Synthesis,cytotoxicity, and interaction with DNA of platinum(II) complexes of (1R,2R)-N1-2-amyl-1,2-diaminocyclohexane

(1R,2R)-N¹-2-amyl-1,2-diaminocyclohexane, which has an amyl substituent as compared with 1,2-diaminocyclohexane, was used as the carrier group to construct three platinum(II) complexes. MTT assay revealed that the complexes showed decent cytotoxicity against all of the four tested tumor cell lines with the IC₅₀ values ranging from 1.08 to 253.36 μM. Particularly, the IC₅₀ values of 2 against A549 and HCT-116 reached 3.32 and 1.08 μM, respectively, which were much lower than those of cisplatin and oxaliplatin. Flow cytometry demonstrated that 2 inhibited HepG2 cells proliferation and caused cytotoxicity by inducing apoptosis and arresting cells in the G2 phase. Furthermore, agarose gel electrophoresis showed that 2 had the ability to interact with DNA in a manner different from cisplatin and oxaliplatin, indicating the carrier ligand with an alkyl moiety had an influence on the action mode of the complex.     

Synthesis and in vitro cytotoxicity of platinum(II) complexes with chiral N-monosubstituted 1,2-cyclohexyldiamine derivatives as the carrier groups

Eight platinum(II) complexes with the new chiral ligands, (1R,2R)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine (R) or (1S,2S)-N ¹-(pyridine-2-ylmethyl) cyclohexane-1,2-diamine (S) as the carrier groups were designed, synthesized, and spectrally characterized. All platinum(II) complexes showed much better aqueous solubility than cisplatin and oxaliplatin. In vitro cytotoxicity of the compounds against human HepG-2, MCF-7, A549, and HCT-116 cell lines was evaluated. Results indicate that all compounds with R as the carrier group showed cytotoxicity against HCT-116, A549, and MCF-7 cell lines; however, all compounds with S as carrier group exhibited disappointing cytotoxicity against tested cell lines. Compound R2, bearing ClCH₂COO^- as leaving group, exhibited better cytotoxicity than that of carboplatin against A549 and MCF-7 cell lines and also showed close activity to oxaliplatin against HCT-116 cell line.     

Two chiral mononuclear and one-dimensional cadmium(II) complexes constructed by (1R,2R)-N1,N2-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives: Effect of positional isomerism

Reactions of (1R,2R)-N¹,N²-bis(pyridinylmethyl)cyclohexane-1,2-diamine derivatives, (1R,2R)-2-bpcd and (1R,2R)-3-bpcd [(1R,2R)-2-bpcd = (1R,2R)-N¹,N²-bis(pyridin-2-ylmethyl)cyclohexane-1,2-diamine, (1R,2R)-3-bpcd = (1R,2R)-N¹,N²-bis(pyridin-3-ylmethyl)cyclohexane-1,2-diamine], with CdI₂ in an analogous way led to the formation of a chiral discrete mononuclear complex and a chiral one-dimensional polymeric chain, respectively, which may be attributed to the positional isomerism of the ligands. The chiral organic ligands and complexes display luminescent properties indicating that they may have a potential application as optical materials. Powder second-harmonic generation (SHG) efficiency measurement shows that the SHG efficiency of the complexes is approximately 0.3 and 0.45 times that of KDP, respectively.     

Platinum and Palladium Complexes Bearing New (1R,2R)‐(–)‐1,2‐Diaminocyclohexane (DACH)‐Based Nitrogen Ligands: Evaluation of the Complexes Against L1210 Leukemia

The reaction of (1R,2R)‐(–)‐1,2‐diaminocyclohexane ( 1 ) [DACH] with the aldehyde (1R)‐(–)‐myrtenal ( 2 ) in MeOH afforded the bidentate diimine ligand, (1R,2R)‐(–)‐N¹,N²‐bis{(1R)‐(–)myrtenylidene}‐1,2‐diaminocyclohexane ( 3 ) in a high yield. Reduction of 3 using LiAlH₄ led to the formation of the desired ligand ( 4 ) (1R,2R)‐(–)‐N¹,N²‐bis{(1R)‐(–)myrtenyl}‐1,2‐diaminocyclohexane. Treatment of compound 4 with K₂PtCl₄ or K₂PdCl₄ yielded the corresponding platinum(II) and palladium(II) complexes, Pt‐5 and Pd‐6 , respectively. The reaction of compound 3 with K₂PtCl₄ gave the diimine complex Pt‐7 . The cytotoxic activity of the complexes Pt‐5 , Pd‐6 and Pt‐7 was tested and compared to the approved drugs, cisplatin ( Cis ‐Pt ) and oxaliplatin ( Ox‐Pt ). The complexes ( Pt‐5 , Pd‐6 and Pt‐7 ) inhibit L1210 cell line proliferation with an IC₅₀ of 0.6, 4.2, and 0.7 μL, respectively as evidenced by measuring thymidine incorporation.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

Palladium(II) complexes with R2edda-derived ligands

Four palladium(II) complexes with R₂edda ligands, dichlorido(O,O′-dialkylethylenediamine-N,N′-diacetate)palladium(II) monohydrates, [PdCl₂(R₂edda)]?H₂O, R = Me, Et, n-Pr, i-Bu, and the new ligand precursor i-Bu₂edda?2HCl?H₂O, O,O′-diisobutylethylenediamine-N,N′-diacetate dihydrochloride monohydrate, were synthesized and characterized by IR, ¹H and ¹³C NMR spectroscopy, and elemental analysis. DFT calculations were performed for the palladium(II) complexes and a high possibility for isomer formation due to stereogenic N ligand atoms was confirmed. Moreover, DFT simulations revealed energetic profile of isomer formation. Computational outcomes are in agreement with spectroscopic instrumental findings, both strongly indicating a non-stereoselective reaction between selected esters and K₂[PdCl₄], forming isomers.     

Synthesis and characterization of model compounds for carbazole-substituted N-acylated linear polyethylenimine (PEI). Synthesis and 1H-NMR spectra of N-acylated diethylamine and N,N′-dimethyl-1,2-ethanediamine containing 9-carbazolylacetyl, (R,S)- or (R)-2-(9-carbazolyl)propanoyl groups

The synthesis of N,N-diethyl-9-carbazolylacetamide ( 6 ), (R,S)- and (R)-N,N-diethyl-2-(9-carbazolyl)propanamide ( 7 ), N,N′-dimethyl-N,N′-di-(9-carbazolylacetyl)-1,2-ethanediamine ( 11 ), and (R)-N,N′-dimethyl-N,N′-di[2-(9-carbazolyl)propanoyl]-1,2-ethanediamine ( 13 ) is reported. The racemic compound, (R,S)-2-(9-carbazolyl)propanoic acid ( 2 ), was resolved by partial crystallization of the diastereomeric salts formed between 2 and (+)-α-methylbenzylamine. The ¹H-NMR spectra of 6 and 7 showed magnetic nonequivalence of the chemically equivalent protons of the methyl and methylene groups in 6 and 7 due to partial double bond character of the amide bond. The upfield resonances corresponding to the two sets of methyl and methylene protons were assigned by the aromatic solvent-induced shift (ASIS) method to the protons anti to the carbonyl oxygen in the conformation of amide bond in 6 and 7 . The ¹H-NMR spectra of 11 and (R)- 13 were used to determine the population of anti-anti, anti-syn (syn-anti) and syn-syn conformers in the structures of these dimer model compounds; the relative conformer populations were 0.45:0.47:0.08 and 0.28±0.02:0.29±0.01:0.43±0.01 in 11 and (R)- 13 .     

Oxidative ring-opening of rel-(2R,3R,5S)-5-aryl-2-benzoylamino-6,7-bis(methoxycarbonyl)-2,3-dihydro-1-oxo-3-phenyl-1H,5H-pyrazolo[1,2-a]-pyrazoles. Synthesis of rel-(2R,3R)-3-phenyl-3-[5-aryl-3,4-bis(methoxycarbonyl)pyrazolyl-1]alanine esters

rel-(2R,3R)-N-Benzoylamino-6,7-bis(methoxycarbonyl)-2,3-dihydro-1-oxo-1H,5H-pyrazolot[1,2-a]-pyrazoles 5 , accesible by cycloaddition of dimethyl acetylenedicarboxylate ( 3 ) to (1Z)-rel-(4R,5R)-1-aryl-methylidene-4-benzoylamino-5-phenyl-3-pyrazolidinone-1-azomethine imines 4 , undergo oxidative ring cleavage with methanolic bromine giving rel-(2R,3R)-N-benzoyl-3-phenyl-3-[5-aryl-3,4-bis(methoxy-carbonyl)pyrazolyl-1]alanine methyl esters 6 as products.     

(1iR,1iiR,2iR,2iiR)-Ni,Nii-(1,3-亚苯基双(亚甲基))环己烷-1,2-二胺作为配体的双核铂配合物的合成及其抗癌活性

以(1ⁱR,1ⁱⁱR,2ⁱR,2ⁱⁱR)-Nⁱ,Nⁱⁱ-(1,3-亚苯基双(亚甲基))环己烷-1,2-二胺(HL)作为配体,设计并合成了7种双核铂配合物,并利用IR,¹H NMR,¹³C NMR,ESI-MS和元素分析等进行了表征。通过MTT法测定目标双核铂配合物对人类HepG-2,A549,HCT-116和MCF-7四种癌细胞系的细胞毒性。结果表明,所有的化合物对HepG-2,A549和HCT-116细胞系均表现了良好的细胞毒活性,但对MCF-7细胞系均无活性。其中,以3-羟基环丁烷-1,1-二羧酸为离去基团的配合物P7对HepG-2和A549细胞系的活性优于卡铂,对HCT-116细胞系的活性接近于奥沙利铂。     

Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamines

An enantioselective synthesis of sterically congested 1,2-di-tert-butyl and 1,2-di-(1-adamantyl)ethylenediamines has been developed. Thus, diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were successfully prepared by optical resolution of (±)-trans-4,5-dimethoxy-2-imidazolidinone using apocamphanecarbonyl chloride (MAC-Cl) followed by stereospecific and stepwise substitution of the dimethoxyl groups using tert-butyl or 1-adamantyl cuprates to provide (4S,5S)-4,5-di-tert-butyl and (4R,5R)-4,5-di-(1-adamantyl)-2-imidazolidinones 12 and 15, respectively. Furthermore, N-acetyl 4,5-di-tert-butyl and 4,5-di-(1-adamantyl)-2-imidazolidinones 16a,b were enantioselectively deacetylated using a catalytic oxazaborolidine system to provide enantiopure 1-p-tolylsulfonyl-4,5-di-tert-butyl-2-imidazolidinones 12 and 19 and 1-p-tolylsulfonyl-4,5-di-(1-adamantyl)-2-imidazolidinones 18 and 20, respectively. Finally, N-p-tolylsulfonyl-2-imidazolidinones 12 and 15 were treated with 30 equiv of Ba(OH)₂·8H₂O to achieve ring cleavage and to provide (1S,2S)-1,2-di-tert-butylethylenediamine 3 and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamine 4.     

New analogues of fosfomycin—synthesis of diethyl (1R,2R)- and (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1R,2R)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised via the intramolecular Williamson reaction from 3-O-protected (trityl or TBDMS) or even unprotected diethyl (1S,2R)-2,3-dihydroxy-1-mesyloxypropylphosphonate, which was obtained from the known diethyl (1S,2R)-2,3-O-cyclohexylidene-1,2,3-trihydroxypropylphosphonate. On the other hand, the cis-analogue, diethyl (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonate, could only be prepared from diethyl (1R,2R)-2-hydroxy-1-mesyloxy-3-trityloxypropylphoshonate.     

Self-assembly of 1-D, 2-D,and 3-D transition-metal coordination polymers based on a T-shaped tripodal ligand 4-(4,5-dicarboxy-1H-imidazol-2-yl)pyridine 1-oxide

Three coordination polymers, {[Co(C₁₀H₅N₃O₅)(H₂O)₂]·H₂O}_n (1), {[Mn₃(C₁₀H₅N₃O₅)₂Cl₂(H₂O)₆]·2H₂O}_n (2), and {[Cu₃(C₁₀H₄N₃O₅)₂(H₂O)₃]·4H₂O}_n (3), based on a T-shaped tripodal ligand 4-(4,5-dicarboxy-1H-imidazol-2-yl)pyridine 1-oxide (H₃DCImPyO), were synthesized under hydrothermal conditions. The polymers showed diverse coordination modes, being characterized by elemental analysis, infrared spectroscopy, and single-crystal X-ray structure analysis. In 1, the HDCImPyO^2? generated a 1-D chain by adopting a μ₂-kN, O : kN′, O′ coordination mode to bridge two Co(II) ions in two bis-N,O-chelating modes. In 2, the HDCImPyO^2? adopted a μ₃-kN, O : kO′, O′′ : O′′′ coordination mode to bridge two crystallographically independent Mn(II) ions, forming a 2-D hcb network with {6³} topology. In 3, by adopting μ₄-kN, O : kO′, O′′ : kN′′, O′′′ : O′′′′ coordination, DCImPyO^3? bridged three crystallographically independent Cu(II) ions to form a 3-D framework having the stb topology.     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.     

A new [(1R,2R)‐1,2‐diaminocyclohexane]platinum(II) complex: formation by nitrate–acetonitrile ligand exchange

The title compound, cis‐diacetonitrile[(1R,2R)‐1,2‐diaminocyclohexane‐κ²N,N′]platinum(II) dinitrate monohydrate, [Pt(C₂H₃N)₂(C₆H₁₄N₂)](NO₃)₂·H₂O, is a molecular salt of the diaminocyclohexane–Pt complex cation. There are two formula units in the asymmetric unit. Apart from the two charge‐balancing nitrate anions, one neutral molecule of water is present. The components interact via N—H...O and O—H...O hydrogen bonds, resulting in supramolecular chains. The title compound crystallizes only from acetonitrile with residual water, with the acetonitrile coordinating to the molecule of cis‐[Pt(NO₃)₂(DACH)] (DACH is 1,2‐diaminocyclohexane) and the water forming a monohydrate.     

Total synthesis of 2-(β-D-ribofuranosyl)thiazole-4-carboxamide (Tiazofurin) and of precursors of ribo-C-nucleosides

(1R,2S,4R)-2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl (1S′)-camphanate ( 5 ) was transformed into (?)-methyl 2,5-anhydro-3,4,6-O-tris[(tert-butyl)dimethylsilyl]-D -allonate ( 2 ), (+)-1,3-diphenyl-2-{2′,3′,5′-O-tris[(tert-butyl)dimethylsilyl]-β-D -ribofuranosyl}imidazolidine ( 3 ), and the benzamide 20 of 1-amino-2,5-anhydro-1-deoxy-3,4,6-O-tris-[((tert-butyl)dimethylsily)]-D -allitol. Compound 2 was converted efficiently into optically active tiazofurin ( 1 ).     

[(1R,2R)‐1,2‐Di­amino­cyclo­hexane‐κ2N,N′](α‐di­imine‐κ2N,N′)­platinum(II) bis­(hexa­fluoro­phosphate), where α‐di­imine is 2,2′‐bi­pyridine and 1,10‐phen­anthroline

The title Pt^II complexes, viz. (2,2′‐bi­pyridine‐κ²N,N′)[(1R,2R)‐1,2‐di­amino­cyclo­hexane‐κ²N,N′]­platinum(II) bis­(hexa­fluoro­phosphate), [Pt(C₆H₁₄N₂)(C₁₀H₈N₂)](PF₆)₂, and [(1R,2R)‐1,2‐di­amino­cyclo­hexane‐κ²N,N′](1,10‐phenanthroline‐κ²N,N′)platinum(II) bis­(hexa­fluoro­phosphate), [Pt(C₆H₁₄N₂)(C₁₂H₈N₂)](PF₆)₂, containing an aromatic α‐di­imine and a non‐planar di­amino­cyclo­hexane, both form a ladder‐type structure, which is constructed via loose π–π stacking on the α‐di­imine ligands and hydrogen bonding between the cyclic amines and the counter‐anions. In the former compound, there are two independent complex cations, both of which have a twofold axis through the Pt atom.     

New lipoxygenase and cholinesterase inhibitory sphingolipids from Carthamus oxyacantha

Two new sphingolipids: oxyacanthin A [(2S,3S,4R)-2-{[(2R,5E)-2-hydroxyoctadec-5-enoyl]amino}hexaeicosane-1,3,4-triol; 1] and B [(2S,3S,4R)-2-{[(2R,5E)-2-hydroxyoctadec-5-enoyl]amino}hexaeicosane-1,3,4-triol-1-O-β-D-glucopyranoside; 2], together with 1-octacosanol, β-sitosterol, β-sitosterol 3-O-β-D-glucopyranoside and luteolin 7-O-β-glucopyranoside were isolated from the methanolic extract of the whole plant of Carthamus oxyacantha. Their structures were elucidated using ¹H and ¹³C NMR spectra and 2D NMR analyses (HMQC, HMBC and COSY) in combination with mass spectrometry (EI-MS, HR-EI-MS, FAB-MS and HR-FAB-MS) experiments and in comparison with the literature data of the related compounds. Both the compounds 1 and 2 showed inhibitory potential against lipoxygenase (LOX) in a concentration-dependent manner with IC₅₀ values 83.3 ± 1.3 and 245.7 ± 1.1 µM, whereas compound 2 showed inhibition against enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC₅₀ values 65.3 ± 0.1 and 93.6 ± 0.1 µM, respectively.     

Reactions of organotin chlorides R2SnCl2 (R = Et, But, or Ph) with lithium 4,6-di( tert -butyl)- N -(2,6-diisopropylphenyl)- o -amidophenolate. Synthesis and structures of tin( IV ) o -iminoquinone complexes

The exchange reactions of tin diorganohalides R₂SnCl₂ (R = Et, Bu^t, or Ph) with lithium amidophenolate APLi₂ (AP is the 4,6-di(tert-butyl)-N-(2,6-diisopropylphenyl)-o-iminobenzo-quinone dianion) in tetrahydrofuran produced the new five-coordinate (Et₂SnAP(THF) (3)) and four-coordinate (R₂SnAP (R = Bu^t, Ph)) tin(IV) complexes. The reaction of Ph₂SnCl₂ with APLi₂ in a nonpolar solvent (hexane or toluene) is accompanied by the additional redox process giving rise to the paramagnetic complex Ph₂Sn(ImSQ)Cl (6) (ImSQ is the 4,6-di(tert-butyl)-N-(2,6-diisopropylphenyl)-o-iminobenzoquinone radical anion). The molecular structures of complexes 3 and 6 were established by X-ray diffraction. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 253–258, February, 2007.     

Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.     

Synthesis and biological evaluation of water-soluble trans-[bicyclo[2.2.2]octane-7R,8R-diamine]platinum(II) complexes with linear or branched alkoxyacetates as leaving groups

Four platinum(II) complexes, trans-[bicyclo[2.2.2]octane-7R,8R-diamine]bis(alkoxyacetato-O,O’) platinum(II) (alkoxyacetate = methoxyacetate (2), ethoxyacetate (3), isopropoxyacetate (4), and tert-butoxyacetate (5)) were synthesized and spectrally characterized. The cytotoxicity of these water-soluble complexes was evaluated by CCK-8 assay in vitro against HCT-116, HepG-2, and A549 cancer cell lines. Most of the complexes had cytotoxic activity against the tested cancer cell lines. Among them, 3 showed more potent antitumor effect than cisplatin or oxaliplatin. Complex 3 could cause HCT-116 cell line death based on an apoptotic pathway since it has a dicyclic moiety similar to 1R,2R-diaminocyclohexane in oxaliplatin. Agarose gel electrophoresis on the interaction between 3 and DNA indicated that it has different behavior from that of cisplatin or oxaliplatin, which has a high correlation with the ligand used.