effectiveness and efficiency, i.e., dosage versus weight and energy recovery, and ash and pyrite rejection, for two ultrafine samples, the Illinois No. 5 (hva) and Illinois No. 2 (hvc) coals. Within the series of structurally related surfactants, molecular size, symmetry, and geometry were found to be influential in determining coal cleanability. In general, the cis-1,2-dialkylethenesulfonate salts were more effective than the commercial surfactants which included an alkanesulfate salt, an alpha-olefin sulfonate salt, polyetheralkanesulfonate and sulfate salts, and some alcohols. In some cases, the dosage required to produce equivalent energy recoveries from the, synthesized cis-1,2-dialkylethenesulfonate salt rea...

The rapid reaction of benzhydryl sulfones with CCl4-KOH. A new route to 1,1-diarylalkenes

Benzhydrylsulfone (I) reagieren mit KOH, tert.-Butanol und Tetrachlorkohlenstoff uber die Zwischenstufen (II), (III) und (IV) zu den Olefinen (V).

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.

(5aS,7S)-7-isopropenyl-3-methyl-5a,6,8,9-tetrahydro-1H,7H-pyrano[4,3-b][1]benzopyran-1-one

A remarkable asymmetric induction was observed in the one-pot condensation reaction of (S)-(-)-perillaldehyde with 4-hydroxy-6-methyl-2-pyrone in the presence of L-proline which provided the title compound, C 16 H 18 O 3 , a tricyclic pyrone, as a single diastereomer in 78% yield. As the configuration of the cyclohexane C atom holding the isopropenyl group is the same as that in the (S)-aldehyde substrate, the total absolute stereochemistry could be elucidated from its X-ray structure. The cyclohexane ring has a chair conformation in which the juncture H atom (H5a) is axially oriented and the isopropenyl substituent is equatorial.