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N-Benzyl pyrrolidinyl sordaricin derivatives have been synthesized from cis-4-hydroxy-d-proline in a stereocontrolled manner. These compounds maintained moderate antifungal activity against several pathogenic fungal strains. Their MIC values against Candida albicans were in the range of 0.25–2 μg/mL. [Copyright &y& Elsevier]

Synthesis of GM-237354 (1), a potent inhibitor of fungal elongation factor 2, was achieved starting from sordaricin using a highly stereoselective glycosylation reaction as a key step. Glycosylation utilizing 2-deoxy-2-iodo-glycopyranosyl acetate 6a gave glycoside 8 as a single product, and 8 was easily converted into 1. [Copyright &y& Elsevier]

Sordaricin analogues possessing 6-methoxy-7-methyl-1,4-oxazepane moiety instead of the sugar part were synthesized and evaluated. It was found that N-substituents on the oxazepane ring had influence on biological activity. In particular, N-(2-methylpropenyl) derivative 12p exhibited potent in vitro antifungal activity. Furthermore, 12p maintained significant activity (MIC 0.25 μg/mL) against Candida albicans SANK51486 even in the presence of 20% horse serum. [Copyright &y& Elsevier]

We synthesized bicyclic ether sialidase inhibitors such as tetrahydro-furan-2-yl, tetrahydro-pyran-2-yl, and oxepan-2-yl derivatives related to zanamivir. These compounds substituted by diol at the C-3′ and C-4′ positions resulted in the retention of low nanomolar inhibitory activities against not only influenza A virus sialidase but also influenza A virus in cell culture. Compound 11a in particular showed comparable efficacy in vivo relative to that of oseltamivir phosphate. [Copyright &y& Elsevier]

We synthesized polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en analogues on the polyglutamic acid back bone, via a spacer of alkyl ether at the C-7 position. These multivalent conjugates 9 and 10 showed enhancement of antiviral activity against infuenza A virus and more potent efficacy in vivo relative to a monomeric sialidase inhibitor. [Copyright &y& Elsevier]

Therapeutic strategies that promote read-through of a mutant gene have proved effective for certain non-neoplastic diseases. However, the efficacy of this approach is unproven regarding neoplastic diseases with germline nonsense mutations, including familial adenomatous polyposis. Here we examined the cancer-preventive efficacy of the macrolide antibiotic azithromycin, with a reported read-through effect, on intestinal tumorigenesis in C3B6F1 Apc Min /+ mice harboring a nonsense Apc mutation resulting in a truncated Apc protein. Mice were given drinking water lacking azithromycin or containing 0.0125–0.2 mg/mL azithromycin from 3 weeks of age. The small intestine and cecum were analyzed for pathological changes and alterations of intestinal flora. Azithromycin suppressed the number of tumors and the proportion of adenocarcinomas, with the most effective drinking-water concentration being 0.0125 mg/mL. Furthermore, azithromycin recovered the cellular level of full-length Apc, resulting in downregulation of β-catenin and cyclin D1. Conversely, the effect of azithromycin on the diversity of the intestinal microbiota depended on the drinking-water concentration. These results suggest that the balance between azithromycin-mediate read-through of mutant Apc mRNA and antibacterial effects influences intestinal tumorigenesis. Thus, azithromycin is a potential anticancer agent for familial adenomatous polyposis patients harboring nonsense mutations. [Display omitted] [ABSTRACT FROM AUTHOR]

To obtain potent liver X receptor (LXR) agonists, a structure–activity relationship study was performed on a series of tert -butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys. [ABSTRACT FROM AUTHOR]

A series of 7-alkyl ether derivatives related to zanamivir were synthesized using direct alkylation of the C-7 alcohol of sialic acid. Alkyl ether moiety of less than 12 carbons in length showed low nanomolar inhibitory activity against influenza A virus sialidase. Furthermore, their moiety improved influenza A virus plaque reduction activity compared to zanamivir. However, removal of the 8,9-diol of the 7-O-alkyl derivatives resulted in loss of antiviral potency. This result suggests that 8,9-diol must play an important role in binding with both influenza A and B virus sialidases. [Copyright &y& Elsevier]

Substitution of 7-OH by small hydrophobic groups on zanamivir resulted in the retaining of low nanomolar inhibitory activities against not only influenza A virus sialidase but also influenza A virus in cell culture. These compounds were prepared by treatment of the corresponding 7-substituted sialic acids derived from 4-modified N-acetyl-d-mannosamine (ManNAc) using enzyme-catalyzed aldol condensation. [Copyright &y& Elsevier]

Abstract: A series of ester prodrugs of 7-O-methyl derivative of Zanamivir (compound 3) was synthesized and their efficacy was evaluated in an influenza infected mice model by intranasal administration. Compound 7c (CS-8958), octanoyl ester prodrug of the C-9 alcohol of compound 3, was found to be much longer-acting than Zanamivir. Furthermore, the in vivo efficacies of compounds 12a, 12b, and 12c, the linear alkyl ester prodrug of the carboxylic acid, were comparable to that exerted by compound 7c. [Copyright &y& Elsevier]