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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.

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.

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 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.

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.

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.

7 examples out of several hundred species of Chinese plants known from herbal sources to have been used for fertility regulation that have been analyzed and tested are presented. The root of Murraya paniculata fam. Rutaceae yields a dimeric indole alkaloid called yuehchukene. This alkaloid which was used as an oxytocic is active in the Allen-Doisy test of estrogenic activity prevents implantation in rats and may be effective as a postcoital agent. 2 pseudolaric acids derived from the root bark of Pseudolarix kaempferi formerly used for ringworm was active in antiimplantation luteolysis and anti-cancer tests but had adverse gastrointestinal and endometrial effects. Marsdekosides steroidal glucosides from Marsdenia koi fam. Asclepediaceae was active as an antiimplantation agent without any estrogenic activity. Gardenic acid and gardenoic acid from Gardenia jasminoides damaged decidual cells in early pregnant women similar to RU-486 but effective at a lower dose. Gossypol the well known derivative from cottonseed oil has been well documented to destroy male seminiferous tubules but has serious side effects on potassium balance. GTW and total alkaloids of Triptergium wilfordii root used for rheumatoid arthritis nephritis and skin diseases also causes impaired fertility in men. It makes sperm non-mobile but does not affect testosterone LH K+ or Na+. It is being tested clinically in combination with lower doses of gossypol.

The genus Murraya has been widely used in traditional medicine in east Asia. In view of the recent isolation of the anti-implantation alkaloid yuehchukene from M. paniculata a search has now been made for other natural sources of this alkaloid within the genus. In this paper we report findings for nine taxa of Murraya.

Khosa & Prasad (1974) conducted a pharmacognostic analysis on the roots of Murraya paniculata and M. koenigii, and concluded that the roots could be differentiated by means of several morphological, anatomical, and crude chemical parameters. Through our studies of the two species in search for biologically active compounds, it was found that the roots of the two species could be qualitatively differentiated with bioactive chemical markers. Roots of M. paniculata (sensu late) can be distinguished from those of M. koenigii by the presence of yuehchukene (I) and the absence of girinimbine (II). Moreover, benzene extracts of the roots of M. paniculata were shown to be active as an anti-implantation agent in rats, while those of M. koenigii were inactive even at sub-lethal dosage of 2.3 g eqv./ml/dose.

Yuehchukene, 11beta-(3'-indolyl-7,9alpha,9beta-trimethyl-5beta,8,9,10beta-tetrahydroindano-[2,3- B]indole, a novel dimeric indole alkaloid from the roots of MURRAY A PANICULATA has potent anti-implantation activity in rats at 3 mg/kg P. O. dosing on pregnancy day 2.