Synthetic anthracyclines: regiospecific total synthesis of D-ring thiophene analogues of daunomycin

The key anhydride 2-acetoxy-[2-carboxy-5-(trimethylsilyl)thiophen-3-yl]acetic acid anhydride (8), prepared from (2-carboxythiophen-3-yl)acetic acid (5), underwent a strong base-induced cycloaddition reaction with the chloroquinone acetal (11) to give the 7,7-ethylenedioxy-2-trimethylsilyl-6,7,8,9- tetrahydroanthra[2,3-b]thiophene-5,10-dione (12) regioselectively. Similarly, the regioisomeric 8,8-ethylenedioxy-2-trimethylsilyl-6,7,8,9-tetrahydroanthra[2,3-b] thiophene- 5,10-dione (30) was obtained by the strong base-induced cycloaddition reaction of 8 with the chloroquinone acetal (29). These cycloadducts (12 and 30) were converted to D-ring thiophene analogues (28 and 38) of daunomycin (1a). Another D-ring thiophene analogue (42) which has a trimethylsilyl substituent in the D-ring was also prepared.     

Pyrimidine derivatives. VI. Synthesis of mono-, di-, tri-, and tetrabromo-substituted pyrimidine derivatives

The following bromo-2,4(1H,3H)-pyrimidinediones possessing a bromo substituent at the 5-position and side chains at the 1- and 6-positions were prepared. The three types of mono-bromo derivatives are: 1-(bromoalkyl)-3,6-dimethyl- 3a-d , 5-bromo-3,6-dimethyl-1-(hydroxyalkyl)- 4a-d , and 1-(acetoxyalkyl)-5-bromo-3,6-dimethyl-2,4(1H,3H)-pyrimidinediones 11a-d . The three types of dibromo derivatives are: 5-bromo-1-(bromoalkyl)-3,6-dimethyl- Sa-d , 1-(acetoxyalkyl)-5-bromo-6-bromomethyl- 8a, 8c , and 8d , and 5-bromo-6-bromomethyl 1-(hydroxyalkyl)-2,4(1H,3H)-pyrimidinediones 9a, 9c , and 9d . Likewise one group of tribromo and one group of tetrabromo derivatives are: 5-bromo-1-(bromoalkyl)-6-bromomethyl -7a-d and 5-bromo-1-(bromoalkyl)-6-dibromomethyl-2,4(1H,3H)-pyrimidinediones 6a-d .     

The Effects of Serum on Cellular Uptake and Phototoxicity of Mono-L-Aspartyl Chlorin e6 (NPe6) In Vitro

Abstract— Previous reports showed that the photosensitizer mono- l -aspartyl chlorin e6 (NPe6) binds to serum proteins. However, the influence of this binding on the cellular uptake and photodynamic therapy (PDT) phototoxicity of NPe6 is still undefined. In this paper, we studied how serum in medium affected the P388 cellular uptake and PDT phototoxicity of NPe6 in vitro. This was assessed by (1) detection of the red shift (654 nm Q band peak of absorption) induced by protein binding NPe6; (2) detection of intracellular concentration of NPe6 by HPLC and (3) measurements of the cell survival ratio after PDT by MTT assay. The 654 nm Q band peak of NPe6 shifted to 665 nm after binding of NPe6 and serum proteins. The protein-bound NPe6 cannot be uptaken by cells, thus there was no PDT phototoxicity. Nevertheless, phototoxicity recovered when the concentration of NPe6 excessed the serum protein binding ability or there was free serum protein in the medium. These data suggested that the cellular uptake of NPe6 is inhibited by serum components in the medium, and that only free NPe6 is accumulated by P388 cells even during relatively long incubations. The cytotoxicity of PDT mainly depends on the free NPe6 level in the medium.     

Photodynamic Therapy with a Diode Laser for Implanted Fibrosarcoma in Mice Employing Mono-L-Aspartyl Chlorin E6

Abstract— The authors performed photodynamic therapy (PDT), avoiding any hyperthermic effects, using a newly developed diode laser and photosensitizer, mono-L-aspar-tyl chlorin e₆ (NPe6), of Meth-A fibrosarcoma implanted in mice and achieved tumor therapeutic benefit. The photodynamic light treatment was performed 5 h following the photosensitizer administration. With 5.0 mg/kg NPe6 and light doses of 50, 100, 150 and 200 J/cm², the tumor cure rates were 20, 50, 70 and 90%, respectively. With 100 J/cm² laser exposure and NPe6 doses of 1.25, 2.5, 5.0, 7.5 and 10.0 mg/kg, the tumor cure rates were 0, 20, 50, 70 and 90%, respectively. A charge-coupled device (CCD) camera system was employed to measure the NPe6 fluorescence intensity correlating with the residual amount of the photosensitizer at deferent depth from the tumor surface. The ratios of the NPe6 fluorescence intensity at 3 mm from the tumor surface following 50, 100, 150 and 200 J/cm² laser exposure to no laser exposure were 0.73, 0.36, 0.22 and 0.16, respectively. With samples sectioned at 1 mm depth, after 50 J/cm² and the same photosensitizer dose (5 mg/kg) this ratio was 0.19. These results suggest that a certain increase in the tumor tissue level of NPe6 and a certain increase of laser light dose reaching deeper layers of tumor caused an increase in percent cure. In addition, the effectiveness of PDT depends on the total laser dose reaching deeper layers of tumors. Furthermore, the effectiveness of PDT tends to correlate with the amount of NPe6 photobleaching by PDT.     

Desymmetrization of 1,4‐Pentadien‐3‐ol by the Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Imines

Desymmetrization of the divinyl carbinol 1,4‐pentadien‐3‐ol was accomplished by the asymmetric 1,3‐dipolar cycloaddition of azomethine imines based on a magnesium‐mediated, multinucleating chiral reaction system utilizing diisopropyl (R,R)‐tartrate as the chiral auxiliary. The corresponding optically active trans‐pyrazolidines, each with three contiguous stereogenic centers, were obtained with excellent regio‐, diastereo‐, and enantioselectivity, with results as high as 99 % ee. This reaction was shown to be applicable to both aryl‐ and alkyl‐substituted azomethine imines. The use of a catalytic amount of diisopropyl (R,R)‐tartrate was also effective when accompanied by the addition of MgBr₂.     

Synthetic anthracyclines: regiospecific total synthesis of a D-ring indole analogue of daunomycin

The 4-methoxy-5-methylpyrano[4,3-b]indole-1,3(4H,5H)-dione (9), prepared from methyl 3-methoxycarbonyl-1-methylindol-2-yl acetate (6), underwent a strong base-induced cycloaddition reaction with 2-chloro-6,6-ethylenedioxy-5,6,7,8-tetrahydro-1,4-naphthoquinone (11) to give the tetrahydronaphtho[2,3-b]carbazole-7,12-dione (10), regioselectively. The cycloadduct (10) was successfully converted to a D-ring indole analogue of daunomycin (1a).     

Catalytic Performance of Ruthenium‐Supported Ionic‐Liquid Catalysts in Sustainable Synthesis of Macrocyclic Lactones

Thirteen‐ to eighteen‐membered lactones were synthesized by ring‐closing olefin‐metathesis reactions of bis‐olefins with heterogeneous Grubbs‐supported ionic‐liquid catalysts (SILCs), in which homogeneous Grubbs catalysts were confined in pores of alumina with the aid of an ionic liquid. The Grubbs‐SILCs exhibited higher catalytic performance than their homogeneous counterparts and could be repeatedly recovered by simple filtration and re‐used several times.     

Total synthesis of the antitumor antibiotic (+/-)-fredericamycin A by a linear approach

A linear approach to the total synthesis of racemic fredericamycin A (1) through the oxidative intramolecular [4 + 2] cycloaddition of a (phenylthio)acetylene-cobalt complex is described, which is applicable for the asymmetric total synthesis of naturally occuring 1. The highlight of this work is the aromatic Pummerer-type reaction with 1-ethoxyvinyl chloroacetate, which effects the introduction of the oxygen functional group to the internal B-ring of the highly functionalized, congested polyaromatic ABC-ring moiety.     

Pyrimidine derivatives. VII. Nucleophilic reactions of 5-bromo-1-(bromoalkyl)-6-bromomethyl-2,4(1H,3H)-pyrimidinediones

The reactions of 1-(bromoalkyl)-5-bromo-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1) with several nucleophiles were examined as follows: by reaction with sodium methoxide, 6-(bismethoxy)methyl-5-debrominated derivatives 2, 3 , and 4 were prepared; the corresponding di-substituted compounds (side chains in 1-and 6-positions) 5, 6, 7 , and 9 were obtained by treatment with silver nitrate, silver acetate, potassium thiocyanate, and potassium thioacetate; the reaction with thioacetamide and iso-butylamine gave bicyclic compounds [1,4]thiazino[4,3-c]- 11 , pyrazino[1,2-c]- 12 , and [1,4]diazepino[1,2-c]pyrimidinedione 13 , respectively; pyrrolidine, morpholine, and sodium azide afforded the corresponding 6-substituted compounds 14, 15 , and 16 .     

HEMATOPORPHYRIN DERIVATIVE UPTAKE BY ATHEROMA IN ATHEROSCLEROTIC RABBITS: THE SPECTRA OF FLUORESCENCE FROM HEMATOPORPHYRIN DERIVATIVE DEMONSTRATED BY AN EXCIMER DYE LASER

Abstract A new diagnostic and therapeutic endoscopic system consisting of an excimer pulse dye laser is presented. This report demonstrates the accumulation of hematoporphyrin derivative (HpD) in atheroma as shown by the fluorescence of HpD using this equipment. Atheroma was induced in the aorta of WHHL (Watanabe heritable hyperlipidemic) rabbits, 5 mg kg⁻¹ HpD was injected intravenously and the rabbits were sacrificed 24 h later. The aorta was dissected and the localization of HpD was examined. Characteristic peaks of the fluorescence of HpD at 630, 665 and 690 nm wavelength were detected in the atheromatous lesion. However, in the fatty plaque, the emission peak at 630 nm was lower and the 665 nm peak faded away. No fluorescence with peaks was detected in the normal area. The ratio of fluorescence intensity in atheroma, border zones and normal areas was 10.4 : 5.0 : 1.0. On normal rabbits made atherosclerotic by diet and balloon damage, an ultra thin endoscopic catheter was inserted from the descending aorta of atherosclerotic rabbits under anesthesia. Essentially the same data was obtained by these studies in vivo as was obtained in the in vitro studies. The above data suggests the possibility of future applications of this equipment for diagnosis of atheroma.