Kinfe K. Redda

Functional evaluation of synthetic flavonoids and chalcones for potential antiviral and anticancer properties

Flavonoids, stilbenes, and chalcones are plant secondary metabolites that often possess diverse biological activities including anti-inflammatory, anti-cancer, and anti-viral activities. The wide range of bioactivities poses a challenge to identify their targets. Here, we studied a set of synthetically generated flavonoids and chalcones to evaluate for their biological activity, and compared similarly substituted flavonoids and chalcones. Substituted chalcones, but not flavonoids, showed inhibition of viral translation without significantly affecting viral replication in cells infected with hepatitis C virus (HCV). We suggest that the chalcones used in this study inhibit mammalian target of rapamycin (mTOR) pathway by ablating phosphorylation of ribosomal protein 6 (rps6), and also the kinase necessary for phosphorylating rps6 in Huh7.5 cells (pS6K1). In addition, selected chalcones showed inhibition of growth in Ishikawa, MCF7, and MDA-MB-231 cells resulting an IC50 of 1-6µg/mL. When similarly substituted flavonoids were used against the same set of cancer cells, we did not observe any inhibitory effect. Together, we report that chalcones show potential for anti-viral and anti-cancer activities compared to similarly substituted flavonoids.

Conformational Analysis and Molecular Properties of N-(Substituted Phenylcarbonylamino)- 4-(1-Hydroxymethylphenyl)-1,2,3,6-Tetrahydropyridines

The three-dimensional structures of active derivatives of N-(substitutedphenylcarbonylamino)-4-(1-hydroxymethylphenyl)-1,2,3,6-tetrahydropyri-dines, which have previously been shown to possess anti-inflammatory activities, were built using BIOMEDCAche 5.0 software program. In addition, the three dimensional structures of some of the inactive ones were similarly generated. The conformational analysis, molecular and electronic structures were examined by molecular mechanics and quantum mechanics calculations. The primary objective was to clarify the effects of physicochemical properties of substituents on activity, since the exact role of the substitution pattern on the phenyl ring is uncertain. In addition, the experimental log P values did not appear to have any influence on the anti-inflammatory potencies of these compounds, since compounds having differing lipid solubilities are equiactive. We found that strongly electron-donating group, such as the para-substituted methoxy group, detracts from activity. The conformational analysis indicated that the 4-ethyl derivative had the lowest energy conformation. Except for compound 1, which showed the lowest surface volume, compounds 2-9 had nearly similar surface volumes.

The Synthesis Of Several N-(Substituted Phenylcarbonylamino)-4-(3-cyclohexenyl)-1,2,3,6-tetrahydropyridines as Potential Anti-Inflam-Matory Agents

Several N-(substituted phenylcarbonylamino)-4-cyclohexenyl-1,2,3,6-tetrahydropyridines 7 were synthesized via sodium borohydride reduction of the corresponding N-(substituted phenylcarbonylimino)-4...

In-Vitro Antiproliferative Activity of New Tetrahydroisoquinolines (THIQs) on Ishikawa Cells and their 3D Pharmacophore Models

The antiproliferative activities of new substituted tetrahydroisoquinolines (THIQs) are described. Their cytotoxicities against Ishikawa human endometrial cell line were determined after 72 h drug expose employing Celtiter-Glo assay at concentrations ranging from 0.01 to 100,000 nM. The antiproliferative activities of the compounds understudy were compared to tamoxifen (TAM). In-vitro results indicated that most of the compounds showed better activity than TAM. The most active compounds obtained in this study were 1, 2, 3 and 22 whose IC50 values are 1.41, 0.91, 0.74 and 0.36 μM respectively. This study helped us to evaluate the risk of developing endometrial cancer in the design of non-steroid estrogen receptor modulators with no agonistic effects on uterus. In-silico pharmacophore hypotheses were generated using GALAHAD and PHASE and the best models with a probable bioactive conformation(s) for these compounds were proposed. These conformations and the alignments of the molecular structures give us an insight in designing compounds with better biological activity.

Synthesis and Biological Evaluation of Substituted N-[3-(1H-Pyrrol-1-yl)methyl]-1,2,5,6-tetrahydropyridin-1-yl]benzamide/benzene Sulfonamides as Anti-Inflammatory Agents

The pharmacological activities of tetrahydropyridine (THP) derivatives are dependent on the substituent ring moiety. In this study, we investigate the anti‐inflammatory activities of 12 newly synthesized substituted N‐[3‐(1H‐pyrrol‐1‐yl)methyl]‐1,2,5,6‐tetrahydrobenzamide/benzene sulfonamides (9a–l) in murine BV‐2 microglial cells. All compounds were initially screened for attenuation of nitric oxide (NO) production in lipopolysaccharide (LPS) (1 µg/mL)‐activated microglial cells. The data show that only SO2‐substituted THPs were effective at sub‐lethal concentrations (IC50 values of 12.92 µM (9i), 14.64 µM (9j), 19.63 µM (9k)) relative to L‐N6‐(1‐iminoethyl)lysine positive control (IC50 = 3.1 µM). The most potent SO2‐substituted compound (9i) also blocked the LPS‐inducible nitric oxide synthase (iNOS) and attenuated the release of several cytokines including IL‐1α, IL‐10, and IL‐6. These findings establish the moderate immuno‐modulating effects of SO2‐substituted THP derivatives.

Synthesis and Biological Evaluations of Ring SubstitutedTetrahydroisoquinolines (THIQs) as Anti-Breast Cancer Agents

Breast cancer is a leading cause of mortality among women, resulting in more than half a million deaths worldwide every year. Although chemotherapeutic drugs remain the main stay of cancer treatment, it is observed that toxicity to normal cells poses a limitation to their therapeutic values. Moreover, the patient recovery rate from advanced breast cancer by chemotherapy is still unacceptably low. Tetrahydroisoqinoline derivatives (THIQs) were reported to act as selective subtype estrogen receptor antagonists/agonists and may serve as potential therapeutic agents for breast cancer. In continuation of previous work we systematically synthesized and characterized the tetrahydroisoquinoline (THIQs) analogs. In-vitro antiproliferative activity of new substituted tetrahydroisoquinoline analogs were evaluated against human ER (+) MCF-7 (breast), ER (−) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines using the CellTiter-Glo luminescent cell viability assay. The most active compounds obtained in this study were 2b, 2i, and 3 g as demonstrated by their activity (IC50=0.2 μg/mL, 0.08 μg/mL; 0.61 μg/mL, 0.09 μg/mL; 0.25 μg/mL, 0.11 μg/mL) against MCF-7 and Ishikawa cell lines respectively, in comparison to Tamoxifen activity (IC50=3.99 μg/mL, 7.87 μg/ml). The newly synthesized molecules were docked in the active sites of the ER-α (PDB: 3ERT), ER-β (PDB: 1QKN) and alpha-beta tubulin taxol complex (1JFF) crystal structures to determine the probable binding modes (bioactive conformations) of the active compounds.

Investigation of the binding of dioxin selective pentapeptides to a polyaniline matrix

Polyaniline in form of emeraldine salt and emeraldine base was used as a matrix to attach several labeled and non-labeled dioxin selective pentapeptides both directly to the polymer and using glutaraldehyde as a linker. The peptides have been selected as a model to study the binding process due to their smaller size, lower sensitivity to the environment and potential application as solid state extraction reagents for chlorinated toxins. The composition and the properties of the compounds were investigated by means of elemental analysis, XPS, FTIR, UV/vis, and fluorescence spectroscopy. The results have shown that 3.30-7.76% peptides were attached to the emeraldine base both with and without a linker. Glutaraldehyde and the peptides were connected to the matrix via chemical bond resulting in formation of compounds whit similar composition and stability in a broad pH range. The influence of the linker and the peptides on the electronic properties and composition of the polymer have been investigated by principal component analysis.

SYNTHESIS OF N-SUBSTITUTED CARBONYLAMINO-1,2,3,6- TETRAHYDROPYRIDINES AS POTENTIAL ANTI- INFLAMMATORY AGENTS

Abstract Several N-substituted carbonyl/sulfonylamino-1,2,3,6-tetrahydropyridines (5a–i and 9a, b) were synthesized via sodium borohydride reduction of the corresponding N-substitutedimino-pyridinium ylides (4a–i and 8a, b) in absolute ethanol.

SYNTHESIS OF 3′-AZIDO-2′,3′- DIDEOXY-4′-KETOHEXOPYRANOID ANALOGUES AS POSSIBLE ANTIVIRAL NUCLEOSIDES

ABSTRACT Peracetylated 2-deoxy-D-glucose was coupled with silylated bases. The product was deacetylated and the 4′,6′-hydroxy groups were then protected. An azido group was introduced at the 3′-carbon via tosylation, followed by deprotection, tritylation, and oxidation to give the final compound.

The influence of a new compound, PATP, on glucose transport in the isolated fat cell☆

A newly synthesized compound, N-(4-pyridylcarbonyl amino) 1, 2, 3, 6 tetrahydropyridine (PATP) was earlier found to elevate the blood glucose level in rats. This suggested that the compound might be accomplishing this by blocking glucose transport into tissue cells. This hypothesis has now been examined in the isolated fat cell system using a modification of the method to improve the accuracy of measurements made. This study indicated that PATP is a competitive inhibitor of glucose transport and metabolism (KI = 0.89 mM) but could not unequivocally prove that the effect was on transporter action alone. That the compounds action was at this level, however was shown by its ability to inhibit the uptake of the transported but non-metabolized sugar, 3-0-methyl glucose (KI = 3 mM). PATP is a nonphenolic inhibitor of glucose transport unrelated in structure to the sugar or to another more potent inhibitor, phloretin.