Synthesis and biological evaluation of novel salicylidene uracils: Cytotoxic activity on human cancer cell lines and inhibitory action on enzymatic activity.

A series of salicylidene uracil (1-18) derived from 5-aminouracil and substituted salicylaldehydes were analyzed for cytotoxic activity and enzyme inhibitory potency. Nine out of eighteen derivatives (6-8, 10, 12-15, 18) are novel molecules synthesized for the first time in this work, and other derivatives were previously synthesized by our group. The compounds were characterized by Proton nuclear magnetic resonance, carbon nuclear magnetic resonance, fourier transform infrared spectroscopy, and elemental analysis. All compounds were tested for their in vitro cytotoxicity against PC-3 (human prostate adenocarcinoma), A549 (human alveolar adenocarcinoma), and SHSY-5Y (human neuroblastoma) cancer cell lines and the nontumorigenic HEK293 (human embryonic kidney cells) cell line. The 3,5-di-tert-butylsalicylaldehyde derived compound (8) was toxic to PC-3 human prostate adenocarcinoma cells, showing a promising IC50 value at 7.05 ± 0.76 µM. The present study also aimed to evaluate the inhibitory effects of the compounds against several key enzymes, namely carbonic anhydrase I and II (CA I and CA II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione reductase (GR), which are implicated in various global disorders, such as Alzheimer's disease, epilepsy, cancer, malaria, diabetes, and glaucoma. The inhibitory profiles of the tested compounds were assessed by determining their Ki values, which ranged from 2.96 to 9.24 nM for AChE, 3.78 to 12.57 nM for BChE, 8.42 to 25.74 nM for CA I, 7.24 to 19.74 nM for CA II, and 0.541 to 1.124 µM for GR. Molecular docking studies were also performed for all compounds. Most derivatives exhibited much more effective inhibitory action compared with clinically used standards. Thus, our findings indicate that the salicylidene derivatives presented in this study are promising drug candidates that need further evaluation.

Semi-Purified Saponins of Holothuria poli Associated Antiproliferation in Tumor Cell Lines.

The incidence of cancer has exhibited an increasing trend in recent years because of many reasons such as environmental and nutritional factors. There is a great need for the development of new and natural molecules with lower side effects in the therapy of cancer. It was aimed to evaluate the antiproliferative effect of semi-purified triterpene glycosides of Holothuria poli on different human cancer cell lines. The body walls of H. poli as the main sources of saponins were used and the saponin content of the extract was characterized by MALDI-TOF/MS. The antiproliferation activity of the characterized extract was tested on cancer cell lines. The extract showed antiproliferative effect on the studied cancer cell lines. The mass analysis results reveal that Holothurin A is one of the saponins within the extract. The measured IC50 values were found as 31.41 ± 2.20, 77.45 ± 0.23, and 34.79 ± 0.90 µg mL-1 for HT-29, UPCI-SCC-131, and T84 cell lines, respectively. H. poli secretes not only specific saponins but also a cocktail of them. Specific versus. cocktails of the saponins and by also applying organic modification must be studied in further research to understand their mechanisms in the antiproliferation studies since this paper reveals promising results.

Analysis of saponins and phenolic compounds as inhibitors of α-carbonic anhydrase isoenzymes.

A series of phenolic and saponin type natural products such as quercetin, rutin, catechin, epicatechin, silymarin, trojanoside H, astragaloside IV, astragaloside VIII and astrasieversianin X, were investigated for their inhibitory effects against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). We here report inhibitory effects of these compounds against five α-CA isozymes (hCA I, hCA II, bCA III, hCA IV and hCA VI). Most of the phenolic and saponin type compounds inhibited the isoenzymes quite effectively at low micromolar K(I)-s ranging between 0.1 and 4 µM, whereas a few derivatives were ineffective (K(I)-s > 100 µM). The results were remarkable which might lead to design of novel CAIs with a diverse inhibition mechanism compared to sulfonamide/sulfamate inhibitors.

L-(+)-Tryptophan methyl ester derived polymeric microbeads as an efficient heterogeneous catalyst for green synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles.

The cross-linked microbeads with average diameter of 106-300 µm, [poly(EGDMA-MATrp)], were obtained by copolymerization reaction of N-methacryloyl-L-(+)-tryptophan methyl ester (MATrp) with ethylene glycol dimethacrylate (EGDMA) and successfully applied as a heterogeneous catalyst in conjugate addition reaction of nitromethane to substituted 2-iminochromenes in aqueous media. A variety of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles has been synthesized in good yields. Polymeric microbeads were very durable and reused 5 times without a significant loss of activity. DFT calculations and experimental results revealed the significant role of π-π interactions as well as hydrogen bonding in the reaction mechanism.

Flavonoid glycosides and methylinositol from Ebenus haussknechtii.

Two flavonoid glycosides (compounds 1 and 3) of which one is reported for the first time and a methylinositol (compound 2) were isolated from the aerial parts of Ebenus haussknechtii (Leguminosae). The structures were established as quercetin-7-O-[alpha-L-rhamnopyranosyl(1 --> 6)-beta-D-galactopyranoside] (1), morin-3-O-[4-[5-(4-hydroxyphenyl)pentanoyl]-alpha-L-rhamnopyranosyl(1 --> 6)-beta-D-galactopyranosyl]-7-4'-di-O-methyleter (3), and methylinositol (2) on the basis of chemical and spectroscopic means. The antimicrobial activities of the extracts have also been examined.

Cycloartane glycosides from Astragalus plumosus var. krugianus and evaluation of their antioxidant potential.

The methanol extracts of Astragalus plumosus var. krugianus Chamb. & Matthews afforded sixteen cycloartane glycosides among which krugianoside A, was never reported before. All compounds were evaluated for their cytotoxic activity in human skin fibroblast WS1 cells. For compounds exhibiting no significant effect on WS1 viability, the antioxidant potential was examined. Compounds 1 and 8 prevented elevation of ROS induced by t-BOOH, suggesting the potential activity of these compounds to protect fibroblasts from oxidative stress.

Triterpene glycosides from Agrostemma gracilis.

Four triterpene saponins, agrostemmosides A-D were isolated from the methanol extract of Agrostemma gracilis. The structures of the compounds were determined as 3-O-beta-D-xylopyranosyloleanolic acid 28-O-beta-D-glucopyranosyl-(1-->2)-[beta-D-xylopyranosyl-(1-->6)]-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl ester, 3-O-alpha-L-rhamnopyranosyl-(1-->2)-beta-D-xylopyranosyloleanolic acid 28-O-beta-D-glucopyranosyl-(1-->2)-[beta-D-xylopyranosyl-(1-->6)]-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl ester, 3-O-beta-D-xylopyranosylechinocystic acid 28-O-beta-D-glucopyranosyl-(1-->2)-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl ester, 3-O-beta-D-xylopyranosylechinocystic acid 28-O-beta-D-glucopyranosyl-(1-->2)-[beta-D-xylopyranosyl-(1-->6)]-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosyl ester by a combination of one- and two-dimensional NMR techniques, and mass spectrometry. To the best of our knowledge this is the first phytochemical report on A. gracilis, and echinocystic acid saponins were encountered for the first time in Caryophyllaceae family.

Triterpene and flavone glycosides from Anchusa undulata subsp. hybrida.

A novel triterpene glycoside, undulatoside (1), which is characterised as 3-O-(beta-D-glucopyranosyl)-29-O-(beta-D-glucopyranosyl)-2alpha,23-dihydroxyolean-12-en-28-oic acid, was isolated from Anchusa undulata subsp. hybrida and its structure was deduced by spectral data. In addition to undulatoside, seven known triterpene glycoside and a flavonoid glycoside were also isolated for the first time from this plant. The structures have been identified by spectroscopic and chemical methods. The antimicrobial activities of all extracts of the plant were investigated by disc diffusion method.