Dispiro Derivatives Research Articles

Stereoselective synthesis of dispiropyrrolidinyl oxindole derivatives and evaluation of their antibacterial efficacy

Antibacterial resistance is a global health crisis that is primarily due to the overuse and misuse of antimicrobial drugs. Therefore, the pharmaceutical industry is continuously striving to develop new antibacterial agents. Herein, we have reported stereoselective synthesis of dispiropyrrolidinyl oxindole derivatives using 1,3-dipolar cycloaddition reaction, between arylidene indanone derivatives as dipolarophile and azomethine ylides formed in situ from isatin and sarcosine in a multicomponent reaction (MCR) mode. The reaction condition was optimized and the absolute configuration of the dispiro products was determined using NMR spectroscopic data and confirmed from the single crystal X-ray crystallography. The newly synthesized spiro derivatives showed good to moderate in vitro antibacterial efficiency against six bacterial species. The preliminary in silico studies revealed that these dispiro derivatives have a potential binding affinity towards the penicillin-binding protein-3 and they could be used as a template for future antibacterial drug discovery.

3+2]-Cycloaddition of azomethine ylides to 5-methylidene-3-aryl-2-сhalcogen-imidazolones: access to dispiro indolinone-pyrrolidine-imidazolones.

A synthesis of dispiro derivatives from 5-methylidene-2-chalcogenimidazolones and azomethine ylides generated from isatins and N-substituted α-amino acids has been developed.

Synthesis and Biological Evaluation of S-, O- and Se-Containing Dispirooxindoles.

A series of novel S-, O- and Se-containing dispirooxindole derivatives has been synthesized using 1,3-dipolar cycloaddition reaction of azomethine ylide generated from isatines and sarcosine at the double C=C bond of 5-indolidene-2-chalcogen-imidazolones (chalcogen was oxygen, sulfur or selenium). The cytotoxicity of these dispiro derivatives was evaluated in vitro using different tumor cell lines. Several molecules have demonstrated a considerable cytotoxicity against the panel and showed good selectivity towards colorectal carcinoma HCT116 p53+/+ over HCT116 p53−/− cells. In particular, good results have been obtained for LNCaP prostate cell line. The performed in silico study has revealed MDM2/p53 interaction as one of the possible targets for the synthesized molecules. However, in contrast to selectivity revealed during the cell-based evaluation and the results obtained in computational study, no significant p53 activation using a reporter construction in p53wt A549 cell line was observed in a relevant concentration range.

Dispirooxindoles Based on 2-Selenoxo-Imidazolidin-4-Ones: Synthesis, Cytotoxicity and ROS Generation Ability.

A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC50) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2–6.9; some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action.

Synthesis and cytotoxicity of oxindoles dispiro derivatives with thiohydantoin and adamantane fragments

An effective and highly regio- and diastereoselective one-pot synthesis of two types of dispiro heterocyclic systems (2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones and 2-thioxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones) comprising pyrrolidinyl-oxindole, thiohydantoin and adamantane moieties has been developed based on a 1,3-dipolar cycloaddition of azomethine ylides, generated from isatin and sarcosine or formaldehyde and sarcosine, to adamantane-containing electron-deficient alkenes. Several molecules have demonstrated a considerable cytotoxicity against A549, HEK293T, MCF7 and VA13 cancer cell lines. The possible mechanism of anticancer activity of the synthesized compounds based on literature data may be the inhibition of p53/MDM2 interaction; however, we did not observe significant p53 activation using a reporter construction in A549 cell line in the relevant concentration range.

Phosphorus-nitrogen compounds. Part 44. The syntheses of N,N-spiro bridged cyclotriphosphazene derivatives with (4-fluorobenzyl) pendant arms: Structural and stereogenic properties, DNA interactions, antimicrobial and cytotoxic activities

Isopropylaminopentachlorocyclotriphosphazene, (N3P3Cl5(NHCHMe2) (1), containing a P–NH group in the alkyl-chain, gives the NN-spirobridged octachlorobiscyclotriphosphazene, [N3P3Cl4(NCHMe2)]2 (2), in the presence of NaH. The reactions of 2 with excess pyrrolidine result in the formation of the fully substituted bridged product 2a. The reactions of 2 with 1:1 and 1:2 equimolar amounts of N-(4-fluorobenzyl)-N'methylethane-1,2-diamine and N-(4-fluorobenzyl)-N'methylpropane-1,3-diamine produce the (4-fluorobenzyl) pendant armed monospiro (2b and 2c) and dispiro (2f and 2g) products. These compounds react with excess pyrrolidine to form stable, fully substituted cyclotriphosphazenes (2d, 2e, 2h and 2i). The structures of 2a and 2f are determined by X-ray crystallography. The stereogenic properties of 2a and 2f having four potential stereogenic P–centers are investigated by crystallography. The monospiro (2b–2e) and dispiro (2f–2i) products have one and two equivalent chiral centers, respectively. The dispiro derivatives may have two meso (trans-trans and cis-cis) and two racemate (trans-cis and cis-trans) mixtures. However, the structure of 2f is found to be as trans-trans (meso) isomer. Besides, in vitro antimicrobial and cytotoxic activities of 2d and 2h are evaluated. The compounds exhibit significant growth inhibitory effects on E. coli and B. cereus bacteria. Compound 2d has high anticancer and apoptotic activities.

Synthesis and cytotoxicity of novel dispiro derivatives of 5-arylidenoxazolones, potential inhibitors of p53—MDM2 protein-protein interaction

Regioselective synthesis of new dispiro indolinones combining both an indolinone and an oxazolone fragment in their structure comprised the 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from isatin and sarcosine, at 2-aryl-5-arylmethylidene-substituted 1,3-oxazol-5(4H)-ones. When ortho and para halogen atoms were present in the aromatic substituents of the starting oxazolones, complex mixtures containing large amounts of oxazoline ring opening products and their dispiro derivatives were formed. The cytotoxicity of compounds was tested by MTT on LNCaP, PC3, HCT116, MCF7, A549, HEK, and VA13 cell lines. The compound possessing the best cytotoxicity revealed the IC50 = 1.08±0.96 μM towards the p53- expressing LNCaP cells and lower activity (IC50 = 3.21±1.45 μM) towards the non-expressing p53 protein PC3 cells, however, it has proved inactive towards the HCT cells, both expressing (HCТ+/+) and non-expressing (HCT–/–) p53.

Synthesis and stereogenic properties of N,N-spiro bridged bis(cyclotriphosphazene) compounds containing two equivalent chiral centres

The stereogenic properties of N,N-spiro bridged bis(cyclotriphosphazene) compound having four potential stereogenic phosphorus centres have been investigated. Two reaction pathways, in which same reactions were done in different order, were used to determine the isomer variety and to compare them. When the first route included unsymmetrically substitution (2-methylaminoethanol), aminolysis (n-butylamine) and deprotonation (sodium hydride) reaction steps, respectively, the second route consisted of aminolysis (n-butylamine), deprotonation (sodium hydride) and unsymmetrically substitution (2-methylaminoethanol) reaction steps, respectively. Both routes resulted in formation of the same products (4a and 4d) containing two equivalent chiral centres. The structures and stereogenic properties of the products, 4a and 4d were characterized by X-ray crystallography and 31P NMR spectroscopy on addition of the chiral solvating agent which is (R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol. These new di-spiro derivatives (4a and 4d) bring about trans–trans and cis–cis geometric isomers and they are meso due to centre of the symmetry and plane of the symmetry.

Stereochemical aspects of cyclotriphosphazenes: Prochiral and pseudo-asymmetric phosphorus atoms

Mono-, di- and trispiro derivatives (2–6) from the reaction of hexachlorocyclotriphosphazene, (1) with 3-aminobenzyl alcohol were reported in order to illustrate stereochemical terms such as prochiral, pseudo-asymmetry, homo-, enantio- and diastereotopic atoms or groups. The dispiro derivatives (3 and 4) were shown to exist as trans and cis geometric isomers and be racemic (RR/SS) and meso (RS), respectively, whereas the trispiro derivatives (5 and 6) exist as cis and trans geometric isomers and are achiral. Pseudo-asymmetry was introduced into the meso form (4) containing two constitutionally equivalent chiral units by the reactions with either 3-amino-1-propanol or phenol. The two meso diastereoisomeric forms, which can be assigned as R,s,S (7a) and R,r,S (7b) or S,s,R (8a) and S,r,R (8b), were identified as the systematic examples of cyclophosphazene derivatives including pseudo-asymmetric phosphorus centers. The corresponding racemic form (3) produced only one diastereoisomer (9 and 10) for each reaction. All the compounds were analysed by standard spectroscopic techniques, such as elemental analysis, MALDI-TOF mass spectrometry, NMR spectroscopy and X-ray crystallography (for 2, 4 and 6). The stereogenic properties of the compounds were confirmed by 31P NMR spectroscopy on addition of the chiral solvating agent (CSA) (R)-(+)-2,2,2-trifluoro-1-(90-anthryl)ethanol.

An Efficient Synthesis of Novel Dispiro Derivatives via Three-Component 1,3-Dipolar Cycloaddition Reactions under Ultrasound Irradiation

The title reaction of acenaphthenequinone, thiazolidine-4-carboxylic acid and (Z)-5-benzylidene-2-thioxothiaazolidin-4-one or (Z)-5-benzylidenethiaazolidin-2,4-dione efficiently provides a series of new spiro compounds.

Synthesis of 5α-Androstane-17-spiro-δ-lactones with a 3-Keto, 3-Hydroxy, 3-Spirocarbamate or 3-Spiromorpholinone as Inhibitors of 17β-Hydroxysteroid Dehydrogenases

We synthesized two series of androstane derivatives as inhibitors of type 3 and type 5 17β-hydroxysteroid dehydrogenases (17β-HSDs). In the first series, four monospiro derivatives at position C17 were prepared from androsterone (ADT) or epi-ADT. After the protection of the alcohol at C3, the C17-ketone was alkylated with the lithium acetylide of tetrahydro-2-(but-3-ynyl)-2-H-pyran, the triple bond was hydrogenated, the protecting groups hydrolysed and the alcohols oxidized to give the corresponding 3-keto-17-spiro-lactone derivative. The other three compounds were generated from this keto-lactone by reducing the ketone at C3, or by introducing one or two methyl groups. In the second series, two dispiro derivatives at C3 and C17 were prepared from epi-ADT. After introducing a spiro-δ-lactone at C17 and an oxirane at C3, an aminolysis of the oxirane with L-isoleucine methyl ester provided an amino alcohol, which was treated with triphosgene or sodium methylate to afford a carbamate- or a morpholinone-androstane derivative, respectively. These steroid derivatives inhibited 17β-HSD3 (14–88% at 1 μM; 46–94% at 10 μM) and 17β-HSD5 (54–73% at 0.3 μM; 91–92% at 3 μM). They did not produce any androgenic activity and did not bind steroid (androgen, estrogen, glucocorticoid and progestin) receptors, suggesting a good profile for prostate cancer therapy.

Production of Unusual Dispiro Metabolites inPestalotiopsis virgatulaEndophyte Cultures: HPLC-SPE-NMR, Electronic Circular Dichroism, and Time-Dependent Density-Functional Computation Study

The endophytic fungus Pestalotiopsis virgatula, derived from the plant Terminalia chebula and previously found to produce a large excess of a single metabolite when grown in the minimal M1D medium, was induced to produce a variety of unusual metabolites by growing in potato dextrose broth medium. Analysis of the fermentation medium extract was performed using an HPLC-PDA-MS-SPE-NMR hyphenated system, which led to the identification of a total of eight metabolites (1-8), six of which are new. Most of the metabolites are structurally related and are derivatives of benzo[c]oxepin, rare among natural products. This includes dispiro derivatives 7 and 8 (pestalospiranes A and B), having a novel 1,9,11,18-tetraoxadispiro[6.2.6.2]octadecane skeleton. Relative and absolute configurations of the latter were determined by a combination of NOESY spectroscopy and electronic circular dichroism spectroscopy supported by time-dependent density-functional theory calculations (B3LYP/TZVP level). This work demonstrates that a largely complete structure elucidation of numerous metabolites present in a raw fermentation medium extract can be performed by the HPLC-SPE-NMR technique using only a small amount of the extract, even with unstable metabolites that are difficult to isolate by traditional methods.

Heterocyclization of N,N′-disubstituted p-phenylenediamines with cyclich β-diketones and formaldehyde. Synthesis of new pyrido[2,3-g]quinoline derivatives

Three-component condensation of N,N′-dibenzyl-p-phenylenediamines with cyclic β-diketones and formaldehyde under mild conditions resulted in selective formation of a series of new dispiro derivatives of pyrido[2,3-g]quinoline.

Substituted Quinolinones, Part 14: Synthesis of Novel Dispiro(heterocycle-N,2′-[1,3]dithietane-4′,3″-quinolinedione) Derivatives Under PTC Conditions

The four-membered spiro-heterocycles ethyl cyano(1-methyl-2,4-dioxospiro{1,3-quinoline-3,4′-[1,3]dithietane}-4′-ylidene)-acetate 2a, -malononitrile 2b, -acetylacetone 2c, and thiazetidine isomer 3 were prepared under phase transfer catalysis (PTC) conditions. The thermal treatment of dithietanes 2a–c led to the bis-quinolinyl sulfide 4. Some interesting nucleophilic additions followed by cyclization reactions were carried out with the dithietane 2a to give the corresponding novel dispiro derivatives 5–8, 10–13, and 15.Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.GRAPHICAL ABSTRACT

Comparison of HPLC and NMR characterization of the stereogenic properties of cyclotriphosphazene derivatives containing two equivalent centres of chirality: Cis (meso) and trans (racemic) isomers

The di-spiro derivatives of the reaction of gem-disubstituted cyclotriphosphazenes, N3P3Cl4X2 (X=Ph, PhS, PhNH, PhO) with 3-amino-1-propanol are expected to exist as cis and trans geometric isomers and exist as meso and racemic, respectively. The geometric isomers were separated by column chromatography on silica gel and analyzed by elemental analysis, mass spectrometry, and 31P and 1H NMR spectroscopies. The stereogenic properties of all the compounds (trans, 2a–5a) and (cis, 2b–5b) were investigated by 31P NMR spectroscopy on the addition of a chiral solvating agent (CSA), (S)-(+)-2,2,2-trifluoro-1-(9′-anthryl)ethanol; one example of a derivative with the trans configuration (compound 5a, X=PhO) has been found where the 31P NMR/CSA method does not lead to the expected separation of the signals of enantiomers, even up to a molar ratio of CSA:compound of 50:1. On the other hand, chiral HPLC methods have been developed in order to characterize the trans (2a–5a) and cis (2b–5b) forms of the cyclotriphosphazene derivatives and give good separation of enantiomers for the trans disubstituted compounds (2a–5a). It is found that chiral HPLC is more reliable than the 31P NMR/CSA method for characterising the stereogenic properties of the cis and trans isomers of di-spiro 3-amino-1-propanoxy cyclophosphazene derivatives.

Stereogenic properties of 1,3-disubstituted derivatives of cyclotriphosphazene: cis (meso) and trans (racemic) isomers

The di-spiro derivatives of the reaction of cyclotriphosphazene with either 3-amino-1-propanol or N-methylethanolamine are expected to exist as cis and trans geometric isomers and be meso and racemic, respectively. The isomers were separated by column chromatography on silica gel and analysed by elemental analysis, mass spectrometry, and 31P and 1H NMR spectroscopies. X-ray crystallography was used to characterise both the cis and trans isomers of the N-methylethanolamino di-spiro derivatives and the cis isomer of the propanolamino di-spiro derivative but, due to a mirror plane for the trans isomer, it was not possible to determine uniquely the NH and O positions and, hence, the cis or trans configuration of the compound. The stereogenic properties of all the compounds were investigated by 31P NMR spectroscopy on addition of a chiral solvating agent (CSA), (S)-(+)-2,2,2-trifluoro-1-(9′-anthryl)ethanol. The CSA results confirm that both cis isomers are meso and the trans isomer of the N-methylethanolamino di-spiro derivative is a racemate, as expected. It was also shown that the second isomer of the propanolamino di-spiro derivative was a racemate, confirming that it is the trans isomer and, hence, confirming the original predictions of the stereogenicity of the 1,3-disubstituted cyclotriphosphazenes.

Stereoisomer Discrimination Through π‐Stacking Interactions in Spirocyclic Phosphazenes Bearing 2,2′‐Dioxybiphenyl Units

AbstractThe molecular structure of the 2,2′‐dioxybiphenyl spirocyclic tetrachlorocyclotriphosphazene [N3P3Cl4(O2C12H8)] (3) was determined by X‐ray crystallography. The structure and conformation of 3 in the crystal are compared and discussed with respect to those of its analogues trispiro and dispiro derivatives, [N3P3(O2C12H8)3] (1) and [N3P3Cl2(O2C12H8)2] (2), respectively. Both the (R) and (S) stereoisomers are present in the lattice of 3 as arranged in pairs (R)···(S) held together through sandwich‐type π‐stacking interactions of the (C7−C12)/(C7−C12)′ phenyl rings of the 2,2′‐dioxybiphenyl groups. The polymer‐like assembly of 2 was formed by interactions between the (R) and (S) portions of two meso molecules [in the sequence ···(R)···(S)···(R)···(S)···(R)···(S)···]. In this case, the pertinent phenyl rings involved in the noncovalent π‐interactions assume a parallel‐displaced configuration. To the best of our knowledge, no chiral discrimination in cyclic phosphazenes has been hitherto described, and the present findings provide the first evidence for the discrimination of stereoisomers in spirophosphazenes and the noncovalent forces that govern the chiral recognition in these systems. The energy of the π‐stacking interaction increases with increasing number of 2,2′‐dioxybiphenyl groups; i.e., on passing from 3 to 2. In the case of molecule 1, the discrimination of enantiomers does not take place at all because the π‐stacking interaction becomes impossible because of steric hindrance. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

ChemInform Abstract: New Reactions with Thiosulfines/Dithiiranes: Cycloadditions Leading to Dispiro Derivatives of 1,2,4‐Trithiolane.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

New Reactions with Thiosulfines/Dithiiranes: Cycloadditions Leading to Dispiro Derivatives of 1,2,4-Trithiolane.

New Reactions with Thiosulfines/Dithiiranes: Cycloadditions Leading to Dispiro Derivatives of 1,2,4-Trithiolane.

An answer to the spiro versus ansa dilemma in cyclophosphazenes: Part XIII. Synthesis and crystal structure of the first di-MACROSPIRO and di-MEGASPIRO species from di- and tri-oxodiamines

Aminolysis of N 3P 3Cl 6 by dioxodiamines and trioxodiamines in suitable conditions yields di-MACROSPIRO and di-MEGASPIRO species which constitute new di-macrocyclic monocyclophosphazenic architectures. X-Ray structures of di-SPIRO derivatives from 4,9-dioxadodecane-1,12-diamine and from 4,7,10-trioxatridecane-1,13-diamine reveal two highly unsymmetrical 15- and 16-membered loops, respectively, grafted on the same N 3P 3 ring.