Design, Synthesis and Biological Evaluation of Novel Analogues of Distamycin

Analogues of distamycin which retain the parent ligand's ability to bind in the DNA minor groove with sequence specificity are widely recognised as potential candidates for drug development. Distamycin binds to DNA with significant, albeit not complete, AT specificity, spanning five base pairs. Its pyrrole rings can partially accommodate the bulky guanine C2-NH2 groups in the minor groove especially at the edges of the binding site, thus leading to some tolerance of GC base pairs. A key objective of this project was to modify a portion of the distamycin structure by substituting its N-terminal pyrrole(-4yl)formamido unit with novel biaryl motifs in an attempt to enhance the AT specificity of the parent ligand. In order to achieve this, solution and solid phase combinatorial approaches were adopted and parallel libraries synthesised using a variety of heterocycles as building blocks. Solid phase combinatorial chemistry, performed on Mimotope Lanterns™, was employed to accelerate the synthesis of polyamides. A protocol for the assembly of the polyamide chain was successfully developed, and Library 3.1 and 3.2 compounds (3.1a-f and 3.2a-f) were prepared rapidly and efficiently. FRET-based DNA melting experiments revealed that some of these molecules are capable of stabilizing a DNA-hairpin oligonucleotide. Library members synthesized in solution phase (2.3a-g) were screened against a 512-member hairpin-DNA oligonucleotide library, containing all possible (non-degenerate) sequences in order to identify recognition events. This screen was based on the ethidium bromide displacement assay reported by Boger, and revealed that enhanced AT sequence selectivity had been achieved with some molecules. In particular, a compound containing the pyrazole-thiazole motif (2.3{5.16}) was found to bind to AT-rich sequences more selectively than distamycin. This result was confirmed by quantitative DNA footprinting experiments using two different DNA fragments in which 2.3{5.16} was shown to bind to TATA sequences with greater selectivity than distamycin, which bound to additional AT- containing sites. Some studies have also been carried out on the synthesis of novel lexitropsins (4.1a-c) specifically designed to target GC sequences. In summary, the results obtained have demonstrated the usefulness of biaryl building blocks in modifying the sequence selectivity of minor-groove binding agents, and lay the foundation for third generation compounds spanning up to five base pairs and designed to have specific recognition of individual bases within their binding site span

2-furyl(phenyl)methanol isolated from Atractilis gummifera rhizome exhibits anti-leishmanial activity

The file attached to this record is the Publisher's final version. Crown copyright.We report for the first time the isolation of 2-furyl(phenyl)methanol (5) from the chloroform extracts of the Atractylis gummifera roots. A. gummifera is a thistle belonging to the Asteraceae family that produces the ent-kaurane diterpenoid glycoside atractyloside (ATR). ATR (1) was isolated and chemically modified to obtain its aglycone atractyligenin (2) and the methylated derivatives ATR-OMe (3) and genine-OMe (4). The compounds 1-5 were structurally characterised and evaluated against the intracellular amastigote, cultured within macrophages, and the extracellular promastigote of Leishmania donovani, the protozoan parasite responsible for the highly infective disease visceral leishmaniasis, which is fatal if untreated. The 2-furyl(phenyl)methanol 5 exhibited notable activity against the promastigote

Synthesis and Biological Evaluation of a Novel C8-Pyrrolobenzodiazepine (PBD) Adenosine Conjugate. A Study on the Role of the PBD Ring in the Biological Activity of PBD-Conjugates

Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD–ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to a ect and modulate the biological and biophysical properties of PBD hybrids

Aminobenzofuran-containing analogues of proximicins exhibit higher antiproliferative activity against human UG-87 glioblastoma cells compared to temozolomide

A new series of proximicin analogues containing a benzofuran moiety as the replacement of the di-furan scaffold of the parent compound were synthesised and evaluated for their anti-proliferative activities against human glioblastoma cells U-87 MG. Proximicins A, B, and C are secondary metabolites produced by Verrucosispora Fiedleri MG-37, a Gram-positive actinomycete isolated from deep-sea sediment. Proximicins exhibit significant cytotoxic and apoptotic effects in a number of tumour cell lines, although further investigations on these natural products biological activity are hampered by the challenging synthesis of their constitutive di-furan unit. Therefore, the easily-synthesisable benzofuran ring was elected as a replacement of the di-furan platform, and a library of proximicin analogues was prepared in which different substituents were introduced at both the N-terminus and C-terminus of the benzofuran core unit. The novel compounds were tested against U-87 MG, as it was previously found that proximicins targeted this cancerous cell line, and the human healthy cell line WI-38. Temozolomide, the chemotherapeutic agent of choice for the treatment of glioblastoma, was used as a control. Analysis of growth inhibitory concentration values revealed that a number of furan-benzofuran-containing proximicin analogues, including 23(16) (IC50 U-87 MG = 6.54 μg mL-1) exhibited higher antiproliferative activity against glioblastoma cells compared to both proximicins A-C and temozolomide (IC50 U-87 MG = 29.19 μg mL-1) in U-87 MG

Aminobenzofuran-containing analogues of proximicins exhibit higher antiproliferative activity against human UG-87 glioblastoma cells compared to temozolomide

open access articleA new series of proximicin analogues containing a benzofuran moiety as the replacement of the di-furan scaffold of the parent compound were synthesised and evaluated for their anti-proliferative activities against human glioblastoma cells U-87 MG. Proximicins A, B, and C are secondary metabolites produced by Verrucosispora Fiedleri MG-37, a Gram-positive actinomycete isolated from deep-sea sediment. Proximicins exhibit significant cytotoxic and apoptotic effects in a number of tumour cell lines, although further investigations on these natural products biological activity are hampered by the challenging synthesis of their constitutive di-furan unit. Therefore, the easily-synthesisable benzofuran ring was elected as a replacement of the di-furan platform, and a library of proximicin analogues was prepared in which different substituents were introduced at both the N-terminus and C-terminus of the benzofuran core unit. The novel compounds were tested against U-87 MG, as it was previously found that proximicins targeted this cancerous cell line, and the human healthy cell line WI-38. Temozolomide, the chemotherapeutic agent of choice for the treatment of glioblastoma, was used as a control. Analysis of growth inhibitory concentration values revealed that a number of furan-benzofuran-containing proximicin analogues, including 23(16) (IC50 U-87 MG = 6.54 μg mL−1) exhibited higher antiproliferative activity against glioblastoma cells compared to both proximicins A–C and temozolomide (IC50 U-87 MG = 29.19 μg mL−1) in U-87 MG

Synthesis and antitubercular activity of novel 4-arylalkyl substituted thio-, oxy- and sulfoxy-quinoline analogues targeting the cytochrome bc1 complex

open access articleA library of 4-substituted quinolines was synthesised based on the structural features of the privileged 4-(benzylthio)-6-methoxy-2-methylquinoline scaffold. Quinoline-based chemical probes have proven to be effective anti-tuberculosis agents with the ability of inhibiting components of Mycobacterium tuberculosis (MTB) respiratory chain including the b subunit of the cytochrome bc1 complex. Novel 4-(arylalkyl)-thio, -oxy and sulfoxy-quinoline analogues were tested for their ability to inhibit the growth of MTB H37Rv and QcrB mutant strains, and the compounds mode of action was investigated. Members of the 4-subtituted thio- and sulfoxyquinoline series exhibited significant growth inhibitory activity in the high nanomolar range against wild-type MTB and induced depletion of intracellular ATP. These probes also showed reduced potency in the QcrB T313I mutant strain, thus indicating the cytochrome bc1 oxidase complex as the molecular target. Interestingly, new 4-(quinolin-2-yl)oxy-quinoline 4i was more selective for the QcrB T313I strain compared to the wild-type strain

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk

Design, synthesis and biological evaluation of novel analogues of Distamycin

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Rifamycins: do not throw the baby out with the bathwater. Is rifampicin still an effective anti-tuberculosis drug?

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link

Structural Characterization and Antimicrobial Evaluation ofAtractyloside, Atractyligenin, and 15-DidehydroatractyligeninMethyl Ester

e report thefirst complete structure elucida-tion of theent-kaurane diterpenoid glycoside atractyloside (1)by means of NMR and X-ray diffractometry techniques.Extensive one- and two-dimensional NMR experiments wereemployed to assign the proton and carbon signals of1, andcrystallography experiments established the configurations ofall stereogenic centers. Furthermore, we present a novelsemisynthetic route for the preparation of the highly cytotoxicaglycone derivative of1, 15-didehydroatractyligenin methylester (3). All compounds were tested for their antibioticactivity againstEnterococcus faecalis,Escherichia coli, and several strains ofStaphylococcus aureus, includingfluoroquinolone-resistant (SA1199B) and two epidemic MRSA (EMRSA-15 and -16) strains. Compound3exhibited moderate activity against allof theStaph. aureusstrains with an MIC value of 128 mg/