Synthesis and biological properties of side-chain-modified bleomycins

Netzler

et al. 2018

Sci Rep

Human norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 µM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 µM), with the best candidate, 54, demonstrating an IC50 of 5.6 µM against the RdRp and a CC50 of 62.8 µM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral.

Section: Chemistrymentioning

confidence: 99%

In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase

Netzler

et al. 2018

Sci Rep

“…. 45 To a solution of 2-aminonaphthalene (0.71 g, 5 mmol) in dry DCM (100 ml) was added triethylamine (TEA, 1.1 ml, 8 mmol) and the mixture was stirred under N 2 for 30 min. Next, bromoacetyl bromide was added dropwise via syringe and the reaction mixture was stirred for an additional 12 h under N 2 .…”

Section: -Bromo-n-(2-naphthyl)acetamide (7)mentioning

confidence: 99%

Structural features directing the specificity and functionality of metallo-supramolecular grid-type architectures

et al. 2009

New ditopic bis-hydrazone type ligands possessing various functional units have been designed to self-assemble into axially and laterally decorated [2 x 2] grids with octahedrally coordinating metal ions. Solution and solid state investigations have provided evidence for the strong influence of the nature of the attached groups on the structure and function of these metallo-supramolecular entities. Various techniques were applied in order to explore the magnetic, optical and structural properties of these functional nanosize platforms. The results obtained showed the effect of ligand functionalization both on the ease of formation of the grid architectures and on their physicochemical properties.

“…A unique feature of the synthetic scheme employed here involves the intermediacy of bleomycin demethyl A 2 . In addition to providing uncharged synthetic intermediates, amenable to purification with greater facility, bleomycin demethyl A 2 is of great interest intrinsically for its DNA binding and cleaving properties and has also been used as a convenient starting material to obtain BLMs modified within the C-substituent via chemical transformation to bleomycinic acid. ,, …”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of Bleomycin Group Antibiotics. Total Syntheses of Bleomycin Demethyl A₂, Bleomycin A₂, and Decarbamoyl Bleomycin Demethyl A₂

Katano

Aoyagi

et al. 1998

J. Am. Chem. Soc.

The total syntheses of bleomycin A2 (1) by two routes are described. The final step in the synthesis of bleomycin A2 involves methylation of bleomycin demethyl A2 (2). This bleomycin derivative is of interest mechanistically, and can also provide access to other bleomycins via its known chemical conversion to bleomycinic acid. Accordingly, the synthetic strategy presented represents a particularly versatile approach for the elaboration of a wide variety of BLM congeners. Bleomycin was constructed from five key intermediates, the syntheses of which are described. 1,6-Di-O-acetyl-3,4-di-O-benzyl-2-O-[2,4,6-tri-O-acetyl-3-O-(N-acetylcarbamoyl)-α-d-mannopyranosyl]-β-l-gulopyranose (3) was converted quantitatively to its disaccharide chloride (4), the latter of which was condensed with N α,N im-bis(t-Boc)-(S)-erythro-β-hydroxyhistidine (7) to provide α-O-glycosidated product 16. The subsequent couplings with benzyl valerate 8, threonylbithiazole 9, and N α -t-Boc-pyrimidoblamic acid (10) afforded access to bleomycin demethyl A2 (2) and decarbamoyl bleomycin demethyl A2 (26). Although it was obtained as a byproduct of the synthesis of BLM, the synthesis of decarbamoyl bleomycin demethyl A2 nonetheless constitutes the first report of synthetic access to this BLM congener that is of particular importance from a mechanistic perspective. This BLM can be used to resolve the issue of the participation of the carbamoyl group as a metal ligand in metallobleomycins. Also reported is a new route to bleomycin demethyl A2 that employed an unprotected carbamoyl group throughout the synthesis. In conjunction with the use of the uncharged methylthiopropylamide C-substituent, the latter strategy permitted improved functional group manipulation and thereby afforded intermediates that could be purified with greater facility. Because the synthesis of bleomycin is limited by the efficiency of elaboration of the carbohydrate moiety, a study was carried out to define improved methods for the preparation of this constituent of BLM. Three new routes were explored, and a route involving the intermediacy of disaccharide activated as a glycosyl bromide was found to be particularly efficient and convenient. Also of importance was the finding that activation of carbohydrate intermediates as their glycosyl trichloroacetimidates permitted the requisite couplings to be carried out conveniently and in good yields. Synthetic BLM demethyl A2 was shown to have the same potency as a naturally derived sample in a plasmid DNA relaxation assay. The sequence selectivity of DNA cleavage by synthetic and authentic Fe(II)·BLMs was also shown to be the same. Also established for the first time for any synthetic bleomycin was the actual chemistry of DNA degradation, which is the same as that for naturally derived bleomycins.