Seven-Step Synthesis of All-Nitrogenated Sugar Derivatives Using Sequential Overman Rearrangements.

All-nitrogenated sugars (ANSs), in which all hydroxy groups in a carbohydrate are replaced with amino groups, are anticipated to be privileged structures with useful biological activities. However, ANS synthesis has been challenging due to the difficulty in the installation of multi-amino groups. We report herein the development of a concise synthetic route to peracetylated ANSs in seven steps from commercially available monosaccharides. The key to success is the use of the sequential Overman rearrangement, which enables formal simultaneous substitution of four or five hydroxy groups in monosaccharides with amino groups. A variety of ANSs are available through the same reaction sequence starting from different initial monosaccharides by chirality transfer of secondary alcohols. Transformations of the resulting peracetylated ANSs such as glycosylation and deacetylation are also demonstrated. Biological studies reveal that ANS-modified cholesterol show cytotoxicity against human cancer cell lines, whereas each ANS and cholesterol have no cytotoxicity.

Synthesis and antimicrobial evaluation of amino sugar-based naphthoquinones and isoquinoline-5,8-diones and their halogenated compounds.

Antibiotic resistance has emerged as a serious global public health problem and lately very few antibiotics have been discovered and introduced into clinical practice. Therefore, there is an urgent need for the development of antibacterial compounds with new mechanism of action, especially those capable of evading known resistance mechanisms. In this work two series of glycoconjugate and non-glycoconjugate amino compounds derived from of isoquinoline-5,8-dione and 1,4-naphthoquinone and their halogenated derivatives were synthesized and evaluated for antimicrobial activity against Gram-positive (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228, S. simulans ATCC 27851) and Gram-negative bacteria (E. coli ATCC 25922, Proteus mirabilis ATCC 15290, K. pneumoniae ATCC 4352 and P. aeruginosa ATCC 27853) strains of clinical importance. This study revealed that glycoconjugate compounds derived from halogeno-substituted naphthoquinones were more active against Gram-negative strains, which cause infections whose treatment is even more difficult, according to the literature. These molecules were also more active than isoquinoline-5,8-dione analogues with minimum inhibitory concentration (MIC = 4-32 µg/mL) within Clinical and Laboratory Standard Institute MIC values (CLSI 0.08-256 µg/mL). Interestingly the minimal bactericidal concentration (MBC) values of the most active compounds were equal to MIC classifying them as bactericidal agents against Gram-negative bacteria. Sixteen compounds among eighteen carbohydrate-based naphthoquinones tested showed no hemolytic effects on health human erythrocytes whereas more susceptibility to hemolytic cleavage was observed when using non-glycoconjugate amino compounds. In silico Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) evaluation also pointed out that these compounds are potential for oral administration with low side effects. In general, this study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials more effective against Gram-negative bacteria.

Alkylating agents from sugars. Alkyl hexopyranoside derivatives as carrier systems for chlorambucil.

Chlorambucil derivatives involving alkyl 2-aminodeoxy sugars have been synthesized in good yield by coupling the chlorambucil moiety to positions C-2 or C-3 of the sugar, directly or via a spacer. The starting material was easily available from 2-acetamido-2-deoxy-D-glucose. The final compounds were tested for cytotoxicity, and some of those that presented the best results were studied for inhibition of cell proliferation.

Rationale for the synthesis and preliminary biological evaluation of highly active new antitumor nitrosoureido sugars.

Various new nitrosoureido derivatives of di- or trideoxy sugars were synthesized. The influence of the hydroxyl substitution pattern, the configuration at the anomeric center, and the absolute configuration of the sugar moiety on the antitumor activity of a series of nitrosoureido derivatives of di- and trideoxy sugars was studied. All compounds showed a very significant activity in vivo against L1210 leukemia, B16 melanocarcinoma, and Lewis lung carcinoma. Methyl 3-[3-(2-chloroethyl)-3-nitrosoureido]-2,3-dideoxy-alpha-D-arabino- hexopyranoside, 24 (NSC 609224), was found to be the most active compound. When treated with 24 (NSC 609224) at 20 mg/kg on day 1, at least 90% of the L1210 leukemia and B16 melanocarcinoma bearing mice showed a survival of over 60 days for a LD50 value for this compound of 42 mg/kg.

Synthesis, analysis and mutagenic activity of N-nitroso derivatives of glycosylamines and Amadori compounds: nitrosated model substances for the early Maillard reaction products.

A series of nine glycosylamines and an Amadori compound and their N-nitroso derivatives were synthesized. The structures were ascertained by spectroscopy and elemental analysis. The N-nitroso compounds were further characterized by denitrosation with hydrogen bromide-acetic acid, followed by detection of the liberated NO by a chemiluminescence detector. N-Nitroso derivatives of N-p-nitrophenyl/p-methylphenyl/p-carboxyphenyl pentosylamines, N-p-methylphenyl-1-deoxy-D-fructosylamine (Amadori compound) and N-3-ethylindole-D-xylosylamine were shown to be directly-acting mutagens in Salmonella typhimurium TA100. The activity of some of the compounds was similar to that of N-ethyl-N-nitrosourea. Their mutagenic activity was shown to be dependent on the structure of the amine and the sugar moieties and requires the presence of free hydroxyl groups in the sugar. The mutagenicity of N-nitrosoglycosylamines was attributed to their hydrolysis to arene diazonium cations. Their formation was detected via azo-coupling with N-ethyl-1-naphthylamine, using spectrophotometric and mass-spectrometric analyses. Our data implicate arene (alkyl) diazonium cations as the ultimate mutagens of N-nitrosoglycosylamines and N-nitroso Amadori compounds, a little explored class of N-nitroso compounds which may be formed in vivo.

Mutagenicity studies on N-nitrosated products of the Maillard browning reaction: N-nitroso-fructose-amino acids.

The N-nitroso derivatives of D-fructose-L-glycine, D-fructose-L-alanine, D-fructose-L-phenylalanine, D-fructose-L-serine, Dfructose-L-aspartic acid and D-fructose-L-tryptophan (a mixture of alpha-N-nitroso-D-fructose-L-tryptophan and 'indolyl-nitrosamine'-D-fructose-L-tryptophan) were tested for mutagenicity in five auxotrophic strains of Salmonella typhimurium with and without metabolic activation (S-9 mix). The alanine, phenylalanine and aspartic acid compounds were not mutagenic. The glycine and serine compounds showed a very low but reproducible increase in the numbers of his+ revertants in strain TA1535 without S-9 mix. The mixture containing both nitrosated D-fructose-L-tryptophan compounds was mutagenic in all five strains, with or without metabolic activation. The alpha-N-nitroso-D-fructose-L-tryptophan component of the mixture, which is nitrosated at the amino group, was isolated and tested without S-9 mix. It was mutagenic in three strains. Unnitrosated D-fructose-L-amino acids, D-fructose, and the individual L-amino acids were non-mutagenic when tested under those conditions for which a positive response had been obtained with the corresponding nitrosated compounds. These results indicate the potential value of developing analytical methods to identify alpha-N-nitroso-D-fructose-L-tryptophan in food or food extracts that are to be screened for mutagenic components.

Studies on antitumor activity of prumycin. II. Studies on distribution and excretion of prumycin.

Tissue distribution, excretion and metabolism of prumycin in normal mice and rats were studied by microbiological assay. Following the injection of prumycin into mice, high activity was detected and continued for 24 hours in the kidney, and the activity was also high in the skin, uterus, bone, liver, lung and stomach in this order. But concentration in the brain, heart, spleen and testis were too low to detect even 5 minutes after the injection. Prumycin was not inactivated by a variety of tissue homogenates in vitro. Therefore, inability to detect activity of prumycin in the spleen and testis appears to result from poor distribution rather than inactivation by these organs. About 70% of injected prumycin was excreted into rat urine in 24 hours but it was not detectable in feces. When prumycin was injected intravenously into dogs at the dose over 10 mg/kg, vomiting was observed in all animals, and LD50 was about 50 mg/kg.