Yuehchukene is a dimeric indole

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

that possesses anti-fertility and

estrogenic Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...

activities. Yuehchukene is isolated from the roots of ''

Murraya paniculata ''Murraya paniculata'', commonly known as orange jasmine, orange jessamine, china box or mock orange, is a species of shrub or small tree in the family Rutaceae and is native to South Asia, Southeast Asia and Australia. It has smooth bark, pin ...

'' and other species of the plant genus '' Murraya''. Its natural abundance is in the range of 10-52 ppm. Yuehchukene consists of a tetracyclic unit with a C6 indole substituent. Since its discovery no other natural product of similar structure has been found. Particularly, yuehchukene differs from other natural bis-indole alkaloids because it does not seem to be derived from

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α- carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...

. The

steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

environments of the two nitrogen atoms are very different. One nitrogen is part of a rigid ring system and is shielded by the C6 indole. The other is part of the freely rotating indole making it readily assessable and therefore more

reactive Reactive may refer to: *Generally, capable of having a reaction (disambiguation) *An adjective abbreviation denoting a bowling ball coverstock made of reactive resin *Reactivity (chemistry) *Reactive mind *Reactive programming See also *Reactanc ...

Biological activity

Interest in this compound stems from its

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

. Yuehchukene possesses a potent anti-fertility activity, with the (''R'')-(+)-

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

having been identified as the active form. The mode of action has been reported to be blockage of blastocyte implantation sites. Extensive structure-activity relationship investigations have been undertaken. Activity was found to be abolished by nitrogen substitution, 2, 5 and 5'-position substitution,

hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...

of the

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...

ring, hydroxylation of C9-C10 double bond and deletion of 7,7-di

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

group. The activity was unaffected by saturation of the C9-C10 double bond. It was concluded that biological activity is dependent upon an optimal conformation defined by a narrowly fixed angle between the planes of the C6-indole and the tetracyclic unit. Yuehchukene also possesses estrogenic activity. This is interesting because the compound lacks oxygen functionalities and phenyl groups common to other natural or synthetic estrogen compounds. It is a mixed

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

, binding competitively to rat uterine estrogen receptors, though with a very low binding affinity of ~1/300. Yuehchukene has not been developed as a

pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

due to the effects of this estrogenic activity.

Synthesis

Synthetic routes to yuehchukene have been developed due to its low natural abundance.

Bergman-Venemalm synthesis

The Bergman-Venemalm synthesis was first reported in 1988. It focuses on building the tetracyclic unit before introducing the second indole unit. Requiring five reactions starting from indole, all of which are reasonably high yielding, this is an effective method for synthesizing yeuhchukene. Importantly, only one diastereomer is produced, with stereoselectivity being introduced in the 3rd reaction. The final

dimerization A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...

step is relatively robust, tolerating nucleophiles such as 2-methylindole, 5-bromoindole and ''N'',''N''-dimethylaniline. Less nucleophillic compounds, however, such as 5-nitroindole, 1,2,3-trimethoxybenzene and 1,2,4-trimethoxybenzene do not react.

Sheu-Chen-Hong synthesis

This method aims to build the entire molecule in one step by exploiting the fact that yuehchukene has been characterized as the structurally unusual dimer of β-(dehydroprenyl)indole. Under acidic conditions a Diels-Alder reaction of β-(dehydroprenyl)indole can produce yuehchukene. This is due to the alcohol precursor dehydrating under acidic conditions to produce both the

diene In organic chemistry a diene ( ) (diolefin ( ) or alkadiene) is a covalent compound that contains two double bonds, usually among carbon atoms. They thus contain two alk''ene'' units, with the standard prefix ''di'' of systematic nomenclature. ...

and dienophile required for this reaction. Requiring only three reactions, this method is shorter than the previous route but the yields of the final step are quite poor.

References

{{Reflist Indole alkaloids Alkaloids found in Rutaceae