The iminoquinone is an important moiety of a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. A series of polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9-diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino-3H-phenoxazin-3-one (3), 3H-phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2-a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were synthesized for developing new anticancer intercalating drugs. The antiproliferative activity of these compounds, evaluated against representative human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6 were the most active compounds inhibiting cell proliferation in a submicromolar range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. All the above KB subclones did not show altered sensitivity to the antiproliferative activity of 5. UV-vis and (1)H NMR spectroscopy experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex. Electrostatic interactions between the hydrogen of the positively charged pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4' and O5') of the cytosine C5 residue together with stacking forces contribute to the high antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is described, and the formation mechanism is proposed.
New antiproliferative compounds, 5H-pyrido[3,2-a]phenoxazin-5-ones (1-10), 5H-benzophenoxazin-5-one (11), 5H-pyrido[2,3-a]phenoxazin-5-one (12), 5H-pyrido[3,4-a]phenoxazin-5-one (13), and 5H-pyrido[4,3-a]phenoxazin-5-one (14), were synthesized and evaluated against representative human neoplastic cell lines. The excellent cytotoxic activity of these polycyclic phenoxazinones, structurally related to the actinomycin chromophore, is discussed in terms of structural changes made to rings A and D (Chart 1). Electron-withdrawing or electron-donating substituents were introduced at different positions of ring A to probe the electronic and positional effects of the substitution. A nitro group in R(2) or in R(1) increases the cytotoxic activity, whereas electron-donating methyl groups in any position lead to 10- to 100-fold decreasing of the activity. The low antiproliferative activity of benzophenoxazinone 11 and pyridophenoxazinones 13 and 14 confirms the crucial role of pyridine nitrogen in the W position of ring D in DNA binding. The unexpected high activity exhibited by 12, which has the nitrogen in the X position, could be ascribed to a different mechanism of action, which needs further investigation.
The aim of this research was to explain the direct plant growth-promoting activity of Trichoderma harzianum strain T-22 (T22), hypothesizing the involvement of different classes of plant growth regulators. Seven days after the transfer to root-inducing medium, in vitro-cultured shoots of GiSeLa6 Ò (Prunus cerasus 9 P. canescens) were inoculated with T22. Root and shoot growth were significantly affected by T22 (?76 and ?61%, respectively). Ten days after inoculation, the levels of indole-3-acetic acid (IAA), trans-zeatin riboside (t-ZR), dihydrozeatin riboside (DHZR), gibberellic acid (GA3) and abscisic acid (ABA) were analyzed by high performance liquid chromatography coupled with mass spectrometry. The results showed that after T22-inoculation, IAA and GA3 significantly increased in both leaves (?49 and ?71%, respectively) and roots (?40 and ?143%, respectively) whereas t-ZR decreased (-51% in leaves and -37% in roots). Changes in DHZR were observed in T22-inoculated roots (-32%) but not in leaves, whereas the levels of ABA did not differ between the two treatments. The extraction method allowed the simultaneous extraction of phytohormones. There is evidence that the change in phytohormone levels is one of the direct mechanism by which T22 promotes rooting and shoot growth, with notable advantages for rootstock production during nursery processes.
Fresh cut vegetables represent a widely consumed food worldwide. Among these, lettuce (Lactuca sativa L.) is one of the most popular on the market. The growing interest for this "healthy" food is related to the content of bioactive compounds, especially polyphenols, that show many beneficial effects. In this study, we report the anti-inflammatory and antioxidant potential of polyphenols extracted from lettuce (var. Maravilla de Verano), in J774A.1 macrophages stimulated with Escherichia coli lipopolysaccharide (LPS). Lettuce extract significantly decreased reactive oxygen species, nitric oxide release, inducible nitric oxide synthase and cycloxygenase-2 expression. A detailed quali/quantitative profiling of the polyphenolic content was carried out, obtaining fast separation (10 min), good retention time and peak area repeatability, (RSD% 0.80 and 8.68, respectively) as well as linearity (R(2)⩾ 0.999) and mass accuracy (⩽ 5 ppm). Our results show the importance in the diet of this cheap and popular food for his healthy properties.
Kv7 K+ channels represent attractive pharmacological
targets for the treatment of different neurological disorders, including
epilepsy. In this paper, 42 conformationally restricted analogues
of the prototypical Kv7 activator retigabine have been synthesized
and tested by electrophysiological patch-clamp experiments as Kv7
agonists. When compared to retigabine (0.93 ± 0.43 μM),
the EC50s for Kv7.2 current enhancements by compound 23a (0.08 ± 0.04 μM) were lower, whereas no change
in potency was observed for 24a (0.63 ± 0.07 μM).
In addition, compared to retigabine, 23a and 24a showed also higher potency in activating heteromeric Kv7.2/Kv7.3
and homomeric Kv7.4 channels. Molecular modeling studies provided
new insights into the chemical features required for optimal interaction
at the binding site. Stability studies evidenced improved chemical
stability of 23a and 24a in comparison with
retigabine. Overall, the present results highlight that the N5-alkylamidoindole moiety provides a suitable pharmacophoric
scaffold for the design of chemically stable, highly potent and selective
Kv7 agonists.
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