Heterocyclic steroids-part ix: Studies on the total synthesis of racemic a-nor-5,7-bisthiabstra-1,5 (10), 8, 14-tetraen-17(e)-ol

1,6-Bisthia-4,5,6,7-tetrahydroinden-4-one (I) was converted to racemic A-nor-3,7-bisthiaestra-1,5 (10),8,14-tetraen-17(e)-o1 (VI).     

Synthesis of 3-methoxy-5,6-secoestra-1,3,5(10),8,14-pentaen-17-one

A facile synthesis of 3-methoxy-5,6-secoestra-1, 3,5(10),8,14-pentaen-17-one from the readily available p-anisaldehyde is reported.     

Studies of novel pentacyclic heterocyclic steroids: Part XXI. Total synthesis of racemic benz[3,4]-6-oxaestra-1,3,5(10),8-tetraen-17 beta-ol

1-Oxo-4-oxa-1,2,3,4-tetrahydrophenanthrene is converted into racemic benz[3,4]-6-oxaestra-1,3,5(10),8-tetraen-17 beta-ol in 45% yield.     

Heterocyclic steroids-part-VI: Studies on the total syntheses of racemic A-nor-3-thiaestra-1,5(10),6,8,14-pentaen-17(e)-OL and A-nor-3-thiaestra-1,5(10),8,14-tetraen-17(e)-OL

4-Oxo-4,5,6,7-tetrahydrothianaphthene(I) is converted into racemic A-nor-3-thiaestra-1,5(10),6,8,14-pentaen-17(e)-01(IX) and A-nor-3-thiaestra-1,5(10),8,14-tetraen-17(e)-01 (VIII).     

Microbiologic oxidation of estratrienes and estratetraenes by Streptomyces roseochromogenes ATCC 13400

Incubation of estrone (1a) with Streptomyces roseochromogenes ATCC 13400 yielded a mixture of 3,16 alpha-dihydroxyestra-1,3,5(10)-trien-17-one (3a) and 3,17 beta-dihydroxyestra-1,3,5(10)-trien-16-one (4a). Transformation of 3-methoxyestra-1,3,5(10)-trien-17-one (1b), 3-hydroxyestra-1,3,5(10),9(11)-tetraen-17-one (2a), and 3-methoxyestra-1,3,5(10),9(11)-tetraen-17-one (2b) with the same microorganism gave the corresponding mixtures of 16 alpha-hydroxy-17-ketones and 17 beta-hydroxy-16-ketones (3b and 4b, 6a and 7a, 6b and 7b, respectively). In addition, in these three last experiments, the 16 beta-17 beta-dihydroxy derivatives 5b, 8a, and 8b, respectively, were also isolated. The complete assignments of the 13C nuclear magnetic resonance spectra of these compounds are given.     

Synthesis of radiolabeled stilbene derivatives as new potential PET probes for aryl hydrocarbon receptor in cancers

New carbon-11 and fluorine-18 labeled stilbene derivatives, cis-3,5-dimethoxy-4'-[11C]methoxystilbene (4'-[11C]8a), cis-3,4',5-trimethoxy-3'-[11C]methoxystilbene (3'-[11C]8b), trans-3,5-dimethoxy-4'-[11C]methoxystilbene (4'-[11C]10a), trans-3,4',5-trimethoxy-3'-[11C]methoxystilbene (3'-[11C]10b), cis-3,5-dimethoxy-4'-[18F]fluorostilbene (4'-[18F]12a), and trans-3,5-dimethoxy-4'-[18F]fluorostilbene (4'-[18F]13a), were designed and synthesized as potential PET probes for aryl hydrocarbon receptor (AhR) in cancers.     

Estrogenic and anti-estrogenic compounds from the Thai medicinal plant, Smilax corbularia (Smilacaceae)

From the rhizomes of Smilax corbularia Kunth. (Smilacaceae), 11 compounds, (2R,3R)-2″-acetyl astilbin, (2R,3R)-3″-acetyl astilbin, (2R,3R)-4″-acetyl astilbin, (2R,3R)-3″-acetyl engeletin, (2R,3S)-4″-acetyl isoastilbin, 2-(4-hydroxyphenyl)-3,4,9,10-tetrahydro-3,5-dihydroxy-10-(3,4-dihydroxyphenyl)-(2R,3R,10R)-2H,8H-benzo [1,2-b:3,4-b′] dipyran-8-one, 2-(4-hydroxyphenyl)-3,4,9,10-tetrahydro-3,5-dihydroxy-10-(3,4-dihydroxyphenyl)-(2R,3R,10S)-2H, 8H-benzo [1,2-b:3,4-b′] dipyran-8-one, 3,4-dihydro-7-hydroxy-4-(3,4-dihydroxyphenyl)-5-[(1E)-2-(4-hydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, 3,4-dihydro-7-hydroxy-4-(3,4-dihydroxy-phenyl)-5-[(1E)-2-(3,4-dihydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, 3,4-dihydro-7-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-5-[(1E)-2-(4-hydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, and 5,7,3′,4′-tetrahydroxy-3-phenylcoumarin along with 34 known compounds were isolated and characterized as 19 flavonoids, 14 catechin derivatives, 6 stilbene derivatives, and 6 miscellaneous substances. All isolates had their estrogenic and anti-estrogenic activities determined using the estrogen-responsive human breast cancer cell lines MCF-7 and T47D. The major constituents were recognized as flavanonol rhamnosides by the suppressive effect on estradiol induced cell proliferation at a concentration of 1 μM. Meanwhile, flavanonol rhamnoside acetates demonstrated estrogenic activity in both MCF-7 and T47D cells at a concentration of 100 μM, and they enhanced the effects of co-treated E2 on T47D cell proliferation at concentrations of more than 0.1 μM.     

Cyclization of 13beta-ethyl-3-methoxy-17beta-ol-8,14-seco-1,3,5(10),9-gonatetraen-14-one and its 17 acetate derivative.

13beta-Ethyl-3-methoxy-17beta-ol-8,14-seco-1,3,5(10),8-gonatetraen-14-one (IIIa) was isolated and its participation in the well-known acidic cyclization process was established.     

Head Space Constituents of Different Varieties of Osmanthus fragrans

This work deals with the head space constituents of different varietiesof Osmanthus fragrans. A porous crosslinked polystyrene resin (Amberite XAD-4)trap was used to absorbing the head space of fresh flowers and the constituents weredetermined by using GC, GC/MS/DS. Thus, fifty six components have been identifiedand thirty seven of them were unreported: i.e. ethyl acetate, 3-methyl butanone, 3-hydroxy-2-butanone, 5-hexen-2-one, 3,3-dimethyl hexane, undecan-6-one, myrcene, decane,limonene,αand β-ocimene, 6-methyl-3, 5-heptadien-2-one,1,6-diacetoxy-hexane,5-phen-ylmethoxy-l-pentanol,3-eyelohexene-l-methanol, ,7-dimethyl-3,5-octadiene, menthone,menthol, ethyl benzaldehyde, 2-cyclohexen-l-yl-2-methyl-5-(1-methylethenyl) acetate, 4-methyl-2-heptanol, 1,4-benzene dicarboxaldehyde, hexyl butanoate, ethyl benzoate, cin-namic aldehyde, 1,4-dimethyl-3-eyclohexen-l-ol ethanone, carvone, 2-hydroxymethyl be-nzoic acid, benzoic acid, 3,4-dihydro-l-2(H)-naphthalenone, 8,8-dimethyl-4-methylene, 1-oxaspiro-[2, 5]-oct-5-ene, 2,4-dimethyl phenyl ethenone, 1-ethoxyethyl benzene, 4,6,6-tri-methyl-bicyelo-[3, 1, 1]-hept-3-en-2-one, 1,4-phenylene bis ethanone-l,1, diethyl O-phtha-late and dibutyl-O-phthalate.     

Curcumin and its analogues as potent inhibitors of low density lipoprotein oxidation: H-atom abstraction from the phenolic groups and possible involvement of the 4-hydroxy-3-methoxyphenyl groups

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, 1) is a yellow ingredient isolated from turmeric (Curcumin longa). It has been shown to exhibit a variety of biological activities including antioxidative activity. In order to find more active antioxidants with 1 as the lead compound we synthesized curcumin analogues, i.e., 1,7-bis(3,4-dihydroxyphenyl)-1,6-heptadiene-3,5-dione (2), 1-(3,4-dihydroxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (3), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (4), 1,7-bis (4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (5), 1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (6), 1,7-bis(3,4-dimethoxyphenyl)-1,6- heptadiene-3,5-dione (7), 1,7-bis(4-methoxyphenyl)-1,6-heptadiene-3,5-dione (8), and 1,7-diphenyl-1,6-heptadiene-3,5-dione (9). Antioxidative effects of curcumin and its analogues against free radical initiated peroxidation of human low density lipoprotein (LDL) were studied. The peroxidation was initiated either by a water-soluble initiator 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), or by cupric ion (Cu2+). The reaction kinetics were monitored either by the uptake of oxygen and the depletion of alpha-tocopherol present in the native LDL, or by the formation of thiobarbituric acid reactive substances. Kinetic analysis of the antioxidation process demonstrates that these compounds, except 7, 8, and 9, are effective antioxidants against AAPH- and Cu2+ -initiated LDL peroxidation by H-atom abstraction from the phenolic groups. Compounds 2 and 3 which bear ortho-diphenoxyl functionality possess significantly higher antioxidant activity than curcumin and other analogues, and the 4-hydroxy-3-methoxyphenyl group also play an important role in the antioxidative activity.     

One-pot synthesis of new A-ring fused steroidal pyridines

The preparation of pyridine rings fused to the 3,4-positions of the steroid nucleus is herein described. These new pyridine derivatives were prepared in good yields by the reaction of propargylamine with 17beta-hydroxyandrost-4-en-3-one, 17alpha-methyl-17beta-hydroxyandrost-4-en-3-one, 17beta-hydroxyestr-4-en-3-one catalyzed by Cu(II). The structure of 17beta-hydroxy-5-ene-androst-3-eno[3,4-b]pyridine was determined by X-ray analysis.     

Inhibition of lipid peroxidation and protein oxidation in rat liver mitochondria by curcumin and its analogues

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, 1) is a yellow ingredient isolated from turmeric (curcumin longa). It has been shown to exhibit a variety of biological activities including antioxidative activity. In order to find more active antioxidants with 1 as the lead compound we synthesized curcumin analogues, i.e., 1-(3,4-dihydroxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (2), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (3), 1,7-bis-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (4), 1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (5), 1,7-bis(3,4-dimethoxyphenyl)-1,6-heptadiene-3,5-dione (6), and 1,7-diphenyl-1,6-heptadiene-3,5-dione (7), and evaluated their antioxidative activity. The in vitro oxidative damage to both lipids and proteins in rat liver mitochondria was used as a model to study the free radical-induced oxidative damage of biological lipids as well as proteins and the protective effects of these curcumin analogues. It was found that these compounds, except 6 and 7, could effectively inhibit the free radical induced lipid peroxidation and protein oxidative damage of rat liver mitochondria by H-atom abstraction from the phenolic groups. Compound 2 which bear ortho-diphenoxyl functionality exhibited remarkably higher antioxidative activity for lipids and proteins than curcumin and other analogues, and the 4-hydroxy-3-methoxyphenyl group also play an important role in the antioxidative activity.     

Characterization and detection of lysine-arginine cross-links derived from dehydroascorbic acid

Covalently cross-linked proteins are among the major modifications caused by the advanced Maillard reaction. So far, the chemical nature of these aggregates is largely unknown. L-dehydroascorbic acid (DHA, 5), the oxidation product of L-ascorbic acid (vitamin C), is known as a potent glycation agent. Identification is reported for the lysine-arginine cross-links N6-[2-[(4-amino-4-carboxybutyl)amino]-5-(2-hydroxyethyl)-3,5-dihydro-4H-imidazol-4-ylidene]-L-lysine (9), N6-[2-[(4-amino-4-carboxybutyl)amino]-5-(1,2-dihydroxyethyl)-3,5-dihydro-4H-imidazol-4-ylidene]-L-lysine (11), and N6-[2-[(4-amino-4-carboxybutyl)amino]-5-[(1S,2S)-1,2,3-trihydroxypropyl]-3,5-dihydro-4H-imidazol-4-ylidene]-L-lysine (13). The formation pathways could be established starting from dehydroascorbic acid (5), the degradation products 1,3,4-trihydroxybutan-2-one (7, L-erythrulose), 3,4-dihydroxy-2-oxobutanal (10, L-threosone), and L-threo-pentos-2-ulose (12, L-xylosone) were proven as precursors of the lysine-arginine cross-links 9, 11, and 13. Products 9 and 11 were synthesized starting from DHA 5, compound N6-[2-[(4-amino-4-carboxybutyl)amino]-5-[(1S,2R)-1,2,3-trihydroxypropyl]-3,5-dihydro-4H-imidazol-4-ylidene]-L-lysine (16) via the precursor D-erythro-pentos-2-ulose (15). The present study revealed that the modification of lysine and arginine side chains by DHA 5 is a complex process and could involve a number of reactive carbonyl species.     

Indole alkoloids from Nauclea officinalis with weak antimalarial activity

Five indole alkaloids (naucleofficines A-E) were isolated from the stems (with bark) of Nauclea officinalis: (E)-2-(1-beta-d-glucopyranosyloxybut-2-en-2-yl)-3-(hydroxymethyl)-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (1), (E)-1-propenyl-12-beta-d-glucopyranosyloxy-2,7,8-trihydro-indolo[2,3-a]pyran[3,4-g]quinolizin-4,5(13H)-dione (2), (E)-2-(1-hydroxybut-2-en-2-yl)-11-beta-d-glucopyranosyloxy-6,7-dihydro-indolo[2,3-a]quinolizin-4(12H)-one (3), (E)-1-propenyl-4-hydroxy-2,4a,7,8,13b,14,14a-hepthydro-(4alpha,4abeta,13balpha,14abeta)indolo[2,3-a]pyran[3,4-g]quinolizin-5(13H)-one (4) and 1-(1-hydroxyethyl)-10-hydroxy-7,8-dihydro-indolo[2,3-a]pirydine[3,4-g]quinolizin-5(13H)-one (10-hydroxyangustoline) (5), together with two known compounds, naucleidinal (6) and angustoline (7). All of the structures of the seven compounds above were elucidated by spectroscopic methods including use of 1D- and 2D-NMR spectroscopic analyses. Compounds 2 and 3 are rare examples of monoterpene indole alkaloids with a glucopyranosyloxy group attached to position C-12. In vitro activity screening of the above seven compounds showed weak to moderate inhibitory activity against Plasmodium falciparum.     

Selective protections on 2-allyloxycarbonylamino-1,6-anhydro-2-deoxy-beta-D-glucopyranose.

Regioselective monoacetylation of 2-allyloxycarbonylamino-1,6-anhydro-2-deoxy-beta-D-glucopyranose (1) gave a mixture of 3-O-acetyl and 4-O-acetyl derivatives, the structures of which were established by two-dimensional, phase-sensitive NOESY and confirmed by chemical proofs. The benzylation of 1, on the other hand, led to 2-allyloxycarbonylamino-1,6-anhydro-3,4-di- (5) or 2-allyloxycarbonylamino-1,6-anhydro-2-N-benzyl-3,4-di-O-benzyl-2-d eoxy-beta-D- glucopyranose (10). The regioselective cleavage of 5 with titanium tetrachloride gave the expected 3-O-benzyl derivative, the structure of which was ascertained by chemical proofs; the same reaction performed on 10 led to the opening of the anhydro ring to afford 3-benzyl-[3,4-di-O-benzyl-1,2-dideoxy-alpha-D-glucopyrano]-[2,1-d] -2- oxazolidone.     

Synthesis and in vitro antitumor activity of thiophene analogues of 5-chloro-5,8-dideazafolic acid and 2-methyl-2-desamino-5-chloro-5,8-dideazafolic acid

N-[5-[N-(2-Amino-5-chloro-3,4-dihydro-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]-L-glutamic acid (6) and N-[5-[N-(5-chloro-3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]-L-glutamic acid (7), the first reported thiophene analogues of 5-chloro-5,8-dideazafolic acid, were synthesized and tested as inhibitors of tumor cell growth in culture. 4-Chloro-5-methylisatin (10) was converted stepwise to methyl 2-amino-5-methyl-6-chlorobenzoate (22) and 2-amino-5-chloro-3,4-dihydro-6-methyl-4-oxoquinazoline (19). Pivaloylation of the 2-amino group, followed by NBS bromination, condensation with di-tert-butyl N-(5-amino-2-thenoyl)-L-glutamate (28), and stepwise cleavage of the protecting groups with ammonia and TFA yielded. Treatment of 9 with acetic anhydride afforded 2,6-dimethyl-5-chlorobenz[1,3-d]oxazin-4-one (31), which on reaction with ammonia, NaOH was converted to 2,6-dimethyl-5-chloro-3,4-dihydroquinazolin-4-one (33). Bromination of, followed by condensation with and ester cleavage with TFA, yielded. The IC(50) of and against CCRF-CEM human leukemic lymphoblasts was 1.8+/-0.1 and 2.1+/-0.8 microM, respectively.     

SAR of a series of anti-HSV-1 acridone derivatives, and a rational acridone-based design of a new anti-HSV-1 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine series

Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a-j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a-i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure-activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile.     

鲍氏层孔菌子实体的化学成分研究

采用硅胶和Sephadex LH20柱层析方法,从鲍氏层孔菌子实体提取物中分离得到8个化合物。运用NMR和MS等波谱法分析和鉴定为7(8),22(23)-二烯-3-酮-麦角甾烷、4,6,8(14),22(23)-四烯-3-酮-麦角甾烷、麦角甾醇、过氧化麦角甾醇、三十烷酸对羟基苯乙酯、4-(3,4-二羟苯基)-3-丁烯-2-酮、hispolon、hispidin。     

Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors

In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-d-homo-3,5-androstadien-17-one (26–31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [³H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC₅₀ being 15.6 nM as compared to clinically used drug finasteride (40 nM). There was also a significant inhibition of 5AR-1 with IC₅₀ 547 nM compared to finasteride (453 nM).     

Phenolic glycosides from Kaempferia parviflora

Three phenolic glycosides were isolated together with two known flavonol glycosides from the H2O-soluble fraction of rhizomes of Kaempferia parviflora. Their structures were determined to be rel-(5aS,10bS)-5a,10b-dihydro-1,3,5a,9-tetrahydroxy-8-methoxy-6H-benz[b]indeno[1,2-d]furan-6-one 5a-O-[alpha-L-rhamnopyranosyl-(1-->6)-beta-d-glucopyranoside] (1), its rel-5aS,10bR isomer (2), and (2R,3S,4S)-3-O-[alpha-L-rhamnopyranosyl-(1-->6)-beta-d-glucopyranosyl]-3'-O-methyl-ent-epicatechin-(2alpha-->O-->3,4alpha-->4)-(5aS,10bS)-5a,10b-dihydro-1,3,5a,9-tetrahydroxy-8-methoxy-6H-benz[b]indeno[1,2-d]furan-6-one 5a-O-[alpha-L-rhamnopyranosyl-(1-->6)-beta-D-glucopyranoside] (3). The structures were elucidated on the basis of analyses of chemical and spectroscopic evidence.