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This review presents all currently known macroheterocyclic compounds that include a bispidine (3,7-diazabicyclo[3.3.1]nonane) fragment in their structure. A classification of bispidine-containing macroheterocycles, which is based on the ring size and the nature of bispidinic nitrogen atoms, is suggested. Synthetic approaches to the studied compounds are classified and considered. The features of the crystal structures and solution behavior of bispidine macroheterocycles are analyzed. Prospects for the development of these organic receptors are proposed.

This review presents all currently known macroheterocyclic compounds that include a bispidine (3,7-diazabicyclo[3.3.1]nonane) fragment in their structure. A classification of bispidine-containing macroheterocycles, which is based on the ring size and the nature of bispidinic nitrogen atoms, is suggested. Synthetic approaches to the studied compounds are classified and considered. The features of the crystal structures and solution behavior of bispidine macroheterocycles are analyzed. Prospects for the development of these organic receptors are proposed. [ABSTRACT FROM AUTHOR]

[Display omitted] Two new potent AMPA receptor allosteric modulators, 6-(1,3-benzodioxol-5-yl)-1,11-dimethyl-3,6,9-triazatri-cyclo[7.3.1.13,11]tetradecane-4,8,12-trione and -4,8-dione were synthesized from 1,3-benzodioxol-5-amine and the corresponding 3,7-dichloroacetyl-3,7-diazabicyclo[3.3.1]-nonanes. In a wide concentration range (10−12–10−7 m), the 12-oxo derivative acts as a positive modulator causing the potentiation of the kainate-induced AMPA receptor currents with maximum potentiation at 1 nm (62%) while its analogue without a ketone group has significant (up to 40%) negative modulator effect. Their tentative mechanisms of action were analyzed by means of molecular modelling [ABSTRACT FROM AUTHOR]

[Display omitted] Six new bispidine-based bis-amides containing residues of haloacetic acids were synthesized and characterized by X-ray crystallography. The dissolution of iodine-containing compound in concentrated hydrogen peroxide afforded bispidine peroxosolvate, in which the peroxide molecules participated in two donor hydrogen bonds with carbonyl oxygen atoms of the distinct adjacent organic molecules thus forming cyclic motifs in crystals. This structure is a first example of peroxosolvate of iodine-containing organic molecule. [ABSTRACT FROM AUTHOR]

Colchicine derivative bearing substituted bispidine moiety, namely N-{7-(3,7-Di-(tert-butoxycarbonyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-yl)-oxy-7-oxoheptanoyl}-N-deacetylcolchicine, was synthesized and tested for its effect on the net of microtubules (MT) in lung cancer cells A549. The compound induced not only MT depolymerization but stimulated the formation of small tubulin aggregates and long tubulin fibrils localized mainly around nuclei. The assemblies were morphologically different from tubulin clusters induced by structurally related anticancer agent tubuloclustin. The biotests data demonstrate that the depolymerization takes place for both pure tubulin and tubulin in cellulo, while fibrils are formed only in the cells. The research data of structure–activity relationship for several similar colchicine derivatives synthesized in the work give evidence for the proposition that the initial conjugate may interact not only with tubulin and MT in the cells, but also with MT-associated proteins, involved in the process of tubulin polymerization. The ability to affect simultaneously MAP – tubulin interactions opens attractive prospects in the design of novel anticancer agents. [ABSTRACT FROM AUTHOR]

Synthesis of 6-[4-methoxy-3-(pyrrolidin-1-ylmethyl)benzyl]-1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.13,11]tetradecane-4,8,12-trione has been carried out and optimized. In vitro studies using electrophysiological patch clamp technique have revealed a negative effect of this compound on kainateinduced currents in Purkinje neurons in a wide range of concentrations from 10−11 to 10−6 m. [ABSTRACT FROM AUTHOR]

The condensation product of adamantan-1-amine with formaldehyde, 1,3,5-tri(1-adamantyl)-1,3,5-triazacyclohexane, was treated with three different types of ketones: symmetric (RCH2)2CO, nonsymmetric RCH2COCH3, and acetone to obtain 1,5-R-N,N′-di(1-adamantyl) bispidin-9-ones, N,N′-di(1-adamantyl)-1-[(1-adamantylamino)methyl]-5-methylbispidin-9-one, and N,N′-di(1-adamantyl)-1,5-bis[(1-adamantylamino)methyl]bispidin-9-one. 1,5-R-N,N′-Di(1-adamantyl)bispidin-9-ones were reduced with sodium borohydride to 1,5-R-N,N′-di(1-adamantyl)bispidin-9-ols. [ABSTRACT FROM AUTHOR]

A new type of 1,3-diazaadanamtan-6-ones was synthesized by heating the 3,7-di( tert-butyl)-1-[( tert-butylamino)methyl]bispidin-9-one derivatives with concentrated hydrobromic acid followed by condensation with formaldehyde. [ABSTRACT FROM AUTHOR]

Abstract: 3,7-Diazabicyclo[3.3.1]nonane is a naturally occurring scaffold interacting with nicotinic acetylcholine receptors (nAChRs). When one nitrogen of the 3,7-diazabicyclo[3.3.1]nonane scaffold was implemented in a carboxamide motif displaying a hydrogen bond acceptor (HBA) functionality, compounds with higher affinities and subtype selectivity for α4β2∗ were obtained. The nature of the HBA system (carboxamide, sulfonamide, urea) had a strong impact on nAChR interaction. High affinity ligands for α4β2∗ possessed small alkyl chains, small un-substituted hetero-aryl groups or para-substituted phenyl ring systems along with a carboxamide group. Electrophysiological responses of selected 3,7-diazabicyclo[3.3.1]nonane derivatives to Xenopus oocytes expressing various nAChR subtypes showed diverse activation profiles. Compounds with strongest agonistic profiles were obtained with small alkyl groups whereas a shift to partial agonism/antagonism was observed for aryl substituents. [Copyright &y& Elsevier]

Abstract: 3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2∗ nAChR. Compounds 15, 25, and 47 with K i values of about 1nM displayed the highest affinities for α4β2∗ nAChR. All evaluated compounds are partial agonists or antagonists at α4β2∗, with reduced or no effects on α3β4∗ with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes. [Copyright &y& Elsevier]

Abstract: A novel series of α4β2 nAChR agonists lacking common pyridine or its bioisosteric heterocycle have been disclosed. Essential pharmacophoric elements of the series are exocyclic carbonyl moiety as a hydrogen bond acceptor and secondary amino group within diaza- or azabicyclic scaffold. Computer modeling studies suggested that molecular shape of the ligand also contributes to promotion of agonism. Proof of concept for improving working memory performance in a novel object recognition task has been demonstrated on a representative of the series, 3-propionyl-3,7-diazabicyclo[3.3.0]octane (34). [Copyright &y& Elsevier]

Condensation of 1,3,5-tri( tert-butyl)-1,3,5-triazacyclohexane with acetone gave 3,7-di( tert-butyl)-1,5-bis[( tert-butylamino)methyl]bispidin-9-one. Reactions with ethyl methyl ketone and other ketones of the formula RCHCOCH yielded 5-R-3,7-di( tert-butyl)-1-[( tert-butylamino)methyl]bispidin-9-ones, while reactions with diethyl ketone and other symmetrical ketones of the formula RCHCOCHR afforded 1,5-R-3,7-di( tert-butyl)bispidin-9-ones. [ABSTRACT FROM AUTHOR]

2-Naphthyl and 2-(2′-hydroxynaphthyl) derivatives of 5,7-dialkyl-1,3-diazaadamantanes were synthesized by the reaction of the corresponding 5,7-dialkyl-3,7-diazabicyclo[3.3.1]nonanes with naphthaldehyde or 2-hydroxynaphthaldehyde. [ABSTRACT FROM AUTHOR]

Alternative methods for the synthesis of 2-spiro-substituted 6-hydroxy-5,7-dimethyl-1,3-diazaadamantanes have been developed. These are the reduction of the ketone group to hydroxyl in the corresponding 6-oxo-1,3-diazaadamantanes and the condensation of 9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane (obtained by different routes from 5,7-dimethyl-6-oxo-1,3-diazaadamantane) in reaction with cyclic ketones. [ABSTRACT FROM AUTHOR]

• Novel 16- and 20-membered bispidine ferrocenophanes were synthesized. Two approaches for the syntheses of bispidine-ferrocene cyclophanes were reported. Both include the acylation of 1,5-dimethylbispidin-9-one (H 2 Bp) or its pendant amino-armed derivative by 1,1'-ferrocenoyl (Fc(CO) 2) dichloride. The first approach allowed to isolate di-, tri- and pentameric cyclic oligomers of composition (BpFc(CO) 2) n. The second one included the preliminary functionalization of H 2 Bp by N-protected glycine followed by deprotection and cyclization with Fc(COCl) 2. The crystal structure of two new bispidine-ferrocene cyclophanes was established by single-crystal X-ray study. This study revealed the anti-conformation of amido-groups attached to the bispidine nitrogen atoms for both molecules. Various NMR techniques were applied to study the solution behavior of the macrocycles; the predominant anti-conformation in solution was also proved. The acyclic model compound Bp(FcCO) 2 also showed only anti-conformer as revealed by VT-NMR and X-ray studies. Cyclic voltammetry study showed the difference in oxidation potentials of the Fc moiety within the row Bp(FcCO) 2 – (BpFc(CO) 2) 2 – (BpFc(CO) 2) 3 with splitting of the oxidation curve in two later cases. The results obtained in this work will find an application in design and study of novel bispidine-ferrocene cyclophanes for the purposes of supramolecular sensing and catalysis. [Display omitted] [ABSTRACT FROM AUTHOR]