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1. Introduction The performance of a SiC MOSFET has not reached the level predicted based on the physical properties of SiC. One of the reasons is that interface state density (Dit) at SiO2/SiC is more than an order of magnitude higher than that at SiO2/Si. [1] Therefore, it is a key for improving the performance of SiC MOSFET to clarify the origin of Dit and SiO2/SiC interface structure formed by thermal oxidation, and to control interface structure based on the knowledge. We have reported the results of the changes in chemical bonding state of SiO2/4H-SiC (0001(_)) (C-face) and 4H-SiC (0001(-)) (Si-face) structure with the progress of thermal oxidation using angle-resolved X-ray photoelectron spectroscopy (AR-XPS). [2, 3] In this paper, we report the results the initial stage of thermal oxidation on 4H-SiC (0001) on-axis and 4° off-axis substrates. 2. Experimental Method 4H-SiC (0001) epitaxial films with on-axis and 4° off-axis were used in this study. We used the flattened 4H-SiC(0001) surface with on-axis which is composed of alternating wide and narrow terraces with single-bilayer-height steps. [4] The samples were prepared as follows. The sample was cleaned in the mixture of H2SO4 and H2O2 (H2SO4:H2O2=4:1) at 80-85 ºC, and the native oxide was removed by dipping in 5% hydrofluoric acid (HF) followed by a rinse in deionized water. The sample was oxidized at 850 °C in dry oxygen with a pressure of 133 Pa. Then, the sample was oxidized in dry oxygen with a pressure of 133 Pa at 900 °C. Subsequently, the sample was oxidized in dry oxygen with a pressure of 133 Pa at 950 °C, 1000 °C and 1050 °C. The Si 2p and C 1s photoelectron spectra, excited by monochromatic AlKα radiation, were measured at a photoelectron take-off angle of 15 and 90 with an energy resolution of 0.37 eV and an acceptance angle of 3.3°, using an ESCA-300 manufactured by Scienta Instruments AB [5]. 3. Result and Discussion The analyses of Si 2p 3/2 photoelectron spectra arising from the sample of on-axis 4H-SiC(0001) (Fig. 1) show that the oxide increases with the increase of oxidation time. The analyses of C 1s photoelectron spectra show that the component with higher binding energy (chemical shift of about 2eV) is reduced by the oxidation. The measured spectra in Si 2p and C 1s regions were also decomposed into peaks convolution of Gaussian and Lorentzian as shown in Fig. 1 (b) and Fig. 2 (b). Fig. 3 shows the oxide thickness dependence of spectral intensity ratio in the case of samples of the on-axis and 4° off-axis 4H-SiC(0001). As seen in Fig. 3, the intensity ratio ISi3+/ISiC in the case of the on axis 4H-SiC(0001) is larger than that in the case of the 4° off-axis 4H-SiC(0001). In the addition, the intensity ratio ISi1+/ISiC and ISi2+/ISiC in the case of the on axis 4H-SiC(0001) is smaller than that in the case of the 4° off-axis 4H-SiC(0001). These imply that there is the defference in SiO2/SiC interfce structure between on-axis 4H-SiC(0001) and 4° off-axis 4H-SiC(0001). Here, ISi1+, ISi2+, ISi3+, and ISiC denote the intensity of component related to Si1+, Si2+, Si3+ and SiC, respectively. Figure 4 shows the oxidation time dependence of oxide thickness in the case of the on-axis and 4° off-axis 4H-SiC(0001) oxidized at the range from 850℃ to 1050℃. As seen in Fig. 4, the oxidation rate decreases at the oxide thickness of 0.6nm in both the on-axis and 4° off-axis 4H-SiC(0001). This implies that the oxidation rate decreases when the 1 ML SiO2was formed by the oxidation. There isn't difference in the oxidation rate between on-axis and 4° off-axis 4H-SiC(0001). 4. Conclusions From the changes of the Si 2p 3/2 and C 1s photoelectron spectra, a changes in chemical bonding state of SiO2/SiC structure with the progress of thermal oxidation were observed. We found that there is the defference in SiO2/SiC interfce structure between on-axis 4H-SiC(0001) and 4° off-axis 4H-SiC(0001). References [1] G. Y. Chung, et al., IEEE Electron Device Lett., vol. 22, pp.176-178, no.4, Apr 2001. [2] T. Sasago, et al., ECS Transactions, 64(7) 245 (2014) [3] H. Arai et al., Jpn. J. Appl. Phys. 55, 04EB04 (2016). [4] K. Arima et al., Appl. Phys. Lett. 90, 202106 (2007). [5] U. Gelius, et al., J. Electron Spectrosc. Rel. Phen. 52, 327 (1990). Figure 1

Graft-copolymerization of vinyl monomer containing silica precursor, p -styryltrimethoxysilane, onto natural rubber microparticles was performed in latex stage to form three-dimensional networks of nanosilica. After the latex was cast into a film, morphology observation by transmission electron microscopy showed that the natural rubber microparticles were dispersed in organic–inorganic nanomatrix consisting of vinyl polymer and silica nanoparticles. In particular, generation of large silica particles was prevented by slow rate of hydrolysis and condensation of silicon alkoxides for p -styryltrimethoxysilane and the nanosilica networks were formed. The nanomatrix structure with the nanosilica networks increased tensile strength of the rubber, and destruction of the structure decreased the strength. Master curves of dynamic moduli of the rubber showed that the value of storage modulus at rubbery plateau region was high and it was almost flat at low-frequency region because of the nanosilica networks.

Here we report the facile network formation of a methacrylate polymer containing polyhedral oligomeric silsesquioxane (POSS) in the side chain by a dynamic cage-scrambling reaction mediated by fluo...

We present the effects of an In-Se surface treatment of Cu-rich ([Cu]/[In] > 1) CuInSe2 absorbers in order to utilize the superior transport properties of Cu-rich absorbers for high-efficiency solar cells. A Cu-poor surface was successfully formed on a Cu-rich absorber by co-evaporation of indium and selenium under appropriate conditions. The aim is to suppress the interface recombination, which is generally observed at the interface between CdS and Cu-rich CuInSe2. A surface-treated device achieved an efficiency of 13.1%, improved from 9.5% obtained with an untreated Cu-rich device. The open-circuit voltage of In–Se treated devices reach the same level as devices made from Cu-poor absorbers grown by a three-stage process. By comparing the results of the experiments and simulations, it is shown that the role of the Cu-poor surface on Cu-rich absorbers is to prevent interface recombination, mainly due to a lower doping level of the Cu-poor surface layer than in the Cu-rich CuInSe2. Thus, it becomes possible to uncouple the interface from the bulk properties in Cu-rich solar cells. Copyright © 2014 John Wiley & Sons, Ltd.

We report the design and synthesis of two new mitomycin dimers, 7-N,7'-N'-(1″,2″-dithiepanyl-3″,7″-dimethylenyl)bismitomycin C (8) and 7-N,7'-N'-(2″,6″-dihydroxy-1″,7″-heptanediyl)bismitomycin C (9). Mitomycins 8 and 9 are dimers connected by a seven-membered cyclic disulfide (a 1,2-dithiepane) and a 2,6-dihydroxyheptane linkers, respectively. Mitomycin 8 was designed to undergo efficient nucleophilic activation and following alkylation to give DNA adducts such as DNA interstrand cross-link (DNA ISC) adducts. The key moiety in 8 is a seven-membered cyclic disulfide linker that can generate two thiol groups in a molecule through disulfide cleavage. The two thiols can serve as probes to activate two mitomycin rings by intramolecular cyclization to quinone rings. The mitomycin 8 was synthesized using mitomycin A (1) and the key intermediate, cyclic disulfide 11 that was prepared through a nine-step synthetic sequence from 1,6-heptadiene (12). The diol mitomycin 9 was also synthesized from 1 and diamine salt 15.

In this paper we study a spiral illusion generated by fractal islands. Furthermore, by a neuro-scientific consideration we present a new class of geometrical illusions. In order to analyse these illusions, we propose a new mathematical method.

Purpose: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700. Experimental Design: The antileukemia activity of FI-700 was evaluated in human leukemia cell lines, mutant or wild-type (Wt)-FLT3–expressing mouse myeloid precursor cell line, 32D and primary acute myeloid leukemia cells, and in xenograft or syngeneic mouse leukemia models. Results: FI-700 showed a potent IC50 value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)–driven growth of Wt-FLT3–expressing cells. These antileukemia activities were induced by the significant dephosphorylations of mutant FLT3 and STAT5, which resulted in G1 arrest of the cell cycle. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. In this experiment, the depletion of FLT3/ITD-expressing cells by FI-700 was more significant than that of Ara-C, whereas bone marrow suppression by FI-700 was lower than that by Ara-C. Conclusions: FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity.

As is well known in neuroscience, simple cells of the mammalian’s striate cortex possess both orientation and spatial-frequency selectivity, and are similar to the Gabor filters or Gaussian derivative filters in shape. The purpose of this paper is to propose a method of designing perfect reconstruction 2D filterbanks which act on finite dimensional linear spaces consisting of 2D signals of a certain size, and have several analogous features to simple cells: (1) the filterbanks consist of several spatial-frequency channels with orientation selectivity, (2) the filterbanks have shift-invariant multiresolution (multiscale) structures, (3) filters contained in them are FIR, and are similar in appearance to not only Gaussian derivatives of 1st and 2nd order, but also ones of higher order. Moreover, they are constructed by finite linear combinations of separable filters. As is described in the text, by virtue of these properties, our 2D filterbanks can become bases of constructing computational nonlinear models of visual information processing. In this paper we construct the 2D filterbanks, and discuss them from the viewpoint of vision science. For example we disclose a possible role of “Gaussian-derivative-like” filters of higher order in our filterbanks. Practical applications of our 2D filterbanks to vision science and image processing will be given in our subsequent papers.

In this survey paper we will deal with applications of our study of mathematical models of visual information processing in the brain. In particular, we will show some of our results on sharpening, edge enhancement and extraction of contours of objects in an image.

A convenient large-scale preparation of the indoloquinone antitumor agent EO9 has been developed. A Nenitzescu reaction has been used to prepare the indole skeleton having all functional groups necessary for its conversion into a key intermediate in a short synthesis of the indoloquinone EO9. Moreover, the hazardous reagent, Fremy's salt was replaced by safer one, [bis (trifluoroacetoxy) iodo] benzene, for oxidation of the 4-aminoindole to the corresponding indoloquinone, and high quality EO9 was easily obtained by choosing acetonitrile as the solvent in the substitution reaction of the methoxy group with ethylenimine to introduce the aziridinyl group into the precursor.

This chapter is a survey of a series of joint works of Shinobu Arai and me. The main purpose of our study is to construct mathematical models of visual information processing in the brain, and to give applications to study of visual illusions and image processing. In this chapter I will describe a part of our simulations of some visual illusions, creations of the so-called “fuyuu illusions”, and an application to image processing.

In this paper, we define an appropriate version of Morrey spaces for spaces of homogeneous type. As our main result, we give a sufficient condition for an operator to be bounded on the version of Morrey spaces (cf. Theorem 3.1 and Corollary 3.5). Moreover, using thin result, we prove Morrey space estimates for various operators arising in harmonic analysis and complex analysis of several variables.

The cell growth inhibitory activity, antitumor activity and toxicity of M-16 and M-18, the major metabolites of a new mitomycin C (MMC) derivative KW-2149, in mouse and human were compared with those of KW-2149 or MMC in vitro and in vivo. The growth inhibitory activity of M-18, a symmetrical disulfide dimer, against human uterine cervix carcinoma HeLa S3 cells was almost equivalent to that of KW-2149 and their IC50 values were about 10-fold smaller than that of MMC. The activity of M-16, a methyl sulfide form, was almost equivalent to that of MMC. The cell-killing activity of MMC and M-16 was augmented in the hypoxic condition, whereas that of KW-2149 and M-18 was reduced. M-16 also exhibited almost equivalent activities to MMC in vivo in terms of many biological profiles, i.e., antitumor activity against murine P388 leukemia, ascitic or solid B16 melanoma or human lung carcinoma xenograft L-27, and bone marrow toxicity in mice. These in vitro and in vivo results indicate that the antitumor activity and toxicity of KW-2149 might not be mediated by M-16 in mice. On the other hand, M-18 exhibited almost equivalent activities to KW-2149 in these regards, suggesting the involvement of M-18 in the biological activities of KW-2149. However, the small values of the area under the curve of M-18 in mice make this unlikely. Thus the biological activities of KW-2149 in mice are not explained by the M-16 or M-18 concentration in plasma and are postulated to be manifested by KW-2149 itself.

Modification studies describing the synthesis of a number of mitomycin derivatives that have appeared in the patent literature during recent years are reviewed. Particular emphasis is placed on the design of the derivatives and their preparation. Biological activities, reaction schemes and structure-activity relationships for the derivatives are also mentioned in this review.

A series of 6-demethylmitomycins and 6-demethyl-6-halomitomycins having various mitomycin skeletons were synthesized, taking into account the electronic effect toward the quinone moiety and the partition coefficients. Treatment of enones 15 and 16 with selenenamide or N-halosuccinimide-Et2NH afforded the 6-demethyl intermediates 17, 18, and 21-24 via the tandem Michael addition/retro-Mannich reaction sequence. Subsequent conversions into the mitomycin skeletons resulted in the formation of the desired derivatives 7a-c, 8a-c, 11a-c, and 12a,b. These mitomycin derivatives including 3a-c and 4a-c were evaluated for their anticellular activity against HeLa S3 cells and antitumor activity against Sarcoma 180 in mice. The anticellular activity of 1 and 3a-c depends on the substituent at the C-6 position and the order of increasing activity is H < CH3 < Br < Cl. A similar tendency was observed in their antitumor potency (ED50). The activities of 9 and 11a-c also follow a pattern similar to that of 1 and 3a-c. Compounds 4b,c, 8b,c, and 12b having both a halogen at the C-6 position and a methoxy group at the C-7 position did not show the activities because of the instability of the compounds. Interestingly, a correlation between the anticellular activity (IC50) and the partition coefficients (log kappa') determined by HPLC was observed within the compounds studied except the unstable compounds, while their antitumor activity (ED50 or T/C) did not correlate with the quinone reduction potential (E1/2). These results would indicate the importance of the C-6 substituents and the mitomycin skeletons for exhibiting both anticellular and antitumor activities.

A key to improving the performance of SiC MOSFETs is to clarify the SiO2/SiC interface structure formed by thermal oxidation. We have investigated the initial stage of thermal oxidation on 4H-SiC(0001) by angle-resolved photoelectron spectroscopy. From the changes in the Si 2p3/2 and C 1s photoelectron spectra, the changes in the chemical bonding state of the SiO2/SiC structure with the progress of thermal oxidation were observed. We also found that the intensity of C–O bonds in the case of 4H-SiC(0001) was smaller than that in the case of 4H-SiC( ) with the same oxide thickness and that the oxidation rate of 4H-SiC(0001) is already slower than that of 4H-SiC( ) in the early stage of oxidation.

A case of cystic tumor due to a retained surgical sponge is reported. A 47-year-old man who had a surgery for gastric ulcer 6 years befor was seen at the department with a diagnosis of pancreatic systic tumor which was made elsewhere. With some examinations the patient was diagnosed as foreign body granuloma and operated on. An elliptical shadow with smooth surface was seen in a abdominal X-ray film. But the main pancreatic duct was normal in ERCP examination. The original organ of the tumor was not able to be determined by angiography. Ultrasonography visualized cystic mass with distinct internal echoes and the internal echoes were occationally curvelinear in shape and floating. Foreign body granuloma is not a common entity. When we encounter a patient with these characteristic findings who has a previous history of undergoing laparotomy, the correct diagnosis can be made by entertaining a possibility of this rare disease.

Synthesis of novel 6-demethyl-6-halomitomycins (3, 4, 6, and 7) and 6-demethyl;6-thiomitomycins (5 and 8) is described from key intermediates, namely, 6-demethyl-7,7-(ethylenedioxy)-6,6-dihalo-6,7-dihydromitosanes (18 and 19) and 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-thiomitosane (20), respectively. Compounds 18-20 were prepared through a tandem Michael addition and a retro-Mannich reaction sequence (N-halosuccinimide or cationic arylsulfenyl species in the presence of Et 2 NH) on 10

A new female-specific protein has been discovered to be a major component of fat body proteins of the last larval instar of Antheraea pernyi and Antheraea yamamai . The new female-specific protein was purified to homogeneity by gel-permeation chromatographies, DE-52 cellulose column chromatography and hydroxyapatite column chromatography. The molecular weight of the protein was estimated to be 24,000 by SDS-PAGE and 43,000 by gel-permeation chromatography, suggesting that the protein is a homodimer protein. The protein was temporarily named “24 kDa peptide” (24K). Developmental changes in 24K titer were followed from the final larval ecdysis to adult emergence by immunoblotting with a specific antiserum against 24K. 24K appeared in the fat bodies at day 9 fifth instar and remained at an almost constant level up to adult emergence. Immunoblot analysis using antisera against Bm 30K proteins and BmLSP showed that the immunological properties of 24K were different from those of these proteins. In vitro culture to label fat body proteins with [ 35 S]-methionine showed that the synthesis of 24K occurred in only female fat bodies. The function of 24K remains unknown.

Photochemical oxetane formation by addition of 1-methyl-2,4,5-triphenylimidazole (1a), 1,2-dimethyl-4,5-diphenylimidazole (1b), and 1-acetylimidazole (1c) to benzophenone (BP), poly(4-vinylbenzophenone) (PVBP), and poly(styrene-co-4-vinylbenzophenone) (PSVBP) was studied in the solution and solid phases. In solution, BP underwent the photoaddition smoothly to all three imidazoles 1a–1c. On the other hand, the photoaddition of PVBP and PSVBP depended on the imidazole employed, that is, 1b and 1c produced the corresponding oxetane, but 1a did not. The lack of oxetane formation from the polymeric BP and 1a is probably due to a rapid triplet-sensitized decomposition of a once-formed oxetane ring as a result of the intramolecular triplet energy transfer from a pendant benzophenone group. © 1993 John Wiley & Sons, Inc.

In this paper we give some characterizations of BMOA functions in terms of Kahler diffusions and Carleson measures on the unit ball in C n n1 (see Theorem 1). This result implies Carleson measure characterizations of BMOA obtained recently by Choa and Choe [2] and Stanton [19]. Furthermore, as a corollary we prove that the spaces BMOA and BMO are isomorphic to closed complemented subspaces of a space of BMO martingales. From this it follows a non-isotropic version of Garnett-Jones theorem.

KW-2149, a new mitomycin C (MMC) derivative, inhibited the growth of murine P388 leukemia in vitro at 20-fold lower concentrations than those of MMC. KW-2149 was also effective in inhibiting the growth of MMC-resistant P388 (P388/MMC) cells. To elucidate these characteristics of KW-2149, its uptake and efflux were compared with those of MMC in MMC-sensitive and -resistant P388 cells. Both MMC and KW-2149 accumulated rapidly in P388 cells after incubation at the concentration of 0.47 and 0.024 microM, respectively, which were the IC50 values at 1-h exposure. Although this concentration of KW-2149 was 20 times lower than that of MMC, its intracellular concentration was little more than that of MMC, suggesting that KW-2149 accumulated in the cells quite efficiently. The accumulated KW-2149 in the cells after 1-h treatment remained for as long as 24 h after the incubation of the cells in drug-free medium, suggesting that most of the intracellular KW-2149 or MMC was bound to cellular components. The ratios of resistance of P388/MMC cells to MMC and KW-2149 were 34 and 8.8, respectively, at 1-h exposure, suggesting that P388/MMC cells were partially resistant to KW-2149 in vitro. P388/MMC cells also showed partial resistance to cisplatin, Adriamycin, m-AMSA, and etoposide. The accumulation of MMC in P388/MMC cells was lower than that in P388 cells, although the size of the former cells was almost equal to that of the latter. As a result, the amount of DNA-bound MMC was lower in P388/MMC cells than in P388 cells, suggesting its involvement in the mechanisms of MMC resistance in P388/MMC cells.

The photocyclization of 2-[2-(2-chlorophenyl)vinyl]-6-methylpyridine and 2-[2-(2-chlorophenyl)vinyl]quinoline in acetonitrile afforded new compounds 1-methylbenzo[c]quinolizinium salt and dibenzo[c,f]quinolizinium salt in 56% and 41% yields, respectively.

Six isomers of the methylbenzo[c]quinolizinium salt 3 including four new monomethyl derivatives were synthesized by thermal-intramolecular quaternization of the cis-methyl-substituted 2-[2-(2-chlorophenyl)-vinyl]pyridines 4 or by the irradiation of trans-4 with selected wavelengths (290 400 nm) in acetonitrile. Among the regioisomeric monomethyl derivatives 3, the 1-, 3-, and 6-methyl derivatives 3b, 3d, and 3g reacted with p-methoxybenzaldehyde in the presence of bis(l-piperidino)-(p-methoxyphenyl)-methane 7 to yield trans-(p-methoxystyryl)benzo[c]quinolizinium salts 6. The reactivity of 3 and methylbenzo[a]quinolizinium salts 1 was discussed on the basis of their π-electron energy.

Synthesis of novel 6-demethyl-6-halomitomycins (3, 4, 6, and 7) and 6-demethyl;6-thiomitomycins (5 and 8) is described from key intermediates, namely, 6-demethyl-7,7-(ethylenedioxy)-6,6-dihalo-6,7-dihydromitosanes (18 and 19) and 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-thiomitosane (20), respectively. Compounds 18-20 were prepared through a tandem Michael addition and a retro-Mannich reaction sequence (N-halosuccinimide or cationic arylsulfenyl species in the presence of Et 2 NH) on 10

A series of 6-alkyl-6-demethylmitomycins (1-5) was synthesized and eva- luated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various carbanion species to 6-de- methyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosane (6 and 9) followed by treatment with NH 3 or MeOH/K 2 CO 3 . Alkylation at the C-6 position of 6-demethyl-6-selenide (7) was also useful for the alterna- tive synthesis of 6-alkyl-6-demethylmitomycins. The antitumor activity of these derivatives was evalulated, and 6-demethyl-6-ethylmitomycin A (2a) was found to exhibit excellent activity against S-180 solid tumor in mice. The structure-activity relationship is also discussed

A series of C-6-substituted methyl mitomycins was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various alcohols or thiols to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosanes followed by treatment with NH3 or MeOH/K2CO3. Most compounds were potent against HeLa S3, and some of them showed superior activity to that of mitomycin C (MMC) against P388 leukemia and sarcoma 180 in mice. In addition, some compounds exhibited remarkable activity against MMC-resistant P388 in mice. FAB-MS spectra of these mitomycin derivatives showed the elimination of the C-6-methyl substituents from the mitomycin skeletons to form quinonemethides. Interestingly, treatment of 6-demethyl-6-[[(2-pyrimidinyl)thio]methyl ]mitomycin C (12v) with diethylamine afforded 6-demethyl-6-[(diethylamino)methyl]mitomycin C (31) in good yield. These results suggested that the C-6-substituted methyl mitomycins would have different biological character from that of MMC.

A series of mitomycin derivatives 1-3 having unique condensed-ring structures was synthesized and evaluated for their anticellular and antitumor activity. These compounds were synthesized by the Michael addition of 1, 3-dicarbonyl compounds to 6-demethyl-7, 7-(ethylenedioxy)-6, 7-dihydro-6-methylenemitosanes (4-6, and 14) and the subsequent cyclization. For the preparation of 1, the allyloxycarbonyl (Aloe) group was employable for the protection of the aziridine (1a-N-H), since the deprotection proceeded without decomposition of the substrates under the mild conditions with Pd(0) and HCO2H-NEt3. Among these structurally unique derivatives, compounds 1a, 1b, 1d and 1e were quite potent against HeLa S3 human tumor cells and sarcoma 180 solid tumor in mice.

A series of 6-demethylmitomycins and 6-demethyl-6-halomitomycins having various mitomycin skeletons were synthesized, taking into account the electronic effect toward the quinone moiety and the partition coefficients. Treatment of enones 15 and 16 with selenenamide or N-halosuccinimide-Et2NH afforded the 6-demethyl intermediates 17, 18, and 21-24 via the tandem Michael addition/retro-Mannich reaction sequence. Subsequent conversions into the mitomycin skeletons resulted in the formation of the desired derivatives 7a-c, 8a-c, 11a-c, and 12a,b. These mitomycin derivatives including 3a-c and 4a-c were evaluated for their anticellular activity against HeLa S3 cells and antitumor activity against Sarcoma 180 in mice. The anticellular activity of 1 and 3a-c depends on the substituent at the C-6 position and the order of increasing activity is H < CH3 < Br < Cl. A similar tendency was observed in their antitumor potency (ED50). The activities of 9 and 11a-c also follow a pattern similar to that of 1 and 3a-c. Compounds 4b,c, 8b,c, and 12b having both a halogen at the C-6 position and a methoxy group at the C-7 position did not show the activities because of the instability of the compounds. Interestingly, a correlation between the anticellular activity (IC50) and the partition coefficients (log kappa') determined by HPLC was observed within the compounds studied except the unstable compounds, while their antitumor activity (ED50 or T/C) did not correlate with the quinone reduction potential (E1/2). These results would indicate the importance of the C-6 substituents and the mitomycin skeletons for exhibiting both anticellular and antitumor activities.

A Nenitzescu reaction has been used to prepare the indole skeleton 6 having all the functional groups necessary for its conversion into 10a, a key intermediate in a short synthesis of the indolequinone EO 9.

A convenient large-scale preparation of the indoloquinone antitumor agent EO9 has been developed. A Nenitzescu reaction has been used to prepare the indole skeleton having all functional groups necessary for its conversion into a key intermediate in a short synthesis of the indoloquinone EO9. Moreover, the hazardous reagent, Fremy's salt was replaced by safer one, [bis (trifluoroacetoxy) iodo] benzene, for oxidation of the 4-aminoindole to the corresponding indoloquinone, and high quality EO9 was easily obtained by choosing acetonitrile as the solvent in the substitution reaction of the methoxy group with ethylenimine to introduce the aziridinyl group into the precursor.

The role of DT-diaphorase (DTD, EC 1.6.99.2) in the bioreductive activation of mitomycin C was examined using purified rat hepatic DTD. The formation of adducts with reduced glutathione (GSH), binding of [3H]mitomycin C to DNA, and mitomycin C-induced DNA interstrand cross-linking were used as indicators of bioactivation. Mitomycin C was metabolized by DTD in a pH-dependent manner with increasing amounts of metabolism observed as the pH was decreased from 7.8 to 5.8. The major metabolite observed during DTD-mediated reduction of mitomycin C was 2,7-diaminomitosene. GSH adduct formation, binding of [3H]mitomycin C and mitomycin C-induced DNA interstrand cross-linking were observed during DTD-mediated metabolism. In agreement with the pH dependence of metabolism, increased bioactivation was observed at lower pH values. Temporal studies and experiments using authentic material showed that 2,7-diaminomitosene could be further metabolized by DTD resulting in the formation of mitosene adducts with GSH. DNA cross-linking during either chemical (sodium borohydride) or enzymatic (DTD) mediated reduction of mitomycin C could be observed at pH 7.4, but it increased as the pH was decreased to 5.8, showing the critical role of pH in the cross-linking process. These data provide unequivocal evidence that the obligate two-electron reductase DTD can bioactivate mitomycin C to reactive species which can form adducts with GSH and DNA and induce DNA cross-linking. The use of mitomycin C may be a viable approach to the therapy of tumors high in DTD activity, particularly when combined with strategies to lower tumor pH.

Six isomers of the methylbenzo[c]quinolizinium salt 3 including four new monomethyl derivatives were synthesized by thermal-intramolecular quaternization of the cis-methyl-substituted 2-[2-(2-chlorophenyl)-vinyl]pyridines 4 or by the irradiation of trans-4 with selected wavelengths (290 400 nm) in acetonitrile. Among the regioisomeric monomethyl derivatives 3, the 1-, 3-, and 6-methyl derivatives 3b, 3d, and 3g reacted with p-methoxybenzaldehyde in the presence of bis(l-piperidino)-(p-methoxyphenyl)-methane 7 to yield trans-(p-methoxystyryl)benzo[c]quinolizinium salts 6. The reactivity of 3 and methylbenzo[a]quinolizinium salts 1 was discussed on the basis of their π-electron energy.

A facile synthesis of the title compounds 2 and 3 is described. The key intermediate in the synthesis, 6-demethyl-7,7-(ethylenedioxy)-6-(phenylselenenyl)mitosane (4) was synthesized in five steps from mitomycin A. Treatment of 4 with [14C]methyl iodide in the presence of K2CO3 afforded the [14C]-labelled mitosane (5). The removal of the phenylselenenyl group of 5 and subsequent treatment of the resultant mitosane 7 with ammonia led to the desired [14C]mitomycin C (MMC) (2) with specific activity of 50 mCi/mmol. Similarly, [3H]-labelled MMC (3) with highly specific activity of 78.4 Ci/mmol was obtained.

5-(1,3,4-Oxadiazol-2-yl)pyrimidine derivative 1 was identified as a new class of FLT3 inhibitor from our compound library. With the aim of enhancement of antitumor activity of 2 prepared by minor modification of 1, structure optimization of side chains at the 2-, 4-, and 5-positions of the pyrimidine ring of 2 was performed to improve the metabolic stability. Introduction of polar substituents on the 1,3,4-oxadiazolyl group contributed to a significant increase in the metabolic stability. As a result, a series of compounds showed increased efficacy against MOLM-13 xenograft model in mice by oral administration.