The relationship between the chemical structures of dihydropyrazine derivatives and DNA strand-breakage activity

Dihydropyrazine, a compound derived from sugars, possesses DNA strand-breakage activity. The relationship between the activity as assayed using pBR 322 ccc-DNA and the chemical structures of derivatives of dihydropyrazine (DHPs) has been investigated. The addition of Cu(2+) enhanced the activity remarkably. The introduction of a methyl or phenyl group onto the DHP ring or a cyclohexyl group fused onto the DHP ring also increased the activity. These properties indicated that the activity was due to the facility of electron release from the DHP ring, followed by radical generation. The determination of ionization potential and electrostatic potential values, and bond dissociation energy via semi-empirical MO calculations suggested strongly that the activity is induced by a DHP ring structure that contains a configuration suitable for hyperconjugation.     

Synthesis and antitumor activities of glucan derivatives

A highly efficient and practical method for the preparation of β-d-Glc-(1→6)-[β-d-Glc-(1→3)]-β-d-Glc-(1→6)-β-d-Glc-(1→6)-[β-d-Glc-(1→3)]-d-Glc-OMe was described. A dendritic nonasaccharide was also synthesized. The antitumor activities of hexasaccharide, the dendrimer, their sulfated derivatives, together with the natural glucan-protein and the corresponding polysaccharide isolated from barmy mycelium of Grifola frondosa, were preliminarily investigated based on Sarcoma-180 studies in mice tests. Our results suggest that the sulfated branching oligosaccharide and natural glycoprotein have better antitumor activities comparing to the parent sugar residue (oligosaccharide or polysaccharide).     

Semisynthesis and antitumor activities of new styryl-lactone derivatives

Nineteen new derivatives of the naturally occurring compound, goniothalamin, were prepared by chemical modification and semi-synthetic methods. The antitumor activities of these derivatives and goniothalamin were evaluated in vitro against human tumor cell lines, and most of them showed an inhibitory effect against HL-60 cancer cells. The derivatives 10-nitro-goniothalamin and 10-amino-goniothalamin gave selective inhibition concentration (IC50) of 1.10 and 1.14 microg/ml, respectively, against human stomach cancer SGC-7901 cells, while that of etoposide (vp-16) as the positive control was 6.07 microg/ml. Finally, the partition coefficients, logP (pi values), of these derivative molecules, were evaluated by calculating the additive approximate organic fragment logP value.     

Synthesis of novel 1,3,4-oxadiazole derivatives and their nucleoside analogs with antioxidant and antitumor activities

A series of new (1,3,4-oxadiazol-2-yl)-1H-benzo[h]quinolin-4-one derivatives were synthesized, including glucose and xylose hydrazones that were obtained by the reaction of hydrazides with monosaccharides. Cyclization of the sugar hydrazones with acetic anhydride afforded substituted oxadiazoline derivatives. The newly synthesized compounds were evaluated for their antioxidant properties and cytotoxicity, and showed moderate to high activities.     

Synthesis, crystal structures and in vitro antitumor activities of some arylantimony derivatives of analogues of demethylcantharimide

A series of novel arylantimony derivatives of analogues of demethylcantharimide with the formulae Ar_nSbL_(5−n) and Ar_nSbL^′_(5−n)(LH=N-hydroxy-demethyldehydrogencantharimide, L^′H=N-hydroxy-demethylcantharimide, n=3, 4; ArC₆H₅, 4-CH₃C₆H₄, 3-CH₃C₆H₄, 2-CH₃C₆H₄, 4-ClC₆H₄, 4-FC₆H₄) were synthesized and characterized by elemental analysis, IR, ¹H NMR and mass spectroscopy. The crystal structures of (C₆H₅)₄SbL, (4-CH₃C₆H₄)₃SbL₂ and (3-CH₃C₆H₄)₃SbL^′₂ were determined by X-ray diffraction. The in vitro antitumor activities of all compounds against six cancer cells are reported.     

Synthesis and antitumor activities of novel benzoylphenylurea derivatives.

Seventy novel benzoylphenylurea compounds were synthesized and their antitumor activities were examined in vivo against P388 leukemia. N-(2-Nitrobenzoyl)-N'-[4-(2-pyrimidinyloxy)phenyl]ureas showed the highest antitumor activities when dosed intraperitoneally or orally. Their structure-activity relationships were examined with particular focus on the position and the variety of substituent on each aryl ring.     

The relationship between the structures of Cu(II) complexes and their chemical transformations

The study of the thermal dehydration of the compounds CuX2.nH₂O, where X^– were formate, salicylate or phtalate anions, was performed, including the observations of structural changes of compounds during their decomposition. It is shown that the dehydration of copper(II) formate tetra- and dihydrates is accompanied by significant changes in the bonding of the formato groups and remaining water molecules. Two structurally different modifications of Cu(HCOO)₂.2H₂O were prepared, the structure differences are clearly demonstrated in their decomposition stoichiometry. The dehydration of copper formate hydrates was found to be controlled by chemical reaction on the phase boundary. The dehydration of the copper salicylate tetrahydrate and copper phtalate monohydrate is accompanied by the structural changes of the whole compounds, as well, however these processes are diffusion or nucleation controlled.

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Zusammenfassung Es wurde die thermische Dehydratation der Verbindungen CuX₂.nH₂O mit dem Formiat-, Salicylat- und Phthalatanion als X^– unter gleichzeitiger Beobachtung eventueller Strukturveränderungen dieser Verbindungen während der Dehydratation untersucht. Es wird gezeigt, dass die Dehydratation von Kupfer(II)-formiat Tetrabzw. Dihydrat von einer eindeutigen Veränderung der Bindungsverhältnisse der Formiatgruppen und der verbleibenden Wassermoleküle begleitet wird. Es wurden zwei strukturell verschiedene Modifikationen von Cu(HCOO)₂.2H₂O hergestellt, die Strukturunterschiede zeigen sich deutlich in der Stöchiometrie ihrer Zersetzung. Die Dehydratation von Kupferformiathydraten wird durch die chemische Reaktion an der Phasengrenze kontrolliert. Die Dehydratation von Kupfersalicylat Tetrahydrat und Kupferphthalat Monohydrat wird von einer Strukturveränderung des ganzen Moleküles begleitet, unabhängig davon, ob der Vorgang durch die Diffusion oder Kernbildung bestimmt wird.

     

The relationship between the structures of Cu(II) complexes and their chemical transformations

The paper presents the results of a study of M ₂ ^I M ^II(SO₄)₂ compounds withM ^I= K, Rb, Cs or Tl, andM ^II=Cu or Ni, in the interval from room temperature to the melting temperature. All the compounds studied show endo- or exothermic excursions in their DTA curves, corresponding to phase transitions connected with colour changes of the compounds. For M ₂ ^I Cu(SO₄)₂, whereM ^I is K or Tl, several modifications could be prepared at laboratory temperature, probably distortion isomers. No modifications of this type could be prepared, however, for M ₂ ^I Ni(SO₄)₂ compounds.

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Zusammenfassung Die Ergebnisse einer Untersuchung von M ₂ ^I M ^II(SO₄)₂-Verbindungen Cs, Tl;M ^II=Cu, Ni) im Temperaturbereich von Raum- bis Schmelztemperatur werden beschrieben. Alle untersuchten Verbindungen zeigen in ihren DTA-Kurven mit Farbänderungen einhergehende, durch Phasenumwandlungen bedingte endo- und exotherme Peaks. Bei Laboratoriumstemperatur konnten verschiedene Modifikationen von M ₂ ^I Cu(SO₄)₂ (mitM ^I gleich K oder Tl) hergestellt werden, wobei es sich wahrscheinlich um Distorsionsisomere handelt. Keine Modifikationen dieses Typs konnten jedoch für M ₂ ^I Ni(SO₄)₂ erhalten werden.

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M ₂ ^I M ^II(SO₄)₂, ¹-, Rb, Cs Tl, aM ¹¹-Cu Ni, . - -, , . M ₂ ^I Cu(SO₄)₂, ¹- l, , , , . , M _i ² Ni(SO₄)₂ .

     

The relationship between the structures of Cu(II) complexes and their chemical transformations

The structures of compounds M ₂ ^I M^II(SEO₄)₂ (M^I=K, Tl; M^II=Cu and Ni), were studied using IR, electronic and EPR spectra. The results indicate a hexacoordination of both central atoms, and a bridging function of selenato groups, the mode of their coordination varies with M^I and M^II. The compound Tl₂Cu(SeO₄)₂ was prepared also in the amorphous glassy form, although with partial decomposition. It is presumed that in the homogeneous smaragd-green material -Cu-O-Cu-, -Cu-OSeO₂-Cu- and -Cu-OSeO₃-Cu- bridges are present simultaneously. The course of the thermal decomposition of the studied compounds depends on the nature of the M^I and M^II cations. According to powder X-ray patterns, the decomposition products do not contain individual oxides. Nearly complete removal of selenium was observed in the decomposition of hydrated ammonium double selenates of Ni(II) and Cu(II).

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Zusammenfassung Mittels IR-, Elektronen- und EPR-Spektren wurden die Strukturen der Verbindungen M ₂ ^I M^II (SeO₄)₂ mit M^I=K und Tl sowie M^II=Cu and Ni bestimmt. Die Ergebnisse zeigen eine Hexakoordination beider Zentralatome und eine Brückenfunktion der Selenatgruppen, deren Koordination sich mit M^I und M^II ändert. Die Verbindung Tl₂Cu(SeO₄)₂ wurde, wenn auch unter geringen Zerfalles, auch in einer amorphen Glasform hergestellt. Es wird angenommen, daß in den Smaragdgrün-Stoffen gleichzeitig-Cu-O-Cu-, -Cu-OSeO₂-Cu- und -Cu-OSeO₃-Cu- Brücken vorkommen. Der Verlauf der thermischen Zersetzung der untersuchten Verbindungen hängt von der Art der M^I und M^II-Kationen ab. In Bezugnahme auf Röntgenpulverdiffraktionsaufnahmen enthalten die Zersetzungsprodukte keine getrennten Oxide. Beim Zerfall von hydratierten Ammoniumdoppelselenaten von Ni(II) und Cu(II) wurde eine fast vollständige Abgabe von Selen beobachtet.

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M ₂ ^I Mⁱⁱ(SeO₄)₂, ⁱ — , , ⁱⁱ , - , . , - ^{i ii}. Tl₂Cu(SeO₄)₂ , . , ----, --OSeO₂- -Cu-OSeO₃-u-. ^{i ii}. , . .

     

The relationship between the structures of Cu(II) complexes and their chemical transformations

The thermal dehydration of the compounds M ₂ ^I [M^II(H₂O)₆](SeO₄)₂, where M^I=NH₄, K, Rb, Cs and Tl, and M=Cu and Ni, was studied in order to correlate the course of the decomposition with the known crystal structures. It was found that the stoichiometry of the reactions is the same as that established for the analogous sulphato compounds of Cu(II) and Ni(II), respectively. Because of the discrepancies between the room-temperature crystal structures and the observed decomposition stoichiometries, high-temperature powder diffractograms were taken. These indicated structural changes of the copper(II) compounds during heating. The powder patterns for different structure changes were calculated and compared with the experimental ones. It was shown that during the heating two axial CuH₂O bonds are shortened and two equatorial bonds are lengthened. The observed decomposition stoichiometry is compatible with the formation of four nearly equal Cu-H₂O bonds. The activation energies (E^*) and pre-exponential factors (log A) for the first dehydration reaction of the Cu(II) compounds display the following sequence of M^I: Tl > Rb > NH₄ > K, and they are the higher, the shorter the split equatorial Cu(II) bonds. For the compounds of Ni(II) the sequence of E^* and log A values is K > Tl > NH₄ > Rb > Cs.

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Zusammenfassung Zur Aufklärung des Zusammenhanges zwischen dem Zersetzungsweg und der bekannten Kristallstruktur wurde die thermische Dehydration der Verbindungen M ₂ ^I [M^II(H₂O)₆](SeO₄)₂ mit M^I=NH₄, K, Rb, Cs and Tl sowie mit m^II=Cu und Ni untersucht. Man fand für diese Reaktion die gleiche Stöchiometrie wie für die analogen Sulfatverbindungen von Cu(II) bzw. Ni(II). Wegen des Widerspruches zwischen der Kristallstruktur bei Raumtemperatur und der festgestellten Stöchiometrie der Zersetzungsreaktion wurden auch Pulverdiffraktionsaufnahmen bei höheren Temperaturen angefertigt. Bei Cu(II)-Verbindungen konnte während des Erhitzens eine Strukturänderung festgestellt werden. Für verschiedene Strukturänderungen wurden Pulveraufnahmen berechnet und mit den experimentellen verglichen. Es konnte gezeigt werden, da sich während des Erhitzens zwei axiale Cu-H₂O-Bindungen verkürzen und zwei äquatoriale Bindungen strecken. Die beobachtete Zersetzungsstöchiometrie entspricht der Bildung von vier anänhernd gleichen Cu-H₂O-Bindungen. Die Aktivierrungsenergie (E^*) und der präexponentielle Faktor (log A) und der ersten Dehydratationsreaktion der Cu(II)-Verbindungen sinken in folgender Reihenfolge für M^I:Tl, Rb, NH₄, K und sind umso größer, je kürzer die gespaltenen äquatorialen Cu(II)-Bindungen sind. Für Ni(II)-Verbindungen nehmen E^* und log A in folgenden Reichenfolge ab: K, Tl, NH₄, Rb, Cs.

     

The relationship between the structures of Cu(II) complexes and their chemical transformations

The paper presents the results of a study of the course of thermal decomposition of complexes Cu(NCO)₂L₂ and Cu(LNCO)₂, withL=pyrazole, 3,5-dimethylpyrazole, 3,4,5-trimethylpyrazole and indazole. The DTA curves of Cu(NCO)₂L₂ show exothermic excursions somewhat below the decomposition temperatures, corresponding to an inner complex nucleophilic addition of a carbon atom (from an NCO group) to the imine nitrogen atom of a pyrazole ligand. In this reaction the carbamoylpyrazolate anion is formed, coordinated to Cu(II). For these reactions the DSC method yielded the followingH values: –12.80 kJ mol^–1 (L=pyrazole), –8.15 kJ mol^–1 (L=3,5-dimethylpyrazole), –19.49 kJ mol^–1 (L=3,4,5-trimethylpyrazole) and –11.59 kJ mol^–1 (L=indazole). The course of thermal decomposition for Cu(NCO)₂L₂ after the nucleophilic addition is the same as for Cu(LNCO)₂. The structure differences between the distortion isomers of Cu(NCO)₂L₂ and Cu(LNCO)₂ were manifested in the decomposition temperatures and, in some cases, also in the stoichiometry of the decomposition reactions.

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Zusammenfassung Der Verlauf der thermischen Zersetzung der Komplexe Cu(NCO)₂L₂ und Cu(LNCO)₂ mitL= Pyrazol, 3,5-Dimethylpyrazol, 3,4,5-Trimethylpyrazol und Indazol wurde untersucht. Die DTA-Kurven von Cu(NCO)₂L₂ zeigen etwas unterhalb der Zersetzungstemperaturen exotherme Effekte, die einer inneren komplexen nukleophilen Addition eines Kohlenstoffatoms (von einer NCO-Gruppe) an das Iminstickstoffatom eines Pyrazol-Liganden entsprechen. In dieser Reaktion wird das an Cu(II) koordinativ gebundene Carbamoylpyrazolat-Anion gebildet. Für diese Reaktionen wurden mit der DSC-Methode folgendeH-Werte erhalten: –12,80 kJ· mol^–1 (L= Pyrazol), –8,15 kJ·mol^–1 (L= 3,5-Dimethylpyrazol), –19,49 kJ·mol^–1 (L=3,4,5-Trimethylpyrazol) und –11,59 kJ·mol^–1 (L= Indazol). Nach der nukleophilen Addition zeigt Cu(NCO)₂L₂ den gleichen thermischen Zersetzungsverlauf wie Cu(LNCO)₂. Die Strukturunterschiede zwischen den Distortionsisomeren von Cu(NCO)₂L₂ und Cu(LNCO)₂ manifestieren sich in der Zersetzungstemperatur und, in einigen Fällen, auch in der Stöchiometrie der Zersetzungsreaktion.

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Cu(NCO₂L₂ Cu(LNCO)₂, L=, 3,5- , 3,4,5- . Cu(NCO)₂L₂ , ( NCO) . -, . H: : –12,80 /, 3,5- — –8,15 /, 3,4,5- –19,49 / — – 11,59 /. , Cu(LNCO)₂. — .

     

The relationship between the structures of Cu(II) complexes and their chemical transformations

The paper reports an attempt to correlate the structures of hydrates of copper(II) sulphate with some characteristic features of the kinetics of their thermal decompositions. Non-isothermal thermogravimetric measurements were employed to obtain values of experimental activation energy and entropy for the dehydration of CuSO₄ · 5 H₂O, CuSO₄ · 3 H₂O and CuSO₄ · H₂O. The values ofE ^* andΔS ^* for the dehydration of CuSO₄ · 3 H₂O were found to be only little affected by the mode of preparation of this compound. On the other hand, the values ofE ^* andΔS ^* for the dehydration of CuSO₄ · ·H₂O are strongly dependent on whether this compound was prepared by thermal decomposition of CuSO₄ · 5 H₂O or CuSO₄ · 3 H₂O, or by crystallization from solution. As regards the crystalline hydrates of copper(II) sulphate, the greatest energetic hindrance for dehydration was observed for CuSO₄ · 3 H₂O. The experimental results are also discussed with respect to the present opinions concerning the possibilities of using thermal analyses to obtain information on the relationship between the structures and reactivities of solids.     

On the relationship between the structures of CuII complexes and their chemical transformations

The thermal decomposition of the complexes M ₂ ^I Cu(SO₄)₂ · 6 H₂O and M₂Ni(SO₄)₂ · · 6 H₂O (M^I=NH₄, K, Rb, Tl) containing the complex cation M^II(H₂O)₆ ²+ (M^Il = =Cu, Ni) was studied. The values of the experimental activation energyE obtained for the dehydration reactions of both complex cations were found to be influenced in different ways by the outer-sphere cations present. It was therefore concluded that the activation energy of the decomposition of Cu(H₂O)₆ ²⁺ depends on the degree of tetragonal distortion of this cation, which increases with the ionic radius of cation M^I. TheΔH values of the studied reactions depend less on the structures of the coordination polyhedra.     

Synthesis of platinum complexes of 2-aminomethylpyrrolidine derivatives for use as carrier ligands and their antitumor activities

In order to study a new antitumor platinum complex, various platinum complexes were prepared from 2-amino-methylpyrrolidine derivatives synthesized to serve as carrier ligands and tested for their antitumor activity against Colon 26 carcinoma (s.c.-i.p. system) and P388 leukemia (i.p.-i.p. system) in mice. 2-Aminomethylpyrrolidine proved to be the most effective carrier ligand in its amine derivatives. The structure-activity relationships of the carrier ligands in the platinum complexes with dichloro, oxalato, 1,1-cyclobutanedicarboxylato and dichlorodihydroxo as leaving group were clearly shown on the Colon 26 carcinoma screen and were as follows: the antitumor activity of the platinum complexes with any leaving groups was considerably decreased by the substitution of hydrogen by alkyl group (Me, Et) on nitrogen of aminomethyl and the effects of 1,1-cyclobutanedicarboxylato Pt(II) complexes completely disappeared with the same substitution on nitrogen of pyrrolidine. In all the tested platinum complexes 2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platin um(II) (15) exhibited the most potent antitumor activity. 15 was superior to 1,1-cyclobutanedicarboxylatodiammineplatinum(II) (CBDCA) and similar to cis-diamminedichloroplatinum(II) (CDDP) on the Colon 26 carcinoma screen but it was inferior to CBDCA and CDDP on the P388 leukemia screen. Furthermore, 15 showed more potent antitumor activity than CBDCA against Colon 38 carcinoma (s.c.-i.p. system).     

Synthesis and antitumor activities of novel 1,4-substituted phthalazine derivatives

<正>A series of 1,4-substituted phthalazine derivatives were designed and synthesized.All the prepared compounds were screened for their cytotoxic activities against A549.HT-29 and MDA-MB-231 cell lines in vitro.Among them,compounds 7a-7h showed excellent selectivity for MDA-MB-231 cell line with IC_(50) values from 1 nmol/L to 0.92μmol/L.A preliminary SAR study of these derivatives was performed.     

X-ray structures and pharmacological activities of lidocaine derivatives

The molecular and crystal structures of the lidocaine analogs 2-(pyrazol-1-yl)-2′-methylacetanilide (1), 2-(3,5-dimethyl-4-iodo-pyrazol-1-yl)-2′-methylacetanilide (2), 2-(3,5-dimethyl-4-iodo-pyrazol-1-yl)-3′-methylacetanilide (3), and 2-(pyrazol-1-yl)-4′-methylacetanilide (4), are reported, with a summary of their pharmacological activities. In this series, the moiety comprising the heterocyclic ring and the amide alkyl linker displays a common conformation. Molecules of 1–4 form identical hydrogen bonded motifs in their crystals, namely linear chains via intermolecular N–H···O=C hydrogen bonding. Moderate anesthetic and anti-arrhythmic potencies recorded for 1–4 relative to lidocaine are countered by their significantly lower toxicities.     

The synthesis of carboxymethyl derivatives of purines and pyrimidines and their condensation with naturally occurring macromolecules

1-Carboxymethylthymine, 1-carboxymethylcytosine and 9-carboxymethyladenine were obtained by the direct carboxymethylation of the appropriate bases. In addition a small amount of 3-carboxymethyladenine was obtained. 9-Carboxymethylhypoxanthine was obtained by deamination of 9-carboxymethyladenine. 1-Carboxymethyluracil, 1-carboxymethylthymine and 9-carboxymethyl-hypoxanthine were each condensed with protamine and with dextran to give water-soluble, base-substituted polymers. The 1-carboxymethylthymine-dextran showed a slow decrease in optical density at 268 nm in 2 × SSC at 20°, of 30%. This did not occur in 7M urea. 1-Carboxymethylthymine-dextran gave an additional hypochromic effect with polyadenylic acid in 2 × SSC at 4° or 14° of 13% and 9% respectively. The ratio of thymine: adenine residues at the point of maximum hypochromicity was 3:1. The other dextran derivatives did not show similar hypochromic effects. The 1-carboxy-methylthymine-protamine gave a precipitate with polyadenylic acid probably due to electrostatic interaction.