Cholesterol balance and fecal neutral steroid and bile acid excretion in normal men fed dietary fats of different fatty acid composition.

Six normal men were fed formula diets containing either highly saturated fat (cocoa butter, iodine value 32) or polyunsaturated fat (corn oil, iodine value 125). The sterol balance technique was used to compare the changes in serum cholesterol concentration with the excretion of fecal steroids. The method used for the analysis of fecal steroids was chemical, with a final identification and quantification by gas-liquid chromatography. It was confirmed that the chemical method for fecal steroid analysis was accurate and reproducible. The three dietary periods were each 3 wk in length. In sequence, cocoa butter (period I), corn oil, and cocoa butter (period III) were fed at 40% of the total calories. All diets were cholesterol free, contained similar amounts of plant sterols, and were identical in other nutrients. Corn oil had a hypocholesterolemic effect. Mean serum cholesterol concentrations were 222 mg/100 ml (cocoa butter, period I), 177 during corn oil, and 225 after the return to cocoa butter. Individual fecal steroids were determined from stools pooled for 7 days. Both neutral steroids and bile acids were altered significantly by dietary polyunsaturated fat. The change in bile acid excretion was considerably greater than the change in neutral steroids. Corn oil caused a greater fecal excretion of both deoxycholic and lithocholic acids. The total mean excretion (milligrams per day) of fecal steroids was 709 for cocoa butter (period I), 915 for corn oil, and 629 for the second cocoa butter period. The enhanced total fecal steroid excretion by the polyunsaturated fat of corn oil created a negative cholesterol balance vis-à-vis the saturated fat of cocoa butter. The hypocholesterolemic effect of polyunsaturated fat was associated with total fecal sterol excretion twice greater than the amount of cholesterol calculated to leave the plasma. This finding suggested possible loss of cholesterol from the tissues as well.

Comparative metabolism in vitro of a novel carcinogenic polycyclic aromatic hydrocarbon, 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene, and its two regioisomeric B-ring fluoro analogues.

A novel biotransformation pathway likely exists for carcinogenic 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene (THDMBA), since this A-ring-reduced polycyclic aromatic hydrocarbon does not have an aromatic bay-region. The comparative metabolism of THDMBA, a non-carcinogenic 5F analogue, and a more carcinogenic 6F-THDMBA species was examined to determine potential DNA-bonding metabolites. Rat liver microsomes from phenobarbital-treated animals were incubated in the presence of THDMBA (or fluoro-THDMBA), NADPH, and O2. Metabolic products and the parent compound were extracted into organic solvent and analyzed/purified using reversed-phase high-performance liquid chromatography. Structure identification of metabolites using proton nuclear magnetic resonance, mass spectroscopy, and ultraviolet/visible spectroscopy indicated that hydroxylations at benzylic C1 and at the C7- and C12-CH3 functions are major oxidation products of THDMBA. Major metabolites for the noncarcinogenic 5F-THDMBA are the C4-hydroxy, C7-hydroxymethyl, and C12-hydroxymethyl derivatives. However, the potent carcinogen 6F-THDMBA only yielded major hydroxylation products at C1 and C12-CH3. These results together with a consideration of the electronic and steric effects of fluorine and the biological activities of these polycyclic aromatic hydrocarbons suggest that hydroxylation at the hindered benzylic C1 position or the C12-CH3 group of THDMBA is important for the biotransformation of such polycyclic aromatic hydrocarbons to DNA-bonding species.

Beta-lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate cancer cells: a p53-independent response.

beta-Lapachone and certain of its derivatives directly bind and inhibit topoisomerase I (Topo I) DNA unwinding activity and form DNA-Topo I complexes, which are not resolvable by SDS-K+ assays. We show that beta-lapachone can induce apoptosis in certain cells, such as in human promyelocytic leukemia (HL-60) and human prostate cancer (DU-145, PC-3, and LNCaP) cells, as also described by Li et al. (Cancer Res., 55: 0000-0000, 1995). Characteristic 180-200-bp oligonucleosome DNA laddering and fragmented DNA-containing apoptotic cells via flow cytometry and morphological examinations were observed in 4 h in HL-60 cells after a 4-h, > or = 0.5 microM beta-lapachone exposure. HL-60 cells treated with camptothecin or topotecan resulted in greater apoptotic DNA laddering and apoptotic cell populations than comparable equitoxic concentrations of beta-lapachone, although beta-lapachone was a more effective Topo I inhibitor. beta-Lapachone treatment (4 h, 1-5 microM) resulted in a block at G0/G1, with decreases in S and G2/M phases and increases in apoptotic cell populations over time in HL-60 and three separate human prostate cancer (DU-145, PC-3, and LNCaP) cells. Similar treatments with topotecan or camptothecin (4 h, 1-5 microM) resulted in blockage of cells in S and apoptosis. Thus, beta-lapachone causes a block in G0/G1 of the cell cycle and induces apoptosis in cells before, or at early times during, DNA synthesis. These events are p53 independent, since PC-3 and HL-60 cells are null cells, LNCaP are wild-type, and DU-145 contain mutant p53, yet all undergo apoptosis after beta-lapachone treatment. Interestingly, beta-lapachone treatment of p53 wild type-containing prostate cancer cells (i.e., LNCaP) did not result in the induction of nuclear levels of p53 protein, as did camptothecin-treated cells. Like other Topo I inhibitors, beta-lapachone may induce apoptosis by locking Topo I onto DNA, blocking replication fork movement, and inducing apoptosis in a p53-independent fashion. beta-Lapachone and its derivatives, as well as other Topo I inhibitors, have potential clinical utility alone against human leukemia and prostate cancers.

Induction of DNA topoisomerase II-mediated DNA cleavage by beta-lapachone and related naphthoquinones.

Recent studies have suggested that 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (beta-lapachone) inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin. To study the mechanism of action of beta-lapachone, a series of beta-lapachone and related naphthoquinones were synthesized, and their activity against drug-sensitive and -resistant cell lines and purified human DNA topoisomerases as evaluated. Consistent with the previous report, beta-lapachone does not induce topoisomerase I-mediated DNA breaks. However, beta-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA breaks in the presence of purified human DNA topoisomerase IIalpha. Poisoning of topoisomerase IIalpha by beta-lapachone and related naphthoquinones is independent of ATP and involves the formation of reversible cleavable complexes. The structural similarity between menadione, a para-quinone, and beta-lapachone, an ortho-quinone, together with their similar activity in poisoning topoisomerase IIalpha, suggests a common mechanism of action involving chemical reactivity of these quinones. Indeed, both quinones form adducts with mercaptoethanol, and beta-lapachone is 10-fold more reactive. There is an apparent correlation between the rates of the adduct formation with thiols and of the topoisomerase II-poisoning activity of the aforementioned quinones. In preliminary studies, beta-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive and drug-resistant tumor cell lines, including MDR1-overexpressing cell lines, camptothecin-resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cell line.

Comparison of hypocholesterolemic activity for cyclic analogs of clofibrate in normolipemic rats.

Chronic administration of ethyl 2-methyl-2(4-chlorophenoxy)-propionate [clofibrate, CPIB], ethyl 6-cyclohexylchroman-2carboxylate, and ethyl 6-phenylchroman-2-carboxylate to normolipemic rats, in vivo, reduced serum cholesterol levels and inhibitid the activiry of hepatic 3-hydroxy-3methyl-glutaryl Coenzyme A. Only clofibrate was found to lower liver cholesterol content after pretreatment for 4 or 18 days. The cyclic analogs, ethyl 6-cholorochromone-2-carboxylate and 9-chloro-2,3-dihydro-5H-1,4-dioxepino [6,5-b] benzofuran were inaffective as cholesterol lowering agents in normolipemic rats. These findings indicate that appropriate modification of clofibrate can lead to the development of compounds which are selective and equally effective to clofibrate as potential hypocholesterolemic agents. Results obtained in these studies are also discussed in terms of the known structural requirements of biological activity for this series of cyclic analogs in the Triton WR-1339 hyperlipemic rat model and modes of action of the parent compound.

Effects of pure capsaicinoids (capsaicin and dihydrocapsaicin) on plasma lipid and lipoprotein concentrations of turkey poults.

The effects of capsaicin and dihydrocapsaicin on blood lipid and lipoprotein concentrations were determined in two groups of turkeys. The first group was maintained on a cholesterol-free diet, while the second received a diet supplemented with 0.2% cholesterol. Daily administration of capsaicinoids occurred at a dose of 4 mg per animal. Neither drug had an effect on serum triglyceride concentrations in the animals receiving the cholesterol-free diet. However, total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations were increased significantly, while VLDL cholesterol concentrations were decreased significantly by both drugs relative to controls. In the cholesterol-fed group triglycerides, total cholesterol and LDL-cholesterol decreased significantly with dihydrocapsaicin treatment. Both compounds reduced VLDL-cholesterol and increased HDL-cholesterol in the cholesterol-fed animals. Dihydrocapsaicin had a greater efficacy in producing beneficial anti-hyperlipidemic effects in the cholesterol-fed animals.

Design, synthesis, and biological evaluation of conformationally constrained aci-reductone mimics of arachidonic acid.

An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-5-[4-(2-((2Z)-hexenyl)phenyl)-3-(1Z)-but enyl]-2 (5H)-furanone (12d). This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid (AA) (1) and its respective aci-reductone analogue (2). Pd(0)-catalyzed cross-coupling of 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone (7) with 2-((2Z)-hexenyl)iodobenzene (8d) followed by Lindlar catalyzed hydrogenation produces 12d. Butynyl intermediate 7 is prepared from 2-(benzyloxy)-5-deoxyascorbic acid (15) by iodination (I2, PPh3, Imd), iodo substitution with lithium acetylide ethylenediamine complex (LiAEDA, HMPA, -5 degrees C), and benzyl group cleavage (Ac2O, Pyr, BCl3). The utility of this synthetic method was demonstrated by the synthesis of analogues 10e-k. Biological testing revealed that certain of these antioxidants inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) with comparable efficacy as reported for aspirin and zileuton, respectively. The antioxidant activity of these aci-reductones, measured as a function of their inhibitory effect on CCl4-induced lipid peroxidation of hepatic microsomes, exceeds that produced by alpha-tocopherol. Synthetic routes and initial structure-activity relationships (SAR) for these novel mixed functioning antioxidants are presented.

Epimeric cis-decahydroquinoline-5-carboxylic acids: effects on gamma-aminobutyric acid uptake and receptor binding in vitro.

The syntheses for two cis-decahydroquinoline-5-carboxylic acid epimers (1 and 2) which contain the =N(C)3CO2H (gamma-aminobutyric acid; GABA) moiety are described. Both intra-and intermolecular [4 + 2] cycloaddition reactions were employed for the construction of key intermediates. 1H NMR studies provided evidence for the preferred solution conformations of the two diastereomers. Pharmacological studies revealed that these isomers have little affinity for GABA receptors in vitro relative to GABA agonists. However, expected but weak stereoselective activity was observed when these analogues were assessed for their ability to inhibit high-affinity [3H]GABA uptake into rat brain synaptosomes. These data are discussed in light of structure-activity studies of other neurotransmitter analogues, and a preliminary hypothesis based upon conformational analysis is presented to explain the results.

Synthesis and mutagenicity of A-ring reduced analogues of 7,12-dimethylbenz[a]anthracene.

The synthesis and mutagenicity of two derivatives of 7,12-dimethylbenz[a]anthracene (DMBA; 1), i.e., 1,2-H2DMBA (4) and 1,2,3,4-H4DMBA (5), are reported. These analogues (4 and 5) represent dihydro and tetrahydro A-ring reduced forms of DMBA, a region in the parent hydrocarbon (1) proposed to be involved in metabolism to the ultimate carcinogen. The synthesis for 4 without isolation of intermediates from the tosylhydrazone of 1,2,3,4-tetrahydrobenz[a]anthracene-4,7,12-trione (10) by successive reaction with 8 molar equiv of CH3Li, HI, and NaBH4 represents a novel approach to this hydrocarbon now available in sufficient quantity for biological studies. Interestingly, both of these reduced analogues 4 and 5 exhibited mutagenic activity in the Ames assay in the presence or absence of microsomal activation for strains TA98 and TA100. In these strains, DMBA was active only in the presence of S-9 fraction. In the plasmid-deficient strain TA1537, only tetrahydro analogue 5 exhibited mutagenic activity both in the absence and presence of S-9 fraction.

Synthesis and antimetastatic properties of stereoisomeric tricyclic bis(dioxopiperazines) in the Lewis lung carcinoma model.

Synthesis of trans- and cis-tetrahydrodipyrazino[1,2-a:1',2'-d] pyrazine-1,3,7,9(2H,4H,8H,10H)-tetrone analogues 10 and 11 belonging to the bis(dioxopiperazine) class of antitumor agents and their bis(morpholinomethyl) derivatives 12 and 13 are described with use of 2,5-dimethylpyrazine as the starting material. Synthetic studies utilizing 3,6-disubstituted 2,5-dioxopiperazine precursors are included. Evaluation of 10-13 in the Lewis Lung carcinoma model indicated the bis(morpholinomethyl) analogue cis-13 to be antimetastatic, whereas the trans isomer 12 was toxic at a similar dose effecting a decrease in the life span of treated mice. The parent bis(dioxopiperazines) 10 and 11 were ineffective as antitumor or antimetastatic drugs.

Stereoselective antitumor properties in the Lewis lung carcinoma model using bis(morpholinomethyl) derivatives of tricyclic bis(dioxopiperazines).

Geometric isomers of 2,11-bis(morpholinomethyl)tetrahydrodipyrazino[1,2-a:2',1'-c]pyraz ine-1, 3,10,12-(2H,4H,9H,11H)-tetrone (3 and 4) and the parent bisimides (1 and 2) were studied for their stereoselective antimetastatic activity in the Lewis Lung carcinoma model. The morpholinomethyl cis-syn-trans isomer 4 was more effective as an inhibitor of metastasis than the other three analogues. Using a postamputation protocol, the order of decreasing activity was cis morpholinomethyl analogue 4 greater than trans morpholinomethyl analogue 3 greater than parent cis imide 2 greater than parent trans imide 1. Increased activity observed for the morpholinomethyl derivatives may reflect differences in solubility and delivery (prodrug) or an intrinsic antitumor activity of the morpholinomethyl-N functionality.

Stereocontrolled syntheses for the six diastereomeric 1,2-dihydroxy-4,5-diaminocyclohexanes: PtII complexes and P-388 antitumor properties.

Stereocontrolled syntheses for the six diastereomeric 1,2-dihydroxy-4,5-diaminocyclohexanes 3a-f from cyclohexene diamines cis-4 and trans-5 are described. Cbz-protected species cis-9 and trans-11, respectively, served as a source of stable Cbz-protected precursors to these cyclohexanediol diamines (CDD), which were liberated upon catalytic (H2, Pd/C) hydrogenation. Catalytic osmylation of 9 afforded a mixture of diastereomeric diols 13 and 14, which served as precursors to cis-anti-cis CDD 3b and cis-syn-cis CDD 3a, respectively, whereas osmylation of 11 yielded the expected single product 12, the precursor to cis-anti-trans CDD 3d. Epoxidation of olefins 9 and 11 afforded oxiranes 15 and 17, respectively, which upon acid-catalyzed hydrolysis produced the corresponding Cbz-protected diols 16 and 18, which served as precursors to CDD trans-anti-cis 3c, and trans-anti-trans 3e. Formation of diol 18 from oxirane 17 was accompanied by formation of 2-oxa-4-azabicyclo[3.3.1]nonan-3-one 19. CDD trans-syn-trans 3f was prepared from diol 12 via regioselective monoacetylation, yielding 22, followed by oxidation to afford ketone 24. Sodium borohydride reduction and acetylation produced diacetate precursor 26. PtIICl2 complexes of five of the diamines (3a-d,f) are described, and their activities were compared with cisplatin (1) by employing P-388 leukemia implanted CDF1 mice. The data indicate that stereochemistry of the amino groups on the cyclohexanediamine ligand modulate the expression of toxic effects, and depending upon hydroxyl and amino group stereochemistry, there is a marked effect on complex formation (e.g., Cl2PtII-3e) and solubility characteristics (e.g., Cl2PtII-3c). Acetylation of the hydroxyl functions in selected isomers (28a-c) rendered the PtII complexes inactive. A single-crystal X-ray structure of compound 3a was determined at room temperature and indicated the cis-syn-cis arrangement of the OH and NH2 groups.

Stereoselective effects of cis- and trans-cyclopropylbis (dioxopiperazines) related to ICRF-159 on metastases of hamster lung adenocarcinoma.

The synthesis for cis-4,4' (1,2-cyclopropanediyl)bis(2,6-piperazinedione) (cis-3) is discussed. Stereoselective effects on metastases of cis-3 and the previously reported trans-2 isomer were compared to conformationally mobile ICRF-159 using a Syrian hamster lung adenocarcinoma (LG1002). Whereas ICRF-159 and cis-3 significantly inhibited lung metastases the trans-2 isomer significantly increased the number of metastatic nodules in the lung. Thus, these studies have revealed that, at least in one tumor model, antimetastatic activity can be separated from metastatic potentiating activity by controlling drug geometry.

Pharmacology on rat ileum of certain 2-substituted 3-(dimethylamino)-5,6-dimethoxyindenes related to 5,6-(methylenedioxy)indene calcium antagonists.

Whereas the 2-propyl- and 2-butyl-5,6-(methylenedioxy)indene calcium antagonists reversed the spasmogenic action of several agonists including PGF2alpha and acetylcholine at 5 X 10(-5) to 10(-4) M on the rat ileum, the corresponding 5,6-dimethoxy analogues exhibited spasmogenic activity at higher concentration (10(-4)-10(-3) M) and exhibited neither spasmogenic nor spasmolytic activity at lower (10(-6)-10(-5) M) concentration. The results are compared to the methyl and 2-ethyl analogues. At 10(-4) M only the butyl analogue was capable of moderate antagonism of acetylcholine and at 10(-3) M all four analogues were capable of moderately antagonizing the actions of acetylcholine.

Synthesis and pharmacological evaluation of reduced diastereoisomeric and quaternary ammonium derivatives of calcium antagonistic (methylenedioxy)indenes on the isolated rat aorta.

Based upon findings that 2-n-propyl- and 2-n-butyl-3-(diethylamino)-5,6-(methylenedioxy)indenes (1 and 2) inhibit a variety of calcium-activated cellular processes, it has previously been proposed that these compounds act as calcium antagonists with an intracellular site of action. In the present investigation, the diastereoisomeric dihydro analogues, cis- and trans-2-n-propyl- and cis- and trans-2-n-butyl-1-(dimethylamino)-5,6-(methylenedioxy)indans (5--8), and the trimethyl quaternary ammonium analogues of the unsaturated (3 and 4) and cis-saturated (9 and 10) systems were synthesized, and the ability of each to reverse norepinephrine- or KCl-induced contraction of the rat aorta was assessed. Saturation of 1 or 2 to produce the corresponding cis-aminoindan analogues (5 and 7) yielded compounds of similar spasmolytic activity, while saturation which yielded the respective trans forms (6 and 8) resulted in significant loss of potency. Methylation of either the cis unsaturated or saturated compounds to yield their respective quaternary derivatives also significantly reduced the potency of each compound. The reduced activity of the quaternary derivatives might be anticipated because of the limited cellular penetration of such compounds and is taken as evidence that the active tertiary analogues have an intracellular site of action. However, the results of the present investigation do not preclude the contribution of membrane effects to the pharmacological activity of the tertiary compounds (1, 2, 5, and 7), since the spasmolytically active analogues demonstrated a somewhat greater antagonistic potency against KCl-induced contractions as compared to their antagonism of the effects of norepinephrine.

Synthesis and antimetastatic properties of steroeoisomeric trycylic bis(dioxopiperazine) analogues in a B16 melanoma model.

The synthesis for trans and cis tricyclic bis(dioxopiperazine)s 5 and 6 from pyrazine-2,3-dicarboxamide (7) is described. Stereoselective antimetastatic activity differences for these analogues were observed following pretreatment of B16-F10 melanoma cells in vitro. Activities for these isomers were compared with selected intermediates, and the data are discussed in relation to previous results obtained with cis- and trans-cyclopropane analogues.

Stereoselective syntheses of the trans-decahydroquinoline-5-carboxylic acid epimers. Diastereomeric zwitterionic probes of gamma-aminobutyric acid related biological properties in vitro and in vivo.

The syntheses of the 5 beta and 5 alpha epimers of trans-(4a alpha,8a beta)-decahydroquinoline-5-carboxylic acids (3 and 4) from vinylogous bicyclic imide 10 are described. The reduction of trans-5-(1,3-dithian-2-ylidene)octahydro-2(1H)-quinolinone (13) to afford the 5 alpha-(1,3-dithian-2-yl) compound 16 was a key step in the synthesis of trans-4 while hydroboration-H2O2 treatment of phenylmethyl trans-octahydro-5-methylene-1(2H)-quinolinecarboxylate (21) to afford the 5 beta-hydroxymethyl compound 22 was a key step in the synthesis of 3. These trans diastereomers 3 and 4 and the previously prepared cis analogues 1 and 2 were investigated for their ability to interact with GABAA and GABAB receptors and picrotoxin binding sites as well as with neuronal GABA transport systems in brain tissue. Like 1 and 2, tonic-clonic seizures were induced when trans-3 or -4 were administered to mice intracerebroventricularly. Only trans-4 weakly inhibited [3H]GABA binding to GABAA and GABAB receptors in vitro. Large doses (10 mg/kg) of diazepam reversed the convulsant activity of both trans-3 and trans-4. Although trans-3 is the more potent convulsant, trans-4 may have GABA antagonist activity in vivo. However, none of the decahydroquinoline diastereomers have a pronounced effect on GABA receptors that can currently be studied in vitro. Results obtained in vivo lead us to propose that these diastereoisomers may serve as unique conformational probes relating certain zwitterionic topographies to stimulatory activity in the central nervous system.

Comparative antiaggregatory activity in human platelets of a benzopyranone aci-reductone, clofibric acid, and a 2,3-dihydrobenzofuran analogue.

A synthetic method for the preparation of aci-reductone 6-chloro-3,4-dihydroxy-2H-1-benzopyran-2-one (3) from 5-chlorosalicylate is presented. In human platelets, the benzopyranone derivative 3, clofibric acid (1), and the 2,3-dihydrobenzofuran analogue 4 inhibited aggregation and serotonin secretory responses to adenosine diphosphate (ADP) with a rank order of potency 3 greater than or equal to 4 greater than 1. Only analogues 3 and 4 consistently blocked the aggregatory responses (greater than 50%) to arachidonic acid (AA) and U46619, a thromboxane A2 agonist. Further, the rank order of inhibitory potency against U46619-induced serotonin secretion was 4 greater than 3 greater than 1. Benzopyranone 3 is of interest since it was the most potent inhibitor of thrombin-induced [3H]AA release (3 much greater than 4 = 1) and more potent than 1 or 4 for the blockade of the ADP- or AA-mediated pathway of platelet aggregation.

9-Chloro-2,3-dihydro-5H-1,4-dioxepino(6,5-b)benzofuran, a novel antilipidemic agent structurally related to clofibrate.

The synthesis and antilipidemic activity of 9-chloro-2,3-dihydro-5H-1,4-dioxepino[6,5-b]benzofuran (3), a novel enol lactone which is considerably more resistant to serum esterase hydrolysis than clofibrate (1), are discussed. Whereas both 3 and 1 reduced hypercholesterolemic and hypertriglyceridemic serum levels in the Triton WR-1339 induced hyperlipidemic Sprague-Dawley rat to normal, the hydrolysis product of 3, namely 5-chloro-3(2'-hydroxyethoxy)-2-benzofurancarboxylic acid (4), was found to be inactive. Further, 3 is comparable to the hydrolysis product of 1 when both were assessed for their ability to block norepinephrine (NE) induced lipolysis in vitro. 4 is inactive at comparable concentrations (5 times 10(-4)-10(-3) M). The antilipidemic action of 3 and 1 may, in part, be due to their ability to block NE-induced lipolysis.

Synthesis of ethyl 6-substituted-chroman- and -chromone-2-carboxylates. A comparative structure-activity study employing the 6-phenyl and phenoxy analogs in the triton hyperlipidemic rat model.

To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.