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Nucleophilic substitution between the 4′-benzoyloxy derivative of cordycepin (3′-deoxyadenosine) and AlMe3proceeds mostly with retention of configuration at the 4′-position: the 4′-benzoyloxy substrate having the β-d-configuration (8a) gave the 4′-methylated β-d-nucleoside (9a) with a high diastereomeric excess, while the substrate 8bhaving the opposite 4′-configuration gave the corresponding α-l-isomer (9b) with a comparatively lower stereoselectivity. The SNi mechanism is proposed for this reaction (from 8to 9). The polarity of the solvent has a significant influence on the stereoselectivity, especially for the formation of 9b.

Purpose: To determine the tolerability and feasibility of double-cycle, high-dose chemotherapy followed by peripheral blood stem-cell transplantation (PBSCT) after conventional chemotherapy or chemoradiotherapy for small cell lung cancer (SCLC). Patients [...]

Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1 and 4-position will be described. During this study, we could discover an anti-HIV agent, 4-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.

Background: Motivated by the reported biological activity of 9-(β-D-xylofuranosyl)adenine (xylo-A), the synthesis of its 4'-alkoxy analogues was carried out.Methods: The starting material 9-(3-deoxy-β-D-glycero-pento–3-enofuranosyl)adenine (1) was prepared from adenosine. Compound 1 was converted to the 2',5'-bis-0–(tert-butyldimethylsilyl) derivative (2) and then to the N6-pivaloyl derivative (3). When 3 was reacted with meta-chloroperbenzoic acid in the presence of a series of alcohols, the β-D-isomer of the respective 4'-alkoxy derivative was obtained exclusively in high yield. Deprotection of these products led to the isolation of the desired 4'alkoxy analogues (8a-I) of xylo-A.Results: Antiviral evaluation revealed that none of these analogues showed inhibitory activity against a wide variety of DNA and RNA viruses.Conclusions: We assume that conformational difference of the sugar moiety of 8a-1 from that of xylo-A could be attributable to their inactivity.

The present paper is concerned with the applicability of the neighboring group participation of a 2-O-(p-substituted benzoyl) group to the stereoregulation of the ring-opening polymerization of 1,6-anhydro deoxysugar derivatives. 1,6-Anhydro-2-O-(p-substituted benzoyl)-3,4-dideoxy-ß-D-erythro-hexopyranoses (5a–d) were polymerized in dichloromethane at different temperatures ranging from -60 and -20°C with phosphorus pentafluoride as an initiator. 1,6-Anhydro-2-O-benzoyl-3-O-benzyl-4-deoxy-ß-D-xylo-hexopyranose (7a) and its 2-O-(p-bromobenzoyl) homolog (7b) were also polymerized under similar conditions. 13C NMR analysis revealed that all the polymers were composed of both the respective (1?6)-a- and (1?6)-ß-linked structural units. Their proportions varied depending on the p-substituents as well as the reaction conditions: An electron-withdrawing p-substituent on the 2-O-benzoyl aromatic ring reduced the ß-unit content of the polymer, although it increased the polymer yield. The presence of a 3-O-benzyl group was favorable for the formation of (1?6)-ß-linked structural units. On the basis of these results, factors disturbing the configurational regularity of the anomeric carbons were discussed.

Background: Although the incidence of urogenital cancers in Japan is lower than that of other cancers, it is increasing steadily. Thus, an epidemiologic study was necessary to determine the measures that would decrease the mortality rate associated with these cancers.

Background:

The significance of prostate specific antigen (PSA) in the mass screening for prostate cancer was investigated.

Abstract: Background: An annual examination is recommended to patients with normal findings from digital rectal examination and transrectal ultrasonography, and less than a 4.0 ng/ml level of prostate specific antigen (PSA). This report investigates the appropriate screening interval for men with less than 4.0 ng/mL PSA. Methods: In 1715 subjects newly examined by our mass screening for prostate cancer, the change of serum PSA level was analyzed. The normal upper limit for PSA was 4.0 ng/ml. Results: Subjects with less than 2.0 ng/mL PSA at the initial examination have a 98.9% chance of having a normal PSA level in 1 to 2 years. However, subjects with 2.1 or 3.0 ng/mL PSA at the initial examination have a 84.4% and 90.9% chance, respectively, of having a normal PSA level in 1 to 2 years. Moreover, the subjects with 3.1 or 4.0 ng/mL PSA will have a 68.7% and 53.8%, respectively, chance of having a normal PSA in 1 to 2 years. Conclusion: We recommend an examination every 2 to 3 years for subjects with less than 2.0 ng/mL PSA. Further studies may suggest that this interval can be extended. Presently, we recommend an annual examination for subjects with 2.1 to 4.0 ng/mL PSA, because they have about a 20% chance of having an abnormal PSA 1 year later.

Dihydrostreptomycin has been synthesized from dihydrostreptobiosamine and streptidine. A glycosyl chloride derivative (10) of the former was coupled with a protected derivative (26) of the latter to give a mixture of four isomeric glycosides, which were separated by chromatography. Deblocking of the desired glycoside led to dihydrostreptomycin. Several other protected derivatives of dihydrostreptobiosamine have also been described.

2-Amino-2,3-dideoxy-l- and -d-ribohexose (1land 1d) were synthesized from 2-amino-2-deoxy-l- and -d-glucose, respectively, through a reaction sequence which involves 3-O→2-N acetyl migration of methyl 3,4,6-tri-O-acetyl-2-amino-2-deoxy-β-l- and -d-glucopyranoside (3land 3d). A preparative method of methyl 4,6-di-O-acetyl-2-amino-2-deoxy-β-d-glucopyranoside (11d) is given.

With an aim to synthesize 4-substituted cordycepins, the 4-phenylthio precursor 4 was prepared from adenosine through an electrophilic addition to the 3,4-unsaturated derivative 2 by using NIS/PhSH system. Nucleophilic substitution of 4 with a series of alcohols in the presence of NBS gave the respective 4--alkoxy cordycepins 6 as the major stereoisomer. Use of DAST, in stead of alcohol in this reaction, gave the 4-fluoro analogue 7. The 4-sulfone derivative 8 obtained by m-CPBA oxidation of 4 was employed for the reaction with organoaluminum reagents. These reactions furnished various types of the 4-carbon-substituted cordycepins 9.

The title 3′,4′‐unsaturated nucleoside (IV) may be used for the preparation of 4′‐branched derivatives.

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Synthesis of 4′-substituted analogues of cordycepin was carried out. Electrophilic addition of <it>N</it>-iodosuccin-imide/benzoic acid to 2′,5′-bis-<it>O</it>-(<it>tert</it>-butyldimethyl-silyl)-3′,4′-unsaturated adenosine (5) enabled the intro-duction of a leaving group to the 4′-position. The resulting product 7 was converted to 4′-(benzoyloxy) cordycepin (8) upon removal of the 3′-iodine atom. Compound 8 serves as a common precursor for the synthesis of the title compounds through nucleophilic substitution using organoaluminum and organosilicon reagents.

Epoxidation of 2′,5′-bis-<it>O</it>-silyl-protected N6 pivaloyl-3′,4′-unsaturated adenine nueleosides (1,2 and 3) with dimethyldioxirane uniformly proceeded face-selectively to give the respective 3′,4′-β-epoxides (4,5 and 6). Ring cleavage of these epoxides examined with Me<inf>3</inf>Al in CH<inf>2</inf>Cl<inf>2</inf> showed that the TBDMS (4) or TES (5) protected epoxide gave the desired 4′-α-methylated product (8 or 10) as the major stereoisomer, while use of the TBDPS protected epoxide (6) resulted in reverse stereoselectivity. Reactions of 4 with other organoaluminum reagents were also carried out.

Dimethyldioxirane-mediated epoxidation of 3′,5′-<it>O</it>-(di-<it>t</it>-butylsilylene)-l′,2′-dehydro undine (6) proceeded face-selectively to give l′,2′-α-epoxyuracil nucleoside (7). When 7 was treated with Me<inf>3</inf>Al, an anomeric mixture of the target l′-<it>C</it>-α-methyluridine derivative 8 and its epimer 9 (86%, 8/9 = 5/1) was obtained. On the other hand, <it>N</it>3-protection improved the stereoselectivity in the ring-opening reaction. Thus, <it>N</it>3-benzyloxymethyl (BOM)-1′,2′-epoxy nucleoside 11 obtained from 10 gave the target 12 as the sole product.