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MexZ is a transcriptional regulator of the mexXY multidrug transporter operon, which confers aminoglycoside resistance on Pseudomonas aeruginosa. Highly purified MexZ showed direct binding with a specific site of the mexZ-mexX intergenic DNA when probed by a gel retardation assay. Both in vitro chemical cross-linking experiments and an in vivo two-hybrid expression system showed that the active form of MexZ, which is capable of binding the intergenic DNA, appeared to be a dimer. These results explain the mechanism by which MexZ represses transcription of the mexXY operon, but do not explain the substrate-induced hyperproduction of MexXY. The presence of inducer antibiotic in the gel-retardation assay mixture failed to detect altered MexZ-probe DNA interaction suggesting the possible involvement of an additional regulator.

MexZ is a transcriptional regulator of the mexXY multidrug transporter operon, which confers aminoglycoside resistance on Pseudomonas aeruginosa. Highly purified MexZ showed direct binding with a specific site of the mexZ-mexX intergenic DNA when probed by a gel retardation assay. Both in vitro chemical cross-linking experiments and an in vivo two-hybrid expression system showed that the active form of MexZ, which is capable of binding the intergenic DNA, appeared to be a dimer. These results explain the mechanism by which MexZ represses transcription of the mexXY operon, but do not explain the substrate-induced hyperproduction of MexXY. The presence of inducer antibiotic in the gel-retardation assay mixture failed to detect altered MexZ-probe DNA interaction suggesting the possible involvement of an additional regulator.

Instead of the original intermediate dose (0.5 g/m2), a modified intermediate-dose 1-beta-D-arabinofuranosylcytosine (ara-C) therapy (1 g/m2, 1-h intravenous infusion) was pharmacologically studied in 11 leukemic patients.The concentrations of ara-C and its inactive metabolite, 1-beta-D-arabinofuranosyluracil (ara-U) in the plasma, urine and cerebrospinal fluid were determined using high performance liquid chromatography.The plasma ara-C reached a peak (61.2 +/- 52.7 microM) that far surpassed the saturating level for intracellular activation of the drug. The plasma ara-U reached its peak (139.8 +/- 40.0 microM) and was maintained with a half-life of 277 +/- 76 min. About 60% of the administered drug was recovered, mainly as ara-U in urine within 12 h. In contrast to the original intermediate dose, the therapeutic ara-C levels (above 0.4 microM) persisted in the central nervous system. The therapy salvaged one relapsed leukemia patient with central nervous system involvement.Modified intermediate-dose ara-C provides a sufficient plasma ara-C level with a concomitant therapeutic concentration in the cerebrospinal fluid.

HEMATOMA ON THE THORACIC WALL is very rare. Recently we encountered 2 such cases. The first case was a rapidly growing tumor on the thoracic wall in a man with a history of a traffic accident 4 years previously. The second was a tumor on the thoracic wall that had grown slowly for more than 10 years in a man with no history of trauma or illness. We also present a review of the literature of such hematomas. CASE REPORT

1-β-D-arabinofuranosylcytosine (ara-C) is one of the most effective drugs for the reatment of hematologic malignancies, such as acute leukemia and malignant lym-phoma. ara-C is one of the deoxycytidine analogs. In its chemical structure OH residue is introduced at the 2′ position of the sugar. One of the shortcomings of the drug is its rapid metabolism to inactive metabolite, uracil arabinoside (ara-U) in human bodies.1,2 On the other hand, when ara-C is incorporated into the cells, it is converted to ara-CTP, its active form, by deoxycytidine kinase3 (Fig. 1). Thus, the efficacy of ara-C as an antileukemic agents are mainly determined by two factors, deamination to ara-U and activation to ara-CTP.

An improved procedure for the syntheses of the two isomeric 8-chloro (4) and 11-chlorobenzanthrone (6) was devised and their condensation, by Ullmann reaction, to the corresponding dibenzanthronyls was achieved with the object of synthesizing violanthronyl derivatives.The product (mp 118°C) of reduction of 1-chloroanthraquinone (2) by Sn and glacial acetic acid which had been reported to be 4-chloro-9-anthrone (5), was found, by chromatographical separation, to be mixed crystals of two isomeric (5) (mp 137°C) and 1-chloro-9-anthrone (3) (mp 118°C), whose ratio was about 2 : 1.(5) was converted into pure (6) (mp 178°C) in 46% yield by the glycerol condensation. On the other hand, (4) (mp 182°C) obtained from (3) in this manner was the same product as the one obtained by the glycerol condensation of the reduction product of (2) in cone. H2SO4 with Al powder. (2) was converted into isomeric chlorobenzanthrones by a simultaneous reaction of reduction with aniline sulfate and condensation with glycerol. The product was separated by alumina chlomatography to (6) in 18% yield and (4) in 15% yield.Ullmann reaction of (4) and (6) was carried out in naphthalene, and 95% yield of 8, 8'-dibenzanthronyl was obtained from the former, while 11, 11'-dibenzanthronyl was obtained only in 7.8% yield from the latter.

9, 9'-Dihalogeno-3, 3-dibenzanthronyls were prepared as intermediates for the synthesis of diviolanthronyl, a possible high molecular weight dyestuff or a possible electric semiconductor. They were fine yellow crystals and dissolved in concentrated sulfuric acid to give a dark red solution.The 9, 9'-dichloro derivative, mp 4425°C, of 3, 3'-dibenzanthronyl (6) was prepared by the dehydrogenation condensation of 9-chlorobenzanthrone in the presence of magnesium dioxide. 9-Chlorobenzanthrone was obtained by the condensation of α-naphthyl-m-chlorophenylketone in the presence of aluminum chloride or by the partial reduction of 4, 9-dichlorobenzanthrone.Though the 9, 9'-diiodo derivatve, mp 4168°C, of (6) was synthesized in a similar manner from 9-iodobenzanthrone, the reaction was extremely slow and the yield was only 18%. 9-iodo-benzanthrone, mp 1979°C, was prepared in 88% yield by the Griess reaction of 9-aminobenzanthrone in concentrated sulfuric acid.When (6) was treated with an excessive amount of bromine, 9, 9'-dibromo-3, 3'- dibenzanthronyl, mp 4414°C, was obtained in 64% yield. The product was identical with the authentic sample obtained by the dehydrogenation condensation of 9- bromobezanthrone. The 9, 9'-dibromo derivative was also prepared by the bromination of (6) in the presence of catalysts such as aluminum halides.

In the course of the studies of biaryl syntheses of aromatic polycyclic hydrocarbons, the Ullmann condensation of 3- and 9-iodobenzanthrones were carried out. While 3-bromobenzanthrone gave 3, 3'-bibenzanthronyl [5] only in 13% yield, 3-iodobenzanthrone [3] gave [5] in 86% yield with the use of the same activated Cu powder.9, 9'-Bibenzanthronyl [4] (mp 399∼4O1°C) was obtained from 9-iodobenzanthrone [2] in 54% yield by the same procedure as [5]. Characteristic band at 336 nm in UV spectrum of [4] provides evidence for the presence of C-C bond between 9-positions of two benzanthrone nuclei. The ullmann condensation of equimolar mixture of [2] and [3] proceeded under the same reaction concition. The crude products were separated chromatographically to give new unsymmetrical diaryl compound, 3, 9'-bibenzanthronyl [6], in 22% yield, as yellow crystals (mp 388∼390°C). The structure was confirmed by IR and mass spectra, and satisfactory C, H analysis was obtained. The yield of [3] by direct iodination of benzanthrone with iodine and periodic acid was improved to 87% by the addition of small amount of H, SO4.

10-Chlorobenzanthrone (6) was synthesized from chlorobenzene by a 5-stage reaction. In the last stage, p-chlorophenyl-α-naphthylketone had been reported to give (6) only in 5% yield, but it was found that the addition of sodium chloride in the reaction medium increased the yield to 25%.(6) was treated with manganese dioxide in the mixture of polyphosphoric acid and conc. sulfuric acid to give 10, 10′-dichloro-3, 3′-dibenzanthronyl in 29% yield.By the Ullmann coupling reaction of (6), the expected 10, 10′-dibenzanthronyl could not be prepared, but dichlorodibenzanthronyl was obtained.

キナクリドン(キノ[2,3-b]アクリジン-7,14-ジオン)(I)系化合物合成研究の一環として, まず出発物質にP-ベンゾキノン(II)とアントラニル酸(III)を選び, 酢酸中で縮合させて2,5-ジアニリノ-P-ベンゾキノン-o',o''-ジカルボン酸(IV)とし,ついで熱濃硫酸中で脱水閉環反応を行なわせてキナクリドン・キノン(キノ-[2,3-b]アクリジン-6,7,13,14-テトラオン)(V)を合成した。この化合物は試みた有機溶剤にほとんど溶解せず,従ってその精製を目的としてVをいったんカリウム塩とし,ついでこれを酢酸と煮沸してVを再生させ,高収率で純粋かつ鮮明な黄色結晶性粉末を得た。モノカリウム塩はカッ赤色針状結晶であるのに対して,ジカリウム塩は黄色粉末である。またVをアルカリ性ハイドロサルファイト溶液または塩酸とスズ粉末で還元し,両方の場合とも98%の収率で不溶性の青紫色のロイコ体粉末をえた。

The condensation product of benzanthrone (1) with 3-chloro or 3-bromo derivatives of (1) by sodium anilide was seperated by elution chromatography to give 3, 4'-dibenzanthronyl (5) mp. 3389°C, with 3-bromo-anilinobenzanthrone, and other by-products.By the same process as above, new 9-bromo (6) and 9-iodo derivative (7) of 4, 3'-dibenzanthronyl were synthesized from 3-bromobenzanthrone with corresponding 9-halogeno benzanthrone, while, 9-chloro (9) and 9-bromo-3, 4'-dibenzanthronyl (10), both new compounds too, were obtained from (1) and its 3, 9-dichloro or 3, 9 dibromo derivative.

As bifunctional derivatives of 3, 3'-dibenzanthronyl, 9, 9'-diamine (1) and 9, 9'-dicarboxylic acid (2) were synthesized for the purpose of preparing new condensation polymers. Compound (1) was prepared as follows. m-Nitrobenzoyl chloride was treated with naphthalene by Friedel-Crafts reaction to give m-nitrophenyl naphtyl ketone (5), mp 125°C, in 30% yield. The ring closure of (5) proceeded at 100°C with a mixture of AlCl3 and NaCl (5:1), then the reaction mixture was treated in the usual method and seperated chromatographically to give 9-nitrobenzanthrone (6) as pale yellow needles, mp 292°C, in 13.3% yield.The dehydrogenation-condensation of (6) was performed under the conditions similar to those for the syntheses of 3, 3'-dibenzanthronyl and its halogen derivatives to give 9, 9'-dinitro-3, 3'-dibenzanthronyl (7), mp>460°C, in 20% yield, which was identified by i.r. spectra and elemental analysis.(8) was reduced by Pd-charcoal and hydrazine hydrate in DMF, to give red violet crystalline powder, mp>500°C, which was identified as (1). (1) was also characterized by comparing with the product obtained by ammonolysis of 9, 9'-dichloro-3, 3'-dibenzanthronyl with 28% aq. ammonia in the presence of As2O5.3, 3'-Dibenzanthronyl-9, 9'-dicarboxylic acid (2), mp 431°C, was synthesized by the oxidation of 9, 9'-dimethyl derivative (16) with KMnO4 in pyridine. The structure of (2) was identified by elemental analysis, i.r. and mass spectrometry. (16) was prepared by the same method as (7), but with shorter reaction time, from 9-methylbenzanthrone (15), as pale yellow needles, mp 3836°C, in 20% yield. Ring closure of 1-naphthyl-m-toluylketone (14) proceeded easily according to Fieser, in 48% yield, but there remained some problems in the synthesis of intermediates, such as m-toluic acid.Partial oxidation of m-xylene is known to give m-toluic acid (12) but in poor yields (less than 10%). We have oxidized m-xylene by dil-HNO3 in the presence of Co salt of naphthenic acid, and obtained (12) (mp 112°C) in 17% yield. Friedel-Crafts condensation of m-toluyl chloride with naphthalene gave (14), mp 75°C, in 33% yield.

Though a pyrazole hydroazine vat dye (1) was formed by the direct cyclization of pyrazoleanthrone with 1-amino-2-bromoanthraquinone, the yield was as low as 10%. I, however, was obtained in 58% over-all yield in a two -step synthesis via cyclization of the intermediate, 2-(1'-amino-2-anthraquinonyl)-pyrazoleanthrone, in pyridine-methanol containing potassium hydroxide . 2-(2'-Aminophenyl)-pyrazoleanthrone was also readily cyclized into a pyrazole hydroazine compound . Similar reactions using 2-(3'-pyrazoleanthronyl)-pyrazoleanthrone and 3-anilino - pyrazoleanthrone, however, failed to take place. It is assumed that the cyclization reaction proceeds through a link formation between a -NH anion formed as shown below and a carbonium cation induced by the electron withdrawing effect of the carbonyl group in the pyrazoleanthrone ring.

The direct iodination of benzanthrone and 3, 3'-dibenzanthronyl with a mixture of various oxidizers and iodine in acidic, neutral and basic media has been studied.Iodination products were separated and purified by alumina column chromatography. When benzanthrone was iodinated with a mixture of periodic acid and iodine dissolved in polyphosphoric acid and 98% sulfuric acid, 3, 9-diiodobenzanthrone was obtained in 76% yield. 3-Iodobenzanthrone was obtained in a maximum yield of 52% in acetic acid with the same oxidizing agents.From 3, 3'-dibenzanthronyl, 9-iodo-3, 3'-dibenzanthronyl was synthesized in a maximum yield of 58%.

A hexa-aza-macrocyclic compound of high thermal stability is readily obtained from 2,9-diamino-1,10-phenanthroline by its thermolysis or by its condensation with 2,9-dihalogeno-1,10-phenanthroline. The structure of this macrocycle has been established as a conjugated system of a novel type, related to some extent to porphin and phthalocyanin. The macrocyclic compound forms copper, cobalt, and nickel complexes.

The dipole moment of acenaphthene (I) was measured in the gaseous phase as 0.93D. Measurement in benzene solution at 25°C gave the following moment values: acenaphthene (I) 0.85D; 5-chloroacenaphthene (II) 2.50D ; and 5,6-dichloroacenaphthene (III) 3.85D. By the comparison with the moments of naphthalene derivatives it was shown that the moments of (II) and (III) are approximately equal to the sums of the moment of (I) and the moments arising from one and two C–Cl bonds, respectively.

The patient is a male of 52 year old and holds managerial position. He suddenly devloped left leg pain and low back pain seven years ago, which were followed by similar pain on his right leg and visited this hospital one year later. On X-ray examination, his right femoral head showed an image of spotty sclerosis and his left femoral head showed a punched-out image of sclerosis and spurs in its inside. As time went by, his symptoms were aggravated, and deformities of femoral heads and bone sclerosis progressed. However, owing to conservative treatment, his clinical symptoms have been alleviated and he walks quite normally now, but with a moderate limitation on internal rotation of hip joints. On X-ray, defor mities of both femoral heads are moderate, but bone sclerosis appears to have become less conspicuous and to be remedied. It would be necessary to follow up this case for an extended period of time.

Condensation of 2,9-diamino- and 2,9-dichloro-1,10-phenanthroline gave a novel macrocyclic ligand in excellent yield.