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(1R,2R,3S,4R,7R)-7-Isopropyl-6-methylbicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic acid anhydride (tetrahydro-4,7-ethanoisobenzofuran-1,3-dione derivative) adduct 2 was prepared via the isomerization of α-pinene and β-pinene in turpentine followed by the Diels-Alder cycloaddition with maleic anhydride in the presence of phosphoric acid/iodine catalysis. The molecular structure of adduct 2 was characterized by IR, 1H NMR, 13C NMR, 1H-1H COSY, DEPT, HSQC, HMBC, 2D NOESY and MS spectra. The single crystal X-ray crystallographic analysis of adduct 2 was performed, and the X-ray powder diffractive spectrum of the sample adduct 2 is consistent with the diffractive spectrum calculated from the single crystal data. Therefore the structure and stereochemistry of adduct 2 was established based on extensive spectral data and single crystal X-ray analysis.

New metal-free DNA cleaving reagent 1, 1,4,7-triazacrown (TACN) both with aminoethyl, hydroxyethyl side arms and a planar anthraquinone linked by an alkyl (1,6-hexamethylene) spacer has been synthesized and characterized by NMR and MS spectrometry. For comparison, the corresponding aminoethyl, hydroxyethyl triazacrown derivative 2 without the anthraquinone has also been synthesized. DNA-binding properties via fluorescence and CD spectroscopy indicate that the binding affinity of 1 with DNA is much stronger than that of 2. Agarose gel electrophoresis was used to assess plasmid pUC19 DNA cleavage. Kinetic data of DNA cleavage promoted by 1, 2 and parent triazacrown (TACN) 3 under physiological condition give the 15-fold and 234-fold rate acceleration of compound 1 over 2 and parent triazacrown 3. Radical scavenger inhibition study suggests that DNA cleavage promoted by 1 may be a non-oxidative pathway through the transphosphorylation and then hydrolysis. The dramatic rate acceleration is due not only to the anthraquinone moiety of compound 1 intercalating into DNA base pairs via stacking interaction, but also the cooperative catalysis of the nucleophilic hydroxyl and the electrophilic ammonium group for the cleavage of phosphodiester of DNA.

Combretastatins-A4 (CA-4) is a natural product with anticancer activity. However, only the cis-isomer exhibits strong antitubulin activity, but the cis-isomer tends to isomerize to the inactive trans-isomer. Thus, this paper reports that an additional pyrrolidone ring was used to replace the cis double bond to arrest the cis-conformation, and a series of 3,4-diaryl pyrrolediones and 3,4-diaryl pyrrolones as CA-4 analogues were synthesized via a four steps reaction from 3,4-dimethoxyacetophenone and 3-fluoro-4-methoxy acetophenone. The structure of the new compounds was confirmed by 1H NMR, 13C NMR, ESI-MS and elemental analysis. The in vitro activities of CA-4 analogues against HL-60, SMMC-7721 and A549 human cancer cell lines were tested using colorimetric MTT assay and the results indicate that they show significant antitumor activity.

A series of H-shaped chromophores with two parallel and non-conjugated D-π-A units have been synthesized, in which a 9,10-dihydroanthracene was employed as molecular backbone. The synthesis of these H-shaped chromophores 9a–11a was accomplished via an eight-step reaction, including double Claisen rearrangement, hydroboration–oxidation, Rieche formylation reaction, Knoevenagel condensation and Corey–Fuchs reaction, with a total yield about 12.5%. The corresponding mono-D-π-A unit compounds 9b–11b were also prepared in a similar procedure for the purpose of comparison. Crystal structures of three intermediates 5a, 7a and 8a were measured, which demonstrate that the two D-π-A units in a single H-shaped chromophore molecule are nearly arranged at the same direction. The studies of UV–vis spectra and the solvatochromic method indicate that the molecular second-order polarizabilities values (μβ) of H-shaped chromophores are remarkably increased compared with the corresponding mono-D-π-A unit reference compounds, without causing a large shift of the absorption band to longer wavelength.

The different DNA cleavage behaviors of 1,3- and 1,4-xylylene spaced bisCu(BPA)Cl2 complexes (BPA, bis(pyridyl-2-methyl)amine) display the positioning effect of xylylene spacers, implying the essential roles of spacers in the related cleavage (Y. Zhao et al., Chem.–Eur. J., 2006, 12, 6621–6629). Herein, a p-xylyl derivative (2,1,3-benzoxadiazole-4,7-dimethylene (BDDM)) was utilized as a bulky spacer to construct a new p-xylyl spaced bisCu(BPA)Cl2 complex 1 to explore the spacer's steric effect on the related DNA cleavage. Agarose gel electrophoresis demonstrated that complex 1 is able to convert the supercoiled plasmid pUC19 DNA into the nicked DNA and linear DNA in the presence of excessive reductant. This DNA cleavage behavior is different from that of simple p-xylylene spaced Cu2(pTPXA)Cl4, which mediates only the nicked DNA and random DNA fragments. The DNA binding ability of complex 1 is higher than that of Cu2(pTPXA)Cl4, while its DNA nicking ability is lower than that of Cu(BPA)Cl2, as well as the dinuclear Cu2(pTPXA)Cl4, which displays a high DNA nicking efficiency due to the internuclear synergy in activating O2 to damage DNA. The linear DNA formation induced by complex 1 is realized via a non-random double-stranded scission process. The temporal profiles of the nicked DNA and linear DNA in the presence of 8 μM complex 1 imply that the two sequential neighboring breaks in the complementary strands lead to the formation of linear DNA. With the DNA cleavage behavior in the presence of different reactive oxygen species (ROS) quenchers, the DNA-bound hydroxyl radical was proposed as the main ROS involved in the cleavage. Structural optimization of this complex disclosed its larger intramolecular Cu–Cu distance than Cu2(pTPXA)Cl4, which may disfavor the internuclear synergic O2 activation. It was also proposed that the bulky BDDM spacer favors the two spaced copper centers function solely to damage in situ the two adjacent deoxyriboses from complementary strands to form the linear DNA, and the specific DNA binding mode of complex 1 due to the BDDM spacer disfavors the DNA-bound ROS to abstract a proton from deoxyribose and results in a lower DNA cleavage efficiency than mononuclear Cu(BPA)Cl2. The non-random linear DNA mediating ability and the decreased DNA cleavage efficiency caused by the bulky internuclear spacer shown in the current study provides a new alternative to regulate the DNA cleavage behavior of polycopper artificial nucleases via spacer modification.

A pair of artificial enantiotopic receptors la and lb composed of (S,S) or (R,R) chiral bicyclic guanidinium, azacrown ether and (t-butyldiphenylsilyloxy) methyl group for amino acid zwitterions have been synthesized. The liquid-liquid competition experiments and 1 H NMR studies indicate that the receptor 1a with (S, S) configuration and 1b with (R,R) configuration selectively recognize L- and D-aromatic amino acids & respectively.

A novel bis(guanidiniums) receptor for the catalytic cleavage of phosphosdiester was prepared and self-assembly architecture through hydrogen bonds and electrostatic interactions among the bis(guanidiniums) receptor, the sulfate anion and water molecule was revealed by X-ray crystallographic analysis.

The p-tetra-tert-butyl calix[4] arene derivatives (3 and 4) with (5,5) chiral bicyclic guanidinium, as the receptors of amino acid zwitterions, have been synthesized via a O-alkylation reaction of p-tetra-tert-butyl calix [4] arene with cbJoromethyl chiral bicyclic guanidinium 2 in the presence of anhydrous K2CO3 in acetonitrile. The results obtained from liquid-liquid competitive extraction experiments indicate that the two receptors may selectively recognize L-aromatic amino acids, and that the enantioselective recognizability of the receptor 4 with two chiral bicyclic guanidinium units reachs up to about 90% for L-Phe.

Ibis paper reports the properties of the novel tetra-p-nitro-tetra-O-alkyl-calix[4]arenes (alkyl= n-C4H9, 1; n-C8H17 2; n-C12H25, 3; n-C16H33, 4). X-ray crystallographic analysis and 1H NMR revealed that they exist as pinched-cone conformation in crystal or cone conformation in solution. EFISH experiments at 1064 nm in CHCl3, indicated that tetra-p-nitro-tetra-O-butyl-calix[4]arene (1) has higher hyperpolarizability β, values than the corresponding reference compound p-nitro-phenyl butyl ether, without red shift of the charge transfer band. Compounds 2, 3 and 4 with longer alkyl chains can form monolayer at the air/water.

The interaction of zinc(II) complex of N,N′-bis(guanidinoethyl)-2,6-pyridinedicarboxamide (Gua) with DNA was studied by CD spectroscopy and agarose gel electrophoresis analysis. The results indicate that the DNA binding affinity of Zn2+-Gua is stronger than that of Gua and the Zn2+-Gua can promote the cleavage of phosphodiester bond of supercoiled DNA under a physiological condition, which is ∼106 times higher than DNA natural degradation. The hydrolysis pathway was proposed as the possible mechanism for DNA cleavage promoted by the Zn2+- Gua. The acceleration is due to cooperative catalysis of the zinc cation center and the functional groups (bisguanidinium groups).

Novel cleft molecule pyridine-2,6-dicarboxamide appending two guanidinoethyl group side arms (Gua) was synthesized. The interactions of the cleft molecule in the absence of copper(II) (Gua) or in the presence of copper(II) (Cu2+-Gua) with calf thymus DNA were studied by fluorescence and CD spectroscopy. The results indicate that the DNA binding affinity of Cu2+-Gua is stronger than that of Gua, and the binding constants of Cu2+-Gua and Gua are 1.61 x 10(6) M(-1) and 2.86 x 10(5) M(-1), respectively. Agarose gel electrophoresis was used to assess the plasmid pUC 19 DNA cleavage activities in the presence of Gua and Cu2+-Gua. Kinetic data of DNA cleavage promoted by Cu2+-Gua under physiological conditions fit a saturation kinetic profile with k(max) of 0.0173 +/- 0.0011 h(-1), which gave a aproximately 10(6)-fold rate acceleration over uncatalyzed supercoiled DNA, while the catalyst concentration is lower than 0.0625 mM. The hydrolysis pathway was proposed as the possible mechanism for DNA cleavage promoted by Cu2+-Gua. The acceleration is due to efficient cooperative catalysis of the copper cation center and the functional groups (bis(guanidinium) groups).

The interaction of Cu2+ complex of N,N′-bis(2-aminoethyl)-2,6-pyridinedicarboxamide (BAP) with DNA was studied by agarose gel electrophoresis analysis. The results indicate that the BAP-Cu2+ complex can promote the cleavage of phosphodiester bond of supercoiled DNA at physiological condition, which is 3.2×106 times higher than DNA natural degradation. A hydrolytic cleaving mechanism through the cooperation of copper ions and functional amino groups was proposed.

The tetraazamacrocycle crown ether (cyclen) containing two pyridine subunits was prepared by a modified procedure and the interaction of its metal complexes with DNA was studied by agarose gel electrophoresis analysis. The results indicate that the Cu2+ complex as nuclease model can promote the hydrolysis of phosphodiester bond of supercoiled DNA. The rate of degradation of the supercoiled DNA (form I) to nicked DNA (form II) obtained at physiological condition in the presence of 2.14 mM Cu2+ complex is 2.31 × 10–3 min−1. The dependence of the rate of supercoiled DNA cleavage from the complex concentration shows an unusual profile and a hydrolytic cleaving mechanism of two monometallic complexes through cooperation from two-point binding to DNA is proposed.

Monolayers of the amphiphilic calixarene derivatives (BSGC, MSGC and MGC) bearing chiral bicyclic guanidinium on the surface of pure water and of aqueous subphases containing l -phenylalanine or d -phenylalanine ( l / d- Phe) were studied by film balance measurements. LB films deposited from the monolayers on the three kinds of subphases were investigated by circular dichroism spectra (CD). All the results indicate that BSGC, MSGC and MGC can form stable monolayers on these subphases. Moreover, BSGC (with two chiral bicyclic guanidinium units) can enantioselectively recognize l -aromatic amino acid and its enantioselectivity for l -Phe is better than MSGC (with one chiral bicyclic guanidinium unit) at the air–water interface, and the enantioselectivity of MGC (without hydrophobic silylether group at the arm of the chiral bicyclic guanidinium unit) for l -Phe is higher than MSGC (with hydrophobic silylether group). Therefore their enantioselectivities for l -Phe depend on the molecular structures.

Four novel calix[4]crowns-4 and calix[4]crowns-5 with two pendant groups were synthesized by the alkylation of calix[4]crowns-4 and calix[4]crowns-5 with 6-methoxy-2-bromoacetylnaphthalene and 2-methoxy-1-bromoacetylaminomethylnaphthalene, respectively in the presence of Na2CO3 or K2CO3. 1H NMR titration and picrate extraction experiments indicated that the cation is encapsulated inside the preorganized ionophoric cavity constructed by the carbonyl oxygens, the crown ether and the phenoxy oxygens so that these calix[4]crowns-4 and calix[4]crowns-5 with two pendant groups exhibit higher complex efficiency than their parent compounds and possess obvious selectivity for Na+ and K+, respectively. The measurement of UV and fluorescent spectra of the hosts and their complexes with perchlorate salts revealed that calix[4]crowns-4 with the 6-methoxy-2-naphthoylmethyl pendant groups (2a) exhibits remarkable cation-induced photophysical effects and they could be utilized as a selective photophysical sensor for Ca2+.

The properties of the monolayer of 5,11,17,23-tetra- tert -butyl-25,27-bis (2-aminoexthoxy)-26,28-dihydroxycalix[4]arene and its recognition capacity for 5′-AMP − and 5′-GMP 2− at the air–water interface were investigated. π– A isotherms and relaxation experiments indicate that it is able to form stable monolayers on pure water and two nucleotide-containing subphases. Moreover, the nucleotides in subphase are beneficial to the stability of its monolayer. The UV, CD, and FT-IR spectra of LB films from three subphases reveal that 5′-AMP − and 5′-GMP 2− in subphase can be transferred onto the substrates along with the monolayer mainly via multiple hydrogen bonding and electrostatic interactions. The host–guest complexes of 5,11,17,23-tetra- tert -butyl-25,27-bis(2-aminoexthoxy)-26,28-dihydroxycalix[4]arene and nucleotides at the air–water interface were studied through the analysis of the X-ray photoelectron spectra data of LB films. The results indicate that 5′-AMP − and 5′-GMP 2− were bound to the calix[4]arene monolayer in 1:1 and 1:2 molar ratio, respectively. Two intermolecular interaction patterns are proposed and the binding constants are estimated to be 1.4±0.1×10 5 and 1.1±0.2×10 5 M −1 for 5′-AMP − and 5′-GMP 2− , respectively.

A pair of artificial enantiotopic receptors 1a, 16 composed of (S,S) or (R,R) chiral bicyclic guanidinium, azacrown ether and (t-butyldiphenylsilyloxy)methyl group for amino acid zwitterions have been synthesized. The liquid-liquid competition extraction experiments and 'H NMR studies indicate that the receptor 1a with (S,S) configuration and 16 with (R,R) configuration selectively recognize L- and D-aromatic amino acids, respectively.

Molecular recognition of biomolecules by synthetic receptors requires modular assembly of various components to complement the molecular characteristics (sizes, topologies, and functional groups) of the substrate. A number of receptors for biorelevant molecules containing oxoanions have been assembled from a bicyclic chiral guanidine subunit. Several receptors accelerate or catalyze reactions proceeding through anionic transition states. Among the structures recently prepared, a receptor incorporating a calix(6)arene subunit has been developed, showing high affhity for phosphocholine derivatives. Chains of tetraguanidinium sulfates form double helices in solution. These substances strongly induce formation of a-helical conformations in Asp rich peptides.

A new metal-free DNA cleaving reagent, bis-tacnorthoamide derivative 1 with two tacnorthoamide (tacnoa) units linked by a spacer containing anthraquinone, has been synthesized from triazatricyclo[5.2.1.0(4,10)]decane and characterized by NMR and mass spectrometry. For comparison, the corresponding compounds mono-tacnorthoamide derivative 2 with one tacnorthoamide unit and 6 with two tacnorthoamide units linked by an alkyl (1,6-hexamethylene) spacer without anthraquinone have also been synthesized. The DNA-binding property investigated via fluorescence and CD spectroscopy suggests that compounds 1 and 2 have an intercalating DNA binding mode, and the apparent binding constants of 1, 2 and 6 are 1.3 × 10(7) M(-1), 0.8 × 10(7) M(-1) and 8 × 10(5) M(-1), respectively. Agarose gel electrophoresis was used to assess plasmid pUC19 DNA cleavage activity promoted by 1, 2, 6 and parent tacnoa under physiological conditions, which gives rate constants k(obs) of 0.2126 ± 0.0055 h(-1), 0.0620 ± 0.0024 h(-1), 0.040 ± 0.0007 h(-1) and 0.0043 ± 0.0002 h(-1), respectively. The 50-fold and 15-fold rate acceleration over parent tacnoa is because of the anthraquinone moiety of compound 1 or 2 intercalating into DNA base pairs via a stacking interaction. Moreover, DNA cleavage reactions promoted by compound 1 give 5.3-fold rate acceleration over compound 6, which further demonstrates that the introduction of anthraquinone results in a large enhancement of DNA cleavage activity. In particular, DNA cleavage activity promoted by 1 bearing two tacnoa units is 3.3 times more effective than 2 bearing one tacnoa unit and the DNA cleavage by compound 1 was achieved effectively at a relatively low concentration (0.03 mM). This dramatic rate acceleration suggests the cooperative catalysis of the two positively charged tacnoa units in compound 1. The radical scavenger inhibition study and ESI-MS analysis of bis(2,4-dinitrophenyl) phosphate (BDNPP) and adenylyl(3'-5')phosphoadenine (APA) cleavage in the presence of compound 1 suggest the cleavage mechanism would be via a hydrolysis pathway by cleaving the phosphodiester bond of DNA.

Molecular recognition of biomolecules by synthetic receptors requires modular assembly of various components to complement the molecular characteristics (sizes, topologies, and functional groups) of the substrate. A number of receptors for biorelevant molecules containing oxoanions have been assembled from a bicyclic chiral guanidine subunit. Several receptors accelerate or catalyze reactions proceeding through anionic transition states. Among the structures recently prepared, a receptor incorporating a calix(6)arene subunit has been developed, showing high affhity for phosphocholine derivatives. Chains of tetraguanidinium sulfates form double helices in solution. These substances strongly induce formation of a-helical conformations in Asp rich peptides.

2-Hydrazinyl-1,4,5,6-tetrahydropyrimidin-5-ol dihydrochloride 2 , as well as 2-hydrazinyl-4,5-dihydro-1 H -imidazole dihydrochloride 1 , was synthesized as metal-free DNA cleaving agent. Agarose gel electrophoresis was used to assess the plasmid pUC 19 DNA cleavage activities in the presence of 1 and 2 . DNA cleavage efficiency of 2 exhibits remarkable increases compared with its corresponding non-hydroxy compound 1 . Kinetic data of DNA cleavage promoted by 2 fit to the Michaelis–Menten-type equation with k max of 0.0378 ± 0.0013 h −1 giving 10 6 -fold rate acceleration over uncatalyzed DNA. The acceleration is driven by the spatial proximity of the nucleophilic hydroxy group and the electrophilic activation for the phosphodiester by the ammonium and/or guanidinium groups. In vitro cytotoxic activities toward Hela cells and human leukemia HL-60 cells were also examined, and 2 exhibits stronger cytotoxic activities than 1 .

A preorganized cleft dinuclear zinc(II) complex of 2,6-bis(1-methyl-1,4,7-triazacyclonon-1-yl)pyridine 1 as an artificial nuclease was prepared via an improved method. The interactions of 1, 2 [1,4,7-triazacyclononane (TACN)], and their zinc(II) complexes with calf thymus DNA were studied by spectroscopic techniques, including fluorescence and CD spectroscopy. The results indicate that the DNA binding affinities of these compounds are in the following order: Zn(II)2 -1Zn(II) -212. The binding constants of the Zn (II)2 -1 and Zn(II)-2 complexes are 3.57 x 10(6) and 1.43 x 10(5) M(-1), respectively. Agarose gel electrophoresis was used to assess the plasmid pUC 19 DNA cleavage activities in the presence of the dinuclear Zn (II)2 -1 complex, which exhibits powerful DNA cleavage efficiency. Kinetic data for DNA cleavage promoted by the Zn(II)2 -1 complex under physiological conditions give the observed rate constant ( k obs) of 0.136 h(-1), which shows an 10(7)-fold rate acceleration over uncatalyzed supercoiled DNA. The comparison of the dinuclear Zn(II)2 -1 complex with the mononuclear zinc(II) complex of 1,4,7-triazacyclononane indicates that the DNA cleavage acceleration promoted by the Zn(II)2 -1 complex is due to the efficient cooperative catalysis of the two proximate zinc(II) cation centers. A hydrolytic mechanism of the cleavage process was suggested, and a preliminary study of the antitumor activity was also conducted.

Novel 1,7-dioxa-4,10-diazacyclododecane artificial receptors with two pendant aminoethyl (3) or guanidinoethyl (4) side arms have been synthesized. Spectroscopy, including fluorescence and CD spectroscopy, of the interactions of 3, 4, and their copper(II) complexes with calf thymus DNA indicated that the DNA binding affinity of these compounds follows the order Cu(2+)-4>Cu(2+)-3>4>3, and the binding constants of Cu(2+)-3 are Cu(2+)-4 are 7.2x10(4) and 8.7x10(4) M(-1), respectively. Assessment by agarose gel electrophoresis of the plasmid pUC 19 DNA cleavage activity in the presence of the receptors showed that the complexes Cu(2+)-3 and Cu(2+)-4 exhibit powerful supercoiled DNA cleavage efficiency. Kinetic data of DNA cleavage promoted by Cu(2+)-3 and Cu(2+)-4 under physiological conditions fit to a saturation kinetic profile with kmax values of 0.865 and 0.596 h(-1), respectively, which give about 10(8)-fold rate acceleration over uncatalyzed supercoiled DNA. This acceleration is due to efficient cooperative catalysis of the copper(II) center and the functional (diamino or bisguanidinium) groups. In-vitro cytotoxic activities toward murine melanoma B16 cells and human leukemia HL-60 cells were also examined: Cu(2+)-4 shows the highest activity with IC(50) values of 1.62x10(-4) and 1.19x10(-5) M, respectively.

A novel phosphodiester receptor 1-(2-guanidinoethyl)-4-(2-hydroxyethyl)-1,4,7-triazacyclononane hydrochloride 1 was synthesized. DNA cleavage efficiency of 1 exhibits remarkable increases compared with its ZnII complex and corresponding nonguanidinium compound N-(2-hydroxyethyl)-1,4,7-triazacyclononane and parent 1,4,7-triazacyclononane. Kinetic data of DNA cleavage promoted by 1 fit to a Michaelis−Menten-type equation with kmax of 0.160 h-1 giving 107-fold rate acceleration over uncatalyzed DNA. The acceleration is driven by the spatial proximity of the nucleophilic hydroxyl group and the electrophilic activation for the phosphodiester by the guanidinium group.

Stable and regular bilayer vesicles can be formed in ethanol by 5,11,17,23-tetra-tert-butyl-25,27-bis(2-guanidinoethoxy)-26,28-dihydroxycalix[4]arene hydrochloride (BGC). Hydrophobic interactions b...

1,4,7-Triazacyclononane (TACN), with DNA cleaving ability, was appended to anthraquinone via different spacers to construct the new compounds 1,8-[2,2′-(1,4,7-triazacyclonon)diethoxy] anthracene-9,10-dione hydrochloride (1) and 1,8-[2,2′-(1,4,7-triazacyclonon)dihexyloxy] anthracene-9,10-dione hydrochloride (2) as new agents for metal-free DNA cleavage. Fluorescence and CD spectroscopic studies suggest an intercalating DNA binding mode, and the apparent DNA binding constants of 1 and 2 are 3.93 × 107 and 6.07 × 107 M−1, respectively. Compound 2, bearing the longer spacer, exhibits the higher DNA binding ability. The apparent initial first-order rate constant (kobs) of DNA cleavage promoted by 1 and 2 (0.05 mM) in physiological media are 0.077 ± 0.0028 and 0.123 ± 0.0027 h−1, respectively. The 51-fold and 82-fold rate accelerations over parent TACN (the kobs is 0.0015 ± 0.00003 h−1 (0.05 mM) under the same conditions) are due to the anthraquinone moiety of compounds 1 and 2 intercalating into the DNA base pairs via stacking interactions. ESI-MS analysis of the dinucleotide cleavage promoted by 1 and 2, and radical scavenger inhibition studies suggest that the cleavage process is a hydrolytic mechanism.