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A concise synthesis of yuehchukene has been achieved using organocatalytic Friedel–Crafts alkylation of indole to a sterically encumbered α-alkyl enal as the key step. A racemization process during the subsequent cyclization steps of the conjugate adduct to yuehchukene was observed.

This review describes a synthesis of indole compounds using multifunctional synthons. The multifunctional synthons, trienes and gramines, were respectively synthesized using Pd-catalyzed tandem cyclization/cross-coupling reaction of indolylborate with vinyl bromide, and reaction of indolylcuprate with iminium chloride. As an application of the multifunctional synthons to the indole alkaloids synthesis, we accomplished the total synthesis of ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, tetrahydroellipticine, μ-alkaloid B, μ-alkaloid D, calothrixin A, calothrixin B, tubifoline, and yuehchukene. We have also developed 6π-electrocyclization of hexatrienes catalyzed by Cu(I) trifluoromethanesulfonate toluene complexe, which is unprecedented.

Objective : This study performed a virtual screening of the Indonesian Herbal Database for the core protein allosteric modulator of the hepatitis B virus (HBV) using AutoDock and AutoDock Vina software, to discover novel safe drugs for patients. Methods : The method was validated using the parameters enrichment factor (EF), receiver operating characteristics, and area under the curve (AUC). The grid box size used in virtual screening with AutoDock was 55 × 55 × 55 with EF10% of 0.7652 and AUC of 0.6709, whereas that used in virtual screening with AutoDock Vina was 20.625 × 20.625 × 20.625 with EF5% of 0.5075 and AUC of 0.7832. Results : The top 10 compounds from virtual screening with AutoDock at G levels −11.74–−10.31 kcal/mol were yuehchukene, lansionic acid, stigmast- 4-en-3-one, myrtillin, sanggenol O, lanosterol, erycrista-gallin, alpha-spinasterol, cyanidin 3-arabinoside, and cathasterone and with AutoDock Vina at G levels −12.1 to −10.7 kcal/mol were sanggenol O, cucumerin A, yuehchukene, palmarumycin CP1, dehydrocycloguanandin, myrtillin, liriodenine, myricetin 3-alpha-L-arabinopyranoside, myricetin 3-galactoside, and cassameridine. Conclusion : Three compounds were in top list of both virtual screening methods against Cp allosteric modulator of HBV are myrtillin, sanggenol O, and yuehchukene have a prospect to be investigated futher for anti HBV.

Yuehchukene (YCK) is a novel bis-indole alkaloid with weak estrogenic activity. Biochemical studies showed that YCK could attenuate estrogenic action. In this study, the response of MCF-7, an estrogen-receptor-positive breast cancer cell line, under different combinations of estradiol, cyclophosphamide and YCK, was tested. From the dose-response curve, we discovered that 10–2 M cyclophosphamide, even in its so-called ‘bio-inert’ form, could inhibit MCF-7 cell growth. However, the cytotoxic effect of cyclophosphamide was lost by reducing its concentration to ∼1 × 10–3 M. On the other hand, a low concentration (∼10–8–10–9 M) of YCK was found to potentiate the cytotoxic effect of cyclophosphamide on the MCF-7 cell line. Such an effect was absent in the estrogen-receptor-negative cell line MDA-MB-231. These findings, together with the dual role of a mixed estrogen and anti-estrogen effect, suggested that YCK and cyclophosphamide can be a potential combination in chemo-hormonal therapy for breast cancer.

Lithiation chemistry has not been well explored in fluorous synthesis because of the lack of appropriate base-resistant fluorous tags; we recently developed a perfluoroalkylated arylsulfonyl tag for the protection of the indole ring nitrogen atom. Mesityllithium was found to be a suitable reagent for the α-lithiation of perfluoroalkyl-tagged 1-(arylsulfonyl)indole, and the fluorous synthesis of yuehchukene was accomplished efficiently using this method as a key step. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

β-(1-Hydroxybut-3-enyl)indoles have been converted into three indole natural products: yuehchukene 1, β-(dehydroprenyl)indole 2, murrapanine 3 and other analogues in a one step procedure under various acid-catalysed reaction conditions in THF. A one-pot synthesis of bisnoryuehchukene 15 starting from indole-3-carboxaldehyde was also achieved using a similar approach. β-(1-Hydroxybut-3-enyl)indoles are presumed to be dehydrated to 1-(β-indolyl)buta-1,3-dienes which then react further to give yuehchukene, murrapanine and other derivatives via a Diels–Alder pathway. The yields of 3 and normurrapanine 31 could be improved by using an aerial oxidation method. Murrapanine and analogues were found to exhibit potent cytotoxicity towards various cancer cell lines.

A total synthesis of inverto-yuehchukene 4 and its 10-(indo-3′-yl) isomer 7 is described. The key tetracyclic ketone intermediate 13 was synthesized by a coupling reaction between 3-indolylzinc reagent and acid chloride 11, followed by Nazarov cyclization of the divinyl ketone 12. The indol-2-yl moiety present in inverto-yuehchukene 4 was introduced by palladium(0)-catalysed cross-coupling between indol-2-ylzinc reagent and the acetate 16.

β-(1-Hydroxybut-3-enyl)indoles, which are prepared in high yields from indole-3-carbonyl compounds, could be converted into 1-(β-indolyl)1,3-butadienes, yuehchukene and derivatives, and murrapanine in one step under various acid-catalyzed reaction conditions in THF. As the reactions of β-(1-hydroxypropenyl)indole 1 3 with alcohol 4 and 8a gave exclusively bisnoryuehchukene 7c and trinoryuehchukene 7d, respectively, our present work also gives strong evidence to support the asssumption that reactions of this type indeed proceed from a Diels-Alder pathway.

A facile synthesis of 2-tert-Butyl-3-(indol-3s'-yl)-1,2,3,4-tetrahydrocyclopent [b]indole (2), a diminished analogue of yuehchukene (1), is described.

Yuehchukene (1) has been synthesized by one-step transformations of both alcohols (E)-β-(3-hydroxy-3-methylbutenyl)indole (3) and β-(1-hydroxy-3-methylbut-3-enyl)indole (4) under various reaction conditions. Alcohol 3 can be prepared efficiently from indole-3-carboxaldehyde (8) via a two-step reaction sequence. Alcohol 4, an isomer of 3, can be obtained from the same starting material 8 in only one step. Alcohol 4 can be converted directly into β-(dehydroprenyl)indole (2) in high yield under mild conditions via a base-induced dehydration. However, alcohol 3 does not give diene 2 under the same reaction conditions. Since diene 2 has been used as the key intermediate for the syntheses of yuehchukene (1) , analogues of 1, and a cytotoxic compound, murrapanine (7), our present work also completes formal total syntheses of these bioactive compounds

Efficient synthesis of the title compound and its R-enantiomer from readily available (1S)–(–)-camphor or (1R)-(+)-camphor, respectively, is described. Stable conformations of the title compounds and yuehchukene were compared by employment of the MM2 force field for energy calculation and minimization. Since yuehchukene occurs in Nature in racemic form, a bioassay study of enantiomerically pure S- and R-enantiomer of the title compound would provide an indication as to which enantiomer of yuehchukene is responsible for its activity. Results of the study led to the conclusion that the enantiomer of yuehchukene which is biologically active should possess the R-absolute configuration at C-6.

Yuehchukene and a number of structural analogues have been synthesized by intromolecular ring closure of α,β-unsaturated 2-acylindoles in the key step. Reduction of the resulting cyclopent[b]indol-3-one derivatives, followed by acid-catalyzed incorporation of a second indole unit, gave the title compounds.

A facile synthesis of 2-tert-Butyl-3-(indol-3s'-yl)-1,2,3,4-tetrahydrocyclopent [b]indole (2), a diminished analogue of yuehchukene (1), is described.

A total synthesis of inverto-yuehchukene 4 and its 10-(indo-3′-yl) isomer 7 is described. The key tetracyclic ketone intermediate 13 was synthesized by a coupling reaction between 3-indolylzinc reagent and acid chloride 11, followed by Nazarov cyclization of the divinyl ketone 12. The indol-2-yl moiety present in inverto-yuehchukene 4 was introduced by palladium(0)-catalysed cross-coupling between indol-2-ylzinc reagent and the acetate 16.

A facile synthesis of 6′β-(indol-3″-yl)-9′- methyl-5′,6′,-6′αβ,7′,8′,10′ αβ-hexahydrospiro[cyclopropane-1,7′-indeno[2,1-b]indole] (2), an analogue of yuehchukene (1), is described.

Many of the alkaloids found in Nitraria and Lupine species can be envisaged to arise from two simple building blocks, namely tryptamine and tetrahydropyridine. In particular in the Nitraria species, the alkaloids occur as racemates, in some cases, despite multi stereocenters. We assume that these alkaloids might be formed without interference of enzymes via spontaneous reactions of highly reactive intermediates. By carrying out a biomimetic approach many of these alkaloids were obtained via chemical synthesis, based on reactive precursors. The paper reviews the preparation of racemic Nitramine, Lupinine, Nazlinin, Nitrarineflitramidine, Spartein and Nitraramine from tryptamine and the trimer of tetrahydropyridine, based on imine-enamine chemistry. A variety of alkaloids, like Nitramin I, Nitrarine 2 and Nitraramine 2, have been isolated from different species of the Nitraria family (ref. 1). An interesting feature of these alkaloids is the fact that they are isolated as racemates, even in cases where the molecule contains four or five stereocenters (ref. 2). This has been observed before for alkaloids like akuammicine (ref. 3), yuehchukene (ref. 4) and lucidene (ref. 5).

Facile syntheses of 2-t-butyl-3-(indol-3′-yl)-1,2,3,4-tetrahydrocyclopent[b]indol-6-ol (3), and its 6-methoxy (4) and 6-acetyloxy (5) derivatives are described.

β-(1-Hydroxybut-3-enyl)indoles have been converted into three indole natural products: yuehchukene 1, β-(dehydroprenyl)indole 2, murrapanine 3 and other analogues in a one step procedure under various acid-catalysed reaction conditions in THF. A one-pot synthesis of bisnoryuehchukene 15 starting from indole-3-carboxaldehyde was also achieved using a similar approach. β-(1-Hydroxybut-3-enyl)indoles are presumed to be dehydrated to 1-(β-indolyl)buta-1,3-dienes which then react further to give yuehchukene, murrapanine and other derivatives via a Diels–Alder pathway. The yields of 3 and normurrapanine 31 could be improved by using an aerial oxidation method. Murrapanine and analogues were found to exhibit potent cytotoxicity towards various cancer cell lines.

Reaction of (dimethylvinylidene)carbene with indole-3-carbaldehyde gives various dehydroprenyl-based indoles. Efficient synthesis of the indole natural products yuehchukene and murrapanine, using this reaction as a key step, is also described.

In a first attempts to define the structural requirements for the expression of anti-implantation activity in Yuehchukene (YCK), it was found that the relative position or planarity of the aromatic centres may be crucial. New synthetic routes leading to analogues with modification of C-7 substituents were established. Results indicated that a bulky group at C-7 that served to restrict the rotation of the C-6 indole was indispensable. Further steric hindrance by 2′-methyl would increase potency in all weak analogues. It was concluded that YCK required an optimal conformation that was defined by a narrowly-fixed angle between the planes of the C-6 indole and the tetracyclic unit.

Yuehchukene and a number of structural analogues have been synthesized by intromolecular ring closure of α,β-unsaturated 2-acylindoles in the key step. Reduction of the resulting cyclopent[b]indol-3-one derivatives, followed by acid-catalyzed incorporation of a second indole unit, gave the title compounds.

(+/-)-Yuehchukene is a dimeric indole alkaloid with potent anti-implantation activity in rats. Since (+/-)-yuehchukene occurs in nature as a racemate, it would be desirable to find out which enantiometer is the bio-active form. To this end, S(-)-camphor-yuehchukene and R(+)-camphor-yuehchukene were synthesised and tested in three bioassay models. It was found that the R(+) enantiomer was the active form. It was equipotent with (+/-)-yuehchukene in both anti-implantation and estrogenic activity tests. It seems fair to conclude that both activities reside in the same molecule.

(±)-Yuehchukene (YCK) is a novel bis-indole alkaloid with potent anti-implantation activity in rats. The present paper reports the activity of YCK derivatives by substitution on the parent compound. Substitutions on the indole nitrogens or on 2- and 5′-positions of the indole moiety abolished activity. N -1′-methylation of the free indole only permitted a 30% residual activity. Saturation of the C 9 C 10 cyclohexenyl double bond did not affect activity at all. Hydroxylation, whether on the C 9 C 10 double bond, or at C 2 or C 5 , rendered the hydroxylated derivatives inactive. This suggests that the active metabolite in anti-implantation was probably not a hydroxylated derivative carrying estrogenic activity.

A detailed study directed toward the development of a versatile synthetic route to the interesting dimeric natural product yuehchukene (1) and its epimer, 6a-epi-yuehchukene (2), has been completed. Due to the anti-implantation activity associated with 1, it was important to provide a synthetic strategy not only to 1, but to a family of yuehchukene analogues that, hopefully, would reveal superior chemical stability and (or) elevated biological activity. The experiments described herein and which utilize the readily available and inexpensive isophorone (6) satisfy these requirements. Key words: yuehchukene synthesis, yuehchukene analogues, anti-implantation activity.

A versatile synthetic strategy for the syntheses of the yuehchukene analogues 6β-(indol-3′-yl)-7β-methyl-5,6,6aβ,7,8,9,10,10aβ-octahydroindeno[2,1-b] indole and 7β-methyl-6β-(2′-methylindol-3′-yl)-5,6,6aβ,7,8,9,10,10aβ-octahydroindeno[2,1-b]indole is described. The key reactions involve trapping of the vinyllithium derivative 6-methylcyclohex-1 -enyllithium, generated from the trisylhydrazone of 2-methylcyclohexanone, with indole-2-carbaldehyde, and Nazarov cyclization of the α,β-unsaturated 2-acylindole 6-methylcyclohex-1-enyl N-phenylsulphonylindol-2-yl ketone.

A facile stereoselective synthesis of 6-oxo-5,6,6aβ,7,8,9,10,10aβ-octahydroindeno[2,l-b]indole, the key intermediate for yuehchukene analogues synthesis, is described.

A number of cyclopent[b]indol-1-ones as well as -3-ones have been synthesized, using a new methodology involving intramolecular ring closure of α,β-unsaturated acylindoles. In some cases 1,2,3,4-tetrahydrocarbazol-4-ones were obtained. This methodology was used in the syntheses of the indole alkaloid yuehchukene and the carbazole alkaloid analogue demethoxycarbazomycin B.

The effect of the N-substituents on the polyphosphate ester-(PPE)-catalysed cyclodehydration of a monoester of N-substituted 5-methyl-3-(indol-3′-yl)cyclohex-4-ene-1,2-dicarboxylic acids (41) is presented. Stereoselective synthesis of methyl 9-methyl-6-oxo-5-tosyl-5,6,6aβ,7β,8,10aβ-hexahydroindeno[2,1-b]indole-7α-carboxylate (2), the key synthetic intermediate for C(7)-functionalized antifertility agent yuehchukene (YCK)(1) analogues, is described.

Diels–Alder reactions between (E)-3-(3-methylbuta-1,3-dienyl)-1-tosylindole (3) and β-substituted acrylic acid derivatives are described. Reaction of (3) with maleic anhydride afforded the adduct (14). The latter compound in the presence of aluminium trichloride underwent intramolecular acylation with rearrangement to give 9-methyl-6-oxo-5-tosyl-6,7,8,11-tetrahydro-7,11-methano-5H-cyclo-oct[b]indole-12-carboxylic acid (16) and its double bond isomer (17) possessing a skeleton with a close resemblance to that of yuehchukene (1), an antifertility agent. Compounds (16) and (17) were stereoselectively converted into the title compounds (28) and (29). The structures of two precursors, (24) and (25), of compounds (28) and (29) have been determined by X-ray crystallography.

A novel carbon–carbon bond-forming reaction between indole and ββ-disubstituted allylic alcohols in lithium perchlorate–diethyl ether containing a catalytic amount of a Bronsted acid is described; the reaction has been applied to a total synthesis of yuehchukene.

Estrogen can be hydroxylated at both 2- and 16α-positions. These two reactions are mutually exclusive. The 2-hydroxylated estrogen is relatively inactive compared with the 16α-derivative; hence, one approach in anti-estrogenic therapy is to look for drugs that can induce the 2-hydroxylation pathway. In the present study, using Balb/c and C57B/6 mice as the animal models, the induction effect of several isoprenyl compounds on estradiol-2-hydroxylase and ethoxyresorufin- O -deethylase activities was studied. The compounds examined included 2′- and 3′-methylbutadienyl-indoles and their respective acid condensation products, isopropyl indolocarbazole and yuehchukene; positional isomers of indole carbinols and carboxyaldehydes, as well as 3-methylcholanthrene, the prototype inducer of cytochrome P450 1A1. Our results demonstrated that while all of them were capable of inducing cytochrome P450 1A1-mediated ethoxyresorufin- O -deethylase activity, only the 3′ isomers could induce estradiol-2-hydroxylase activity. The induction of these two activities did not show any direct correlation, suggesting that cytochrome P450 1A1 was not the same enzyme catalyzing both ethoxyresorufin- O -deethylation and estradiol-2-hydroxylation. Nevertheless, both inductions were mediated by the aryl hydrocarbon receptor. Among the compounds tested, yuehchukene showed competitive binding to estrogen receptor. This, together with the induction of estradiol-2-hydroxylase activity, may account for the anti-estrogenic effect of yuehchukene.

Many of the alkaloids found in Nitraria and Lupine species can be envisaged to arise from two simple building blocks, namely tryptamine and tetrahydropyridine. In particular in the Nitraria species, the alkaloids occur as racemates, in some cases, despite multi stereocenters. We assume that these alkaloids might be formed without interference of enzymes via spontaneous reactions of highly reactive intermediates. By carrying out a biomimetic approach many of these alkaloids were obtained via chemical synthesis, based on reactive precursors. The paper reviews the preparation of racemic Nitramine, Lupinine, Nazlinin, Nitrarineflitramidine, Spartein and Nitraramine from tryptamine and the trimer of tetrahydropyridine, based on imine-enamine chemistry. A variety of alkaloids, like Nitramin I, Nitrarine 2 and Nitraramine 2, have been isolated from different species of the Nitraria family (ref. 1). An interesting feature of these alkaloids is the fact that they are isolated as racemates, even in cases where the molecule contains four or five stereocenters (ref. 2). This has been observed before for alkaloids like akuammicine (ref. 3), yuehchukene (ref. 4) and lucidene (ref. 5).

Anti-estrogenic effects of yuehchukene were observed in rat uterotrophic, mice vaginal smear and MCF-7 cell growth assays. Whereas yuehchukene per se was estrogenic in these bioassay models, the co-administration of yuehchukene and an optimal dose of 3,17 beta-estradiol (estradiol) could attenuate the maximum estrogenic response due to estradiol alone. The anti-estrogenic effect of yuehchukene in rat uterine hypertrophy was corroborated by a parallel attenuation of ornithine decarboxylase activity in these tissues. Yuehchukene binds to rat, mice and MCF-7 cell estrogen receptors with a relative binding affinity of 1/150 to 1/300. This binding affinity was positively related to estrogenicity as determined by uterotrophic assay and MCF-7 cell growth. However, this estrogenic effect did not correlate with the degree of competitive receptor binding by a weaker agonist. Indole-3-carbinol and methylbutadienylindole could induce ethoxyresorufin O-deethylase and estradiol-2-hydroxylase in rat liver and MCF-7 cells. It is postulated that the 'free' indole moiety of yuehchukene could possess similar induction activity. Thus yuehchukene may have a dual pharmacological function. While the intact molecule is a weak estrogen, the 'free' indole moiety in yuehchukene may induce an enhancement of estradiol-2-hydroxylase, thus terminating the biological activity of the endogenous estrogen pool. There is obvious benefit in attenuating the estrogen level in post-menopausal breast cancer patients without going directly to the use of tamoxifen or aromatase inhibitor. Yuehchukene may serve this purpose. In this context, the pharmacological evaluation of a hydroxylated yuehchukene analogue and the anti-estrogenic effect of methylbutadienylindole acid-condensation products are now being studied in earnest.