Structure optimization and preliminary bioactivity evaluation of N-hydroxybenzamide-based HDAC inhibitors with Y-shaped cap

Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA.     

Plant growth promoting rhizobacterium Proteus vulgaris JBLS202 stimulates the seedling growth of Chinese cabbage through indole emission

Backgrounds and aims

The functional role of volatile indole in interaction between rhizobacteria and plant remains unknown. In this study, we investigated the functional role of the volatile indole emitted by rhizobacterial strain Proteus vulgaris JBLS202 in plant growth promoting activity.

Methods

P. vulgaris strain JBLS202 was used to study the role of volatile organic compounds (VOCs) on growth stimulation of Chinese cabbage (cabbage) at seedling stage. SPME-GC/MS analysis employed to identify headspace VOCs emitted from the rhizobacterium. Synthetic indole was assayed at various concentrations for the growth stimulation of cabbage and the emission of indole from the bacterized cabbage seeds was identified.

Results

P. vulgaris JBLS202 promoted the growth of cabbage via volatiles in a dose-dependent manner. VOC emission assay by SPME-GC/MS revealed that indole was a major headspace volatile compound emitted from the rhizobacterium. Moreover, the growth of cabbage was promoted significantly in the presence of 0.63 μg of synthetic indole. The vigor index and fresh weight of the seedlings were increased by 39.9 % and 32.6 %, respectively when the seeds of cabbage were bacterized with P. vulgaris JBLS202 cells (1?×?10⁷?CFU/ml). The emission of indole from the bacterized seeds was demonstrated by SPME-GC/MS.

Conclusions

Results indicated that either synthetic or biological/bacterial indole could increase the growth of cabbage significantly. Though the molecular biological role of indole in plant growth promotion remains to be investigated, this is the first report on detailed interaction between bacterial indole and plants.     

Metabolism of ingested indole compounds in the gut of three species of heteroptera

• 1.1. All kinds of indole compounds used for the experiment were more or less metabolized in the gut of Dolycoris baccarum, Eurydema rugosum and Elasmostethus humeralis.
• 2.2. The metabolic pattern of the bugs was classified into four types (I–IV) for several indole compounds in the same way as for IAA.
• 3.3. The IAA metabolites in the excreta of the three species were probably the high-molecular compound combining with such substances as amino acids, sugars or proteins to some position of indole nucleus.
• 4.4. The crude excreta of E. humeralis fed with each of several indole compounds had a significant auxin activity.
• 5.5. Most of the metabolites of indole-3-acetaldehyde in the excreta of E. humeralis had also a significant auxin activity.
• 6.6. The significance of auxin metabolism in the gut of the bugs and the difference of auxin metabolism between aphids and bugs are discussed.

     

Melohenryines A and B,two new indole alkaloids from Melodinus henryi

Two new monoterpenoid indole alkaloids, melohenryines A and B (1 and 2), along with six known indole alkaloids, were isolated from the twigs and leaves of Melodinus henryi. Structures of the new alkaloids were established by extensive spectroscopic techniques including NMR spectroscopy and mass spectrometry. Melohenryine A (1) represents the first example of monoterpenoid indole alkaloids characterized an ester carbonyl group at C-19 position. All of the new compounds were evaluated for in vitro cytotoxicity against several human cancer cell lines.     

Caecal environment of rats fed far East Asian-modelled diets

To clarify the effect of type of foods on the intestinal environment, Far East Asian- (FEA; rich in rice starch, soy protein and soy oil) and Far East Asian marine- (FEAM; rich in rice starch, fish meal, fish oil and brown alga) modelled diets and sucrose, casein and beef tallow-rich (SCB) diet were prepared. After the 2-week administration of diets in rats, caecal organic acids and putrefactive compounds (ammonia, indole, phenol and H₂S, which are regarded as putative risk factors for tumours) were determined. The caecal microbiota was also analyzed using denaturing gradient gel electrophoresis and pyrosequencing with bar-coded primers targeting the bacterial 16S rRNA gene. Levels of n-butyrate, acetate, indole and phenol were high in rats fed FEA. On the other hand, H₂S was clearly suppressed by both FEA and FEAM comparing with SCB. These results suggest that FEAM is preferable to FEA for optimal intestinal environment and host health. Both microbial analyses showed that the diversity of microbiota in the FEAM group was lower than in the other diet groups. Ratio of Firmicutes, Bacteroidetes and Proteobacteria in the SCB group was about 5:4:1. Firmicutes, particularly Lachnospiraceae, was promoted by FEA and FEAM.     

Polycyclic phloroglucinols as PTP1B inhibitors from Hypericum longistylum: Structures,PTP1B inhibitory activities,and interactions with PTP1B

Protein tyrosine phosphatase 1B (PTP1B) has been regarded as a target for the research and development of new drugs to treat type II diabetes and PTP1B inhibitors are potential lead compounds for this type of new drugs. A phytochemical investigation to obtain new PTP1B inhibitors resulted in the isolation of four new phloroglucinols, longistyliones A–D (1–4) from the aerial parts of Hypericum longistylum. The structures of 1–4 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of these compounds were established by comparing their experimental electronic circular dichroism (ECD) spectra with those calculated by the time-dependent density functional theory method. Compounds 1–4 possess a rare polycyclic phloroglucinol skeleton. The following biological evaluation revealed that all of the compounds showed PTP1B inhibitory effects. The further molecular docking studies indicated the strong interactions between these bioactive compounds with the PTP1B protein, which revealed the possible mechanism of PTP1B inhibition of bioactive compounds. All of the results implied that these compounds are potentially useful for the treatment of type II diabetes.     

Design,synthesis and evaluation of novel indole derivatives as AKT inhibitors

Herein, we describe the discovery and synthesis of a new series of 1,2,4,7-tetra-substituted indole derivatives as novel AKT inhibitors by optimization of a weak hit methyl 4-(2-aminoethoxy)-1H-indole-2-carboxylate (1). Both representative compounds 6a and 6o exhibited the most potent inhibitory activities against AKT1, with inhibition rates of 72.5% and 78.6%, respectively, at concentrations of 10 nM. In addition, compounds 6a and 6o also potently inhibited the phosphorylation of the downstream GSK3 protein and displayed slightly better anti-proliferative activities in a prostate cancer cell line.     

Synthesis and tyrosinase inhibition activity of trans-stilbene derivatives

Synthesis of a focussed library of trans-stilbene compounds through Wittig and other base catalysed condensation reactions is presented. The synthesized stilbenes were screened for their inhibitory potential against murine tyrosinase activity to explore the structure activity relationship (SAR). Presence of electron withdrawing group (–CN) at the double bond and hydroxyl group or halogen atom especially at para-position on the aromatic rings was found to significantly elevate the inhibitory activity. Among all the compounds screened, compounds 2, 6, 8, 10, 11, 15 and 21 were found to exhibit appreciable inhibitory activity. Compound 21 ((E)-2,3-bis(4-Hydroxyphenyl)acryonitrile) was found to be the most active with an IC₅₀ value of 5.06 μM which is less than half of the value 10.78 μM observed for resveratrol (common standard used in murine tyrosinase activity studies) under similar conditions. The results obtained from the present study reveal structural/functional group sensitivity for the tyrosinase inhibitory activity of stilbenoid moieties and are expected to be very helpful for the design and synthesis of novel, selective and effective tyrosinase inhibitors.     

2-(Substituted phenyl)amino analogs of 1-methoxyspirobrassinol methyl ether: Synthesis and anticancer activity

New analogs of indole phytoalexin 1-methoxyspirobrassinol methyl ether have been designed by replacement of its 2-methoxy group with 2-(substituted phenyl)amino group. Synthesized by spirocyclization methodology, trans- and cis-diastereoisomers of target compounds were isolated and evaluated as potential anticancer and antimicrobial agents. Their molecular geometries were refined by ab initio minimizations. Pharmacophore modeling and QSAR studies were performed in order to correlate their molecular structure and biological activity.     

Synthesis of novel indenoquinoxaline derivatives as potent α-glucosidase inhibitors

A series of new N-(11H-Indeno[1,2-b]quinoxalin-11-ylidene)benzohydrazide derivatives (3a–3p) were synthesized and evaluated for their α-glucosidase inhibitory activity. The synthesized compounds 3d, 3f, 3g, 3k, 3n, 3p and 4 showed significant α-glucosidase inhibitory activity as compared to acrabose, a standard drug used to treat type II diabetes. Structures of the synthesized compounds were determined by using FT-IR, ¹H NMR, ¹³C NMR, mass spectrometry and elemental analysis techniques.     

Catalytic asymmetric synthesis of indole derivatives as novel α-glucosidase inhibitors in vitro

Indole containing compounds have acquired conspicuous significance due to their wide spectrum of biological activities. Synthesis of a series of enantiomerically pure indole derivatives 3a-r via Friedel–Crafts alkylation of indole 1 with enones 2a-r were described here. The products were isolated in a moderate to excellent yields (upto 89%) with excellent enantioselectivities (upto 99.9% ee). These compounds 3a-r were evaluated for their in vitro α-glucosidase inhibitory activity and some of them were identified as potent inhibitors (IC₅₀ = 4.3 ± 0.13–43.9 ± 0.51 μM) with several fold higher activity than the clinically used α-glucosidase inhibitor, acarbose (IC₅₀ = 840 ± 1.73 μM). To the best of knowledge, this is the first report of the propanone substituted indole ring containing compounds by in vitro α-glucosidase enzyme inhibition.     

Prenylated indole alkaloids from the stem bark of Hexalobus monopetalus

Seven new prenylated indole alkaloids (1–7) together with two known compounds (8–9) were isolated from the stem bark of Hexalobus monopetalus. Their structures were established on the basis of comprehensive spectroscopic analysis, including HR-MS, 1D and 2D NMR and by comparison of their spectral data with those reported in literature. The new compounds were tested for antimicrobial activity against selected pathogenic bacteria and fungi but showed no activity. The marked presence of prenylated indole alkaloids in Hexalobus and closely related genera makes them useful chemotaxonomic markers.     

Phytochemical constituents from Neolamarckia cadamba (Roxb.) Bosser

Phytochemical study on Neolamarckia cadamba (Roxb.) Bosser has yielded ten indole alkaloids, neolarmarckine A-E (1–5), cadamine (6), 3β-isodihydrocadambine (7), angustine (8) and naulafine (9) and harmane (10). The structural elucidation of all the compounds were conducted based on the thorough analysis of spectroscopic data and comparison with reported data. The chemotaxonomic significance of all these compounds were summarized. Among all the indole alkaloids, compound 3–5 were new compounds and isolated from Neolamarckia cadamba (Roxb.) Bosser for the first time. Compounds 1 and 2 were only found in Neolamarckia species while compounds 6 and 7 were only isolated from the family of Rubiaceace. Besides, compound 8 has been found in six genera of Rubiaceae and two genera of Apocynaceae while compound 9 was isolated from Neolamarkia species for the first time. Compound 10 can be found in many genera of Rubiaceae and also more than ten families such as Zygophyllaceae, Cyperaceae, Passifloraceae, Bignoniaceae, Sapotaceae, Elaeagnaceae, Leguminosae, Loganiaceae, Apocynaceae, Combretaceae, Chenopodiaceae, Commelinaceae and Polygalaceae.     

Modification of Bischler-Möhlau indole derivatives through palladium catalyzed Suzuki reaction as effective cholinesterase inhibitors,their kinetic and molecular docking studies

Due to the immense importance of aryl indole nucleus, herein we report the palladium-catalyzed arylation of N-substituted 2-aryl indole utilizing Suzuki-Miyaura cross coupling methodology. The biological screening for cholinesterase inhibition of the resulted biaryl indole moieties was carried out to evaluate their pharmacological potential, expecting to involve the development of new therapeutics for various inflammatory, cardiovascular, gastrointestinal and neurological diseases. This research work also involved the use of utilization of microwave-assisted organic synthesis (MAOS) for the synthesis of Bischler-Möhlau indole which is further biarylated via palladium-catalyzed cross coupling reaction. All the synthetic compounds (3a-n) were tested for cholinesterase inhibition and exhibited high level of AChE inhibitory activities. Interestingly, compounds 3m and 3n were found to be dual inhibitors, however, remaining compound exhibited no inhibitory activity against BChE. The biological potential of the resulted compounds was explained on the basis of molecular docking studies, performed against AChE and BChE, exploring the probable binding modes of most potent inhibitors.     

Design,synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2

Sirtuins (SIRTs), class III HDAC (Histone deacetylase) family proteins, are associated with cancer, diabetes, and other age-related disorders. SIRT1 and SIRT2 are established therapeutic drug targets by regulating its function either by activators or inhibitors. Compounds containing indole moiety are potential lead molecules inhibiting SIRT1 and SIRT2 activity. In the current study, we have successfully synthesized 22 indole derivatives in association with an additional triazole moiety that provide better anchoring of the ligands in the binding cavity of SIRT1 and SIRT2. In-vitro binding and deacetylation assays were carried out to characterize their inhibitory effects against SIRT1 and SIRT2. We found four derivatives, 6l, 6m, 6n, and 6o to be specific for SIRT1 inhibition; three derivatives, 6a, 6d and 6k, specific for SIRT2 inhibition; and two derivatives, 6s and 6t, which inhibit both SIRT1 and SIRT2. In-silico validation for the selected compounds was carried out to study the nature of binding of the ligands with the neighboring residues in the binding site of SIRT1. These derivatives open up newer avenues to explore specific inhibitors of SIRT1 and SIRT2 with therapeutic implications for human diseases.     

Rapid linkage of indole carboxylic acid to the plant cell wall identified as a component of basal defence in Arabidopsis against hrp mutant bacteria

Changes occurring to plant cell walls were examined following inoculation of Arabidopsis leaves with pathogenic and non-pathogenic (hrpA mutant) strains of Pseudomonas syringae pv. tomato. We have targeted low molecular weight, cross-linked phenolic and indolic compounds that were released from wall preparations by alkaline hydrolysis at 70 °C and in a microwave bomb. Significantly higher concentrations of syringaldehyde, p hydroxybenzaldehyde and indole carboxylic acid were recovered from cell walls isolated from leaves 24 h after challenge with the hrpA mutant compared with wild-type DC3000. Time course experiments showed that the accumulation of indole carboxylic acid and the other group of differentiating metabolites had occurred within 12 h of inoculation. The callose synthase deficient mutant pmr4-1 was more resistant than wild-type Columbia plants to P. syringae pv. tomato. Restricted bacterial multiplication was associated with increased accumulation of indole carboxylic acid on the plant cell wall. In the absence of callose deposition in the pmr 4-1 mutant, indolic derivatives may serve as a structural scaffold for wall modifications following bacterial challenge.     

Efficient synthesis of novel dialkyl-3-cyanopropylphosphate derivatives and evaluation of their anticholinesterase activity

Based on the broad spectrum of biological activities associated with organophosphates, a novel type of this class of compounds was synthesized, bearing a nitrile group, from the sodium alkoxide-catalyzed reaction of dialkylphosphites with γ-ketonitriles at 80 °C under solvent-free conditions. A reaction mechanism involving a phospha-Brook type rearrangement is proposed. Eight title compounds were investigated for their in vitro inhibitory potency and selectivity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using Ellman’s spectrophotometric method. The synthesized derivatives exhibited mostly a moderate activity against both cholinesterases. The IC₅₀ values for BChE were in a smaller concentration range (5.96–23.35 µM) compared to those for AChE inhibition (9.61–53.74 µM). The diethyl-3-cyano-1-p-tolylpropylphosphate which displayed the higher dual inhibitory potency towards both cholinesterases could be considered as a potential candidate for developing new drugs to treat Alzheimer’s disease.     

Floral scent in natural hybrids of Ipomopsis (Polemoniaceae) and their parental species

Background and Aims

Floral traits, such as floral volatiles, can contribute to pre-zygotic reproductive isolation by promoting species-specific pollinator foraging. When hybrid zones form, floral traits could also influence post-zygotic isolation. This study examined floral volatiles in parental species and natural hybrids in order to explore potential scent mediation of pre-zygotic and post-zygotic isolation.

Methods

Floral bouquets were analysed for the sister species Ipomopsis aggregata and I. tenuituba and their natural hybrids at two contact sites differing in both hybridization rate and temporal foraging pattern of hawkmoth pollinators. Floral volatiles were quantified in diurnal and nocturnal scent samples using gas chromatography–mass spectrometry.

Key Results

The bouquets of parental species and hybrids showed qualitative overlap. All flowers emitted similar sets of monoterpenoid, sesquiterpenoid, aliphatic and benzenoid compounds, but separated into groups defined by multivariate analysis of quantitative emissions. The parental species differed most strikingly in the nitrogenous compound indole, which was found almost exclusively in nocturnal bouquets of I. tenuituba. Natural hybrid bouquets were highly variable, and showed emission rates of several compounds that appeared transgressive. However, indole emission rates were intermediate in the hybrids compared with rates in the parents. Volatile bouquets at the contact site with lower hybridization did not show greater species specificity in overall scent emission, but I. tenuituba presented a stronger indole signal during peak hawkmoth activity at that site.

Conclusions

The two species of Ipomopsis differed in patterns of floral bouquets, with indole emitted in nocturnal I. tenuituba, but not in I. aggregata. Natural hybrid bouquets were not consistently intermediate between the parents, although hybrids were intermediate in indole emission. The indole signal could potentially serve as a hawkmoth attractant that mediates reproductive isolation both before and after hybrid formation.