Structure of methylene-bis-cytisine

Turgunov, K. K.; Ташходжаев, Б.; Ibragimov, T. F.; Rakhimov, Sh. B.

doi:10.1007/s10600-006-0196-1

Cited by 3 publications

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“…The overall conformation of the two molecules is defined by the torsion angles (1)8, respectively, giving rise to a trans orientation of the two terminal pyridinone rings with respect to the central molecular skeleton in one case, and cis in the molecule labeled a. Crystals are nona-hydrates accounting for their poor quality, as the H 2 O channels forward the flexibility of the ethylene bridge. The easy solvation of these kinds of alkaloids has been observed also in the X-ray structure of the methylenebis(cytisine) [23], the molecular conformation of which is analogous to that of 3 (molecule labeled a, cis-oriented) in presence of only one H 2 O molecule. A close examination of the molecular packing shows a different behavior of the two conformers: the cis molecules are connected to each other via a H 2 O bridge (O7w) linking the pyridinone O-atoms at the two ends of the molecules with the formation of molecular chains, while the transmolecules form numerous contacts with the surrounding H 2 O molecules without a welldefined orientation, but creating a three-dimensional network of H-bonds that involves also the molecular chains previously described, with the formation of a supramolecular structure (Fig.…”

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The Influence of the Nitrogen Substitution in Three Cytisine Derivatives as Ligands for the Neuronal nAChRs: A Structural and Theoretical Study

Bombieri

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et al. 2008

Chemistry & Biodiversity

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Three cytisine derivatives, (-)-(7R,9S)-1-phenyl-3-(cytisin-12-yl)propan-1-one (1), (-)-(7R,9S)-1-phenyl-2-(cytisin-12-yl)ethane (2), and (-)-(7R,9S)-1,2-bis(cytisin-12-yl)ethane (3), with different electronic and steric features have been characterized by X-ray analysis and theoretical calculations in order to evaluate how structural modulations affect the intrinsic binding affinity at the neuronal nicotinic receptors (nAChRs). The crystal structures of 1 and 2, which display comparable affinities, are characterized by the same conformation of the cytisine moiety with different orientations of the substituent at N2. In 3, two independent molecules have the pyridinone rings diversely oriented. This compound has a lower affinity with respect to 1 and 2, but it increases the expression of neuronal nAChRs. Compounds 1, 2, and 3 retain the key prerequisite of the classical pharmacophoric models, with sp(3)-N-atom--HBA distances close to the expected value, both in solid state and in solution (theoretical calculations), where, in contrast with the extended in the crystal state, a curled-up conformation has been found, though maintaining the N-substituent in equatorial position.

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confidence: 83%

The Influence of the Nitrogen Substitution in Three Cytisine Derivatives as Ligands for the Neuronal nAChRs: A Structural and Theoretical Study

Bombieri

Meneghetti

Artali

et al. 2008

Chemistry & Biodiversity

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“…The PMR spectrum showed that 3a and 3 had the same spectrum. An x-ray structure analysis proved that 3a was a crystal hydrate of 3 [2].…”

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confidence: 97%

“…The PMR spectrum showed that 3a and 3 had the same spectrum. An x-ray structure analysis proved that 3a was a crystal hydrate of 3 [2].Thus, all attempts to prepare 1 were inconclusive, probably due to the high reactivity of 1, which led to its further reaction with cytisine and formation of the bis-product 3, which was not only the synthetic product but also a natural compound (12,12′-methylenedicytisine) that was isolated from Maackia amurensis [3]. …”

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Reaction of cytisine with formalin

2006

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547.945The reaction of cytisine with formalin in various solvents was studied. Methylene-bis-cytisine was produced in addition to the expected N-methylolcytisine in all solvents except acetone, in which N-(3-oxobutyl)cytisine was produced.The combination of various natural fragments in a single molecule is interesting regarding their mutual effect on the biological activity of the resulting compounds. In this regard, N-methylolcytisine (1) might be an interesting synthon [1].The preparation of 1 by reaction of cytisine (2) with formalin (35%) in ether and the formation of bis-cytisinomethane (3) by the reaction in absolute alcohol with added Ca(OH) 2 have been reported [1].The use of ether as the solvent for production of 1 was impractical because of the poor solubility of cytisine in it. Therefore, we compared the reaction of cytisine with formalin (30%) in various solvents (ether, methanol, ethanol, hexane, chloroform, water, dioxane, acetone).The reaction mixture of cytisine and formalin in the appropriate solvents was held at room temperature for 4-6 h. Chromatographic monitoring showed that a certain amount of unreacted cytisine remained in all reactions regardless of the solvent and that a product with R f 0.7 was formed.The reaction in ether produced crystals of 3a, mp 131-132°C; in acetone, 115°C (4), in other solvents, 213-215°C (3). The mass spectrum of the last had peaks for a molecular ion with m/z 392 and for ions with m/z 204, 203, 190, 160, 159, 147, and 146, which confirmed the structure of 3 as bis-cytisinomethane.According to the literature [1], it can be hypothesized that N-methylolcytisine forms in ether, for which mp 110-114°C was reported [1].The IR spectrum of 3a obtained from the reaction in ether contained a broad absorption band for active H with a maximum at 3490 cm -1 . However, the melting point of 3a was higher than that found for 1. The PMR spectrum showed that 3a and 3 had the same spectrum. An x-ray structure analysis proved that 3a was a crystal hydrate of 3 [2].Thus, all attempts to prepare 1 were inconclusive, probably due to the high reactivity of 1, which led to its further reaction with cytisine and formation of the bis-product 3, which was not only the synthetic product but also a natural compound (12,12′-methylenedicytisine) that was isolated from Maackia amurensis [3].

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