Synthesis and Biological Evaluation of Acyclic Phosphonic Acid Nucleoside Derivatives

As part of a project to generate a library of nucleosides as potential antiviral agents, a small subset of novel acyclic phosphonic acid nucleosides was prepared. Practical synthetic routes are described for three targets, which were then tested against HIV, hepatitis C virus (HCV), and Dengue virus.     

Phosphonic and Phosphinic Acid Derivatives as Novel Tyrosinase Inhibitors: Kinetic Studies and Molecular Docking

A dozen of phosphonic and phosphinic acid derivatives containing pyridine moiety were synthesized and its inhibitory activity toward mushroom tyrosinase was investigated. Moreover, molecular docking of these compounds to the active site of the enzyme was performed. All the compounds ( 1 – 10 ) demonstrated the inhibitory effect with the IC₅₀ and inhibition constants ranging millimolar concentrations. The obtained results indicate that the compounds show different types of inhibition (competitive, noncompetitive, mixed), but all of them are reversible inhibitors. The obtained outcomes allowed to make the structure–activity relationship (SAR) analysis. Compound 4 ([(benzylamino)(pyridin‐2‐yl)methyl]phenylphosphinic acid) revealed the lowest IC₅₀ value of 0.3 mm and inhibitory constant of K_i 0.076 mm , with noncompetitive type and reversible mechanism of inhibition. According to SAR analysis, introducing bulky phenyl moieties to phosphonic and amino groups plays an important role in the inhibitory potency on activity of mushroom tyrosinase and could be useful in design and development of a new class of potent organophosphorus inhibitors of tyrosinase. Combined results of molecular docking and SAR analysis can be helpful in designing novel tyrosinase inhibitors of desired properties. They may have broad application in food industry and cosmetology.     

Synthesis,Antiproliferative and Cytotoxic Activities,DNA Binding Features and Molecular Docking Study of Novel Enamine Derivatives

Novel enamine derivatives were synthesized from the reaction of lactone and chalcones and their antiproliferative and cytotoxic activities against six cancer cell lines (e. g., HeLa, HT29, A549, MCF7, PC3 and Hep3B) and one normal cell lines (e. g., FL) were investigated along with their mode of interactions with CT‐DNA. Most of the enamine derivatives with IC₅₀ values of 86–168 μM demonstrated much stronger antiproliferative activity than the starting molecules against the cancer cells. While, among the enamine derivatives, four compounds displayed higher cytotoxic potency than the control drugs (5‐fluorouracil and cisplatin) against the Hep3B cell lines, these compounds did not exhibit any significant toxicity against normal cells, FL. The UV/VIS spectral data suggest that eight compounds cause hypochromism with a slight bathochromic shift (～6 nm), indicating that they bind to the DNA by way of an intercalative or minor groove binding mode. The binding constants of the compounds are in the range of 0.1×103 M^?1–2.3×104 M^?1. The antiproliferative activity of studied enamine derivatives could possibly be due to their DNA binding as well as their cytotoxic properties. In addition to these assays, the chalcones and enamine derivatives were investigated by molecular docking to calculate the synergistic effect of antiproliferative activities against six human cancer cell lines.     

Inhibition of Aminopeptidases by Phosphonic Acid and Phosphinic Acid Analogues of Aspartic and Glutamic Acids

Abstract

More than 30 phosphonic and phosphinic acid analogues of aspartic and glutamic acids were synthesized in order to probe how the structural differences of these molecules were reflected in their ability to inhibit cytosolic (LAP) and microsomal (APM) aminopeptidases. Although most of the compounds studied were found to exert only a modest inhibitory effect, the studies provide some information on the structural requirements of the binding subsites and catalytic centers of both enzymes.     

Synthesis and Characterization of Novel Thiazolo[3,2‐a]pyrimidine Derivatives and Evaluation of Antioxidant and Cytotoxic Activities

A series of novel thiazolo[3,2‐a]pyrimidines were synthesized and characterized by FT‐IR, ¹H, ¹³C‐NMR and mass techniques. Their antioxidant activities were investigated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical scavenging assay and the results showed that all the synthesized compounds exhibit good antioxidant activity. In addition, it was found that any substituent on the aromatic ring of the products plays an important role in their antioxidant activity. In vitro cytotoxicity of compounds 4a – 4j was investigated using MTT cell viability assay. Among these compounds, 6‐ethyl 2,3‐dimethyl 5‐(4‐chlorophenyl)‐7‐methyl‐2,3‐dihydro‐5H‐[1,3]thiazolo[3,2‐a]pyrimidine‐2,3,6‐tricarboxylate ( 4e ) bearing a chlorine substituent displayed the highest cytotoxic effect (IC₅₀=6.26±0.6 μm ) in comparison with doxorubicin (IC₅₀=0.68±0.1 μm ) as a standard after 72 h. Therefore, it is assumed that these compounds could be used as effective antioxidant and cytotoxic agents.     

Phloroglucinol Derivatives from the Fruits of Eucalyptus globulus and Their Cytotoxic Activities

A new phloroglucinol derivative, named eucalyptin B ( 1 ), along with five related known compounds ( 2 – 6 ), was isolated from the fruits of Eucalyptus globulus. Their structures were elucidated by means of 1D‐ and 2D‐NMR spectroscopy, with the absolute configuration of 1 determined by electronic circular dichroism (ECD) calculations. All isolated compounds ( 1 – 6 ) were evaluated for their cytotoxic activities against lung (A549), breast (4T1), and skin (B16F10) cancer cell lines. On the basis of cell viability assay, the cytotoxic activity of eucalyptin B ( 1 ) was further confirmed by apoptosis assay. Additionally, after treatment with eucalyptin B ( 1 ), the apoptosis factor proteins (Bcl2 and Bax) and caspase‐3 levels in A549 cells were also determined by Western‐blot analysis. By cytotoxic assay, eucalyptin B ( 1 ) exhibited potent cytotoxicity against A549 cells with an IC₅₀ value of 1.51 μm and induced concentration dependent apoptosis of up to 49%. Additionally, eucalyptin B ( 1 ) inhibited 5‐fold and increased 10‐folds in the level of Bcl2 and Bax, respectively. Furthermore, the 11‐fold increase in the level of caspase‐3 confirmed eucalyptin B ( 1 ) activated caspase dependent apoptosis pathway. In conclusion, the isolated compound eucalyptin B ( 1 ) has promising cytotoxic activity in tumor cells, especially in A549.     

Synthesis and Antiviral Evaluation of Novel 5′-Norcarboacyclic Phosphonic Acid Nucleosides

This article describes a very simple route for synthesizing a novel 5′-norcarboacyclic nucleotides. The condensation of the mesylates 17 and 18 with the natural nucleosidic bases (A,U,T,C) under standard nucleophilic substitution (K₂CO₃, 18-Crown-6, DMF) and deprotection afforded the target nucleotide analogues 27–34. In addition, these compounds were evaluated for their antiviral properties against various viruses.     

Design and Synthesis of Novel Cytotoxic Indole‐Thiosemicarbazone Derivatives: Biological Evaluation and Docking Study

In this work, two novel series of indole‐thiosemicarbazone derivatives were designed, synthesized, and evaluated for their cytotoxic activity against MCF‐7, A‐549, and Hep‐G2 cell lines in comparison to etoposide and colchicine as the reference drugs. Generally, the synthesized compounds showed better cytotoxicity towards A‐549 and Hep‐G2 than MCF‐7. Among them, (2E)‐2‐{[2‐(4‐chlorophenyl)‐1H‐indol‐3‐yl]methylidene}‐N‐(4‐methoxyphenyl)hydrazinecarbothioamide ( 8l ) was found to be the most potent compound against A‐549 and Hep‐G2, at least three times more potent than etoposide. The morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that compound 8l induced apoptosis in A‐549 cells. Moreover, molecular docking methodology was exploited to elucidate the details of molecular interactions of the studied compounds with putative targets.     

Diastereoselective Sonochemical Synthesis of Spirocyclopropaneoxindoles and Evaluation of Their Antioxidant and Cytotoxic Activities

An efficient diastereoselective synthesis of spirocyclopropaneoxindoles is reported using three‐component reactions of various phenacylidenetriphenylphosphorane, isatins and phenacyl bromide under ultrasonic irradiation. The structures of synthesized spirocyclopropaneoxindoles were characterized by their spectral data. The antioxidant activities of the synthesized compounds were evaluated by 1,1‐diphenyl‐2‐picrylhydrazyl radical scavenging assay. Among the products, those with NH group in their structure exhibited higher antioxidant activities than other derivatives. Also, in vitro cytotoxicity of compounds 4b , 4e , 4j , 4k were examined against heLa cancer cell lines using MTT assay. The results revealed that compound 4j with chlorine substituent on phenyl group displayed higher cytotoxicity activity (IC₅₀=4.50±0.30 μg/mL) after 48 h.     

Design,Synthesis, and Cytotoxic Activities of Indole and Indazole-Based Stilbenes

To develop new highly effective anticancer agents derived from naturally occurring stilbene scaffold, in total of 24 indole and indazole-based stilbenes including 17 new compounds were designed according to molecular hybridization strategy and synthesized via Witting reaction. The cytotoxic screening results against human tumor cell lines (K562 cells and MDA-MB-231 cells) showed that indole and indazole-based stilbenes are of great interest for developing anticancer agents as eight derivatives possessed strong antiproliferative activities with IC₅₀ values less than 10 μM, and those synthetic derivatives displayed more higher cytotoxicities against K562 cells than MDA-MB-231 cells. In particular, indole-based stilbene bearing piperidine exhibited the most potent cytotoxicities against both K562 and MDA-MB-231 cells with IC₅₀ values 2.4 μM and 2.18 μM, respectively, along with a remarkable selectivity towards human normal L-02 cells. Together, the results suggested that indole and indazole-based stilbenes are promising anticancer scaffolds worthy of further investigation.     

Synthesis,Molecular Modeling,and Biological Evaluation of Novel Chiral Thiosemicarbazone Derivatives as Potent Anticancer Agents

A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF‐7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC‐27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound 17b exhibited the most potent activity (IC₅₀ 4.6 μM) against HGC‐27 as compared with the reference compound, sindaxel (IC₅₀ 10.3 μM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents. Chirality 27:177–188, 2015. © 2014 Wiley Periodicals, Inc.     

Synthesis and Cytotoxicity Evaluation of Panaxadiol Derivatives

In this study, 13 panaxadiol (PD) derivatives were synthesized via reactions with aromatic compounds and amino acids. Following this, the cytotoxicity of these compounds was evaluated against four cancer cell lines (human hepatoma cells HepG‐2, human lung cancer cells A549, human breast cancer cells MCF‐7, and human colon cancer cells HCT‐116) and one normal cell lines (human gastric epithelial cells GES‐1). The results showed that the panaxadiol derivatives 3 , 12 , and 13 showed significant inhibition of cellular proliferation against cancer cells compared with PD, and the panaxadiol derivative 12 had the lowest IC₅₀ value for A549 (IC₅₀=18.91±1.03 μm ). For MCF‐7 cells, most compounds exhibited good inhibition of cellular proliferation, and the panaxadiol derivative 13 showed the strongest inhibitory effect (IC₅₀=8.62±0.23 μm ), which significantly increased the cytotoxicity of PD and was stronger than the positive control (mitomycin). For normal cells, all compounds exhibited low or no toxic effects; thus, these derivatives can be used to develop novel antiproliferative agents.     

Design,Synthesis, Antiviral,and Cytostatic Evaluation of Novel Isoxazolidine Analogues of C-Nucleotides

5-Aryl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesised from N-methyl-C-diethoxyphosphorylnitrone and vinyl aryls in good yields. Isoxazolidine phosphonates obtained herein were evaluated for activity against a broad range of DNA and RNA viruses. None of the compounds were endowed with antiviral activity nor cytostatic activity at 100 to 250 μM concentrations.     

Molecular Design,Synthesis and Docking Study of Alkyl and Benzyl Derivatives of Robustic Acid as Topoisomerase I Inhibitors

Robustic acid is reported to be a bioactive compound, isolated from the medicinal plant Dalbergia benthamii Prain . Ten alkyl and benzyl derivatives ( 2a – 2j ) of robustic acid were designed and synthesized based on molecular docking approaches. The biological activities of most of the synthesized compounds (such as 2g , 2h , and 2i ) were closely consistent with the docking results. In particular, 4‐O‐phenylpropyl substituted compound 2g displayed potent topoisomerase I inhibitory activity as well as cytotoxicity against SMMC‐7721, HepG2, and HeLa cell lines. Further biological testing suggests that compound 2g acted mainly by an arrest of the tumor cells in G1 phase of the cell cycle and suppressed cell proliferation by inducing apoptosis. The findings of this study are encouraging with respect to potential utilization of these compounds as new topoisomerase I inhibitors.     

Synthesis and Cytotoxic Evaluation of Novel Thiazolocarbazoles

Novel thiazolocarbazole derivatives 4 and 5 have been synthesized via the corresponding imino-1,2,3-dithiazoles 3. In vitro antitumor activity of these polyheterocyclic compounds was studied and the results show that 2-cyano derivatives exhibit a medium in vitro antiproliferative effect.     

Caffeoylquinic Acids,Cytotoxic, Antioxidant,Acetylcholinesterase and Tyrosinase Enzyme Inhibitory Activities of Six Inula Species from Bulgaria

Chlorogenic (5‐CQA), 1,5‐, 3,5‐, 4,5‐ and 3,4‐dicaffeoylquinic (DCQA) acids were identified and quantified in the methanol extracts of Inula oculus‐christi L., I. bifrons L., I. aschersoniana Janka var. aschersoniana, I. ensifolia L., I. conyza (Griess .) DC. and I. germanica L. by HPLC analysis. The amount of 5‐CQA varied from 5.48 to 28.44 mg/g DE and the highest content was detected in I. ensifolia. 1,5‐DCQA (4.05–55.25 mg/g DE) was the most abundant dicaffeoyl ester of quinic acid followed by 3,5‐DCQA, 4,5‐DCQA and 3,4‐DCQA. The extract of I. ensifolia showed the highest total phenolic content (119.92±0.95 mg GAE/g DE) and exhibited the strongest DPPH radical scavenging activity (69.41±0.55 %). I. bifrons extract was found to be the most active sample against ABTS^.+ (TEAC 0.257±0.012 mg/mL) and the best tyrosinase inhibitor. The studied extracts demonstrated a low inhibitory effect towards acetylcholinesterase and possessed low cytotoxicity in concentration range from 10 to 300 μg/mL toward non‐cancer (MDCK II) and cancer (A 549) cells.     

Synthesis and Anti‐HIV Activity of Guanine Modified Fluorinated Acyclic Nucleoside Phosphonate Derivatives

The preparation of an unprecedented series of nucleobase modified 3‐fluoro‐2‐(phosphonomethoxy)propyl (FPMP) acyclic nucleosides in both their (R) and (S) enantiomerically pure forms is described. The synthesis focuses on a Mitsunobu alkylation reaction to construct the C?N(9) bond between a chiral fluorinated side‐chain residue and 6‐ or 7‐modified guanine analogs. Prodrugs of FPMP‐7‐deazaguanine were also synthesized by derivatization of the corresponding phosphonic acid functionality with (bis)diamyl aspartate amidate groups, leading to moderate activity against human immunodeficiency virus type 1 (HIV‐1).     

Synthesis of New Lathyrane Diterpenoid Derivatives from Euphorbia lathyris and Evaluation of Their Anti‐Inflammatory Activities

Euphorbia factor L₃, a lathyrane diterpenoid extracted from Euphorbia lathyris, was found to display good anti‐inflammatory activity with very low cytotoxicity. To find more potent anti‐inflammatory drugs, two series of Euphorbia factor L₃ derivatives with fatty and aromatic acids were designed and synthesized. Among them, lathyrane derivative 5n exhibited most potent inhibition on LPS‐induced NO production in RAW264.7 cells with no obvious cytotoxicity. To determine the key characteristics of Euphorbia factor L₃ derivatives that contribute to anti‐inflammatory activity, we conducted a structure‐activity relationship study of these compounds.     

Antibacterial,Cytotoxic and Genotoxic Assessment of New Sulfonamide Derivatives

In the last few years, the interest in sulfonamides has expanded owing to their broad spectrum of biological activities. Their flexible structure turns them into amazing candidates to replace old drugs or develop modern multi-target agents. In this study, a series of new sulfonamides ( sul1-5 ) was evaluated, in vitro, for the antibacterial, cytotoxic and genotoxic effects. The antibacterial activity was investigated against 12 clinical and 4 reference strains. Cytotoxic activity was carried out by the brine shrimp bioassay and the genotoxicity was assessed in the Ames test. An interesting antibacterial activity was showed especially against Gram negative strains. The inhibition zones varied between 15 and 30 mm, and the Minimum Inhibitory Concentrations (MIC's) values between 0.5 and 256 μg/ml. No antibacterial activity was shown with S. aureus isolates. Only Sul1 and Sul4 were active against P. aeruginosa. Compounds Sul1 and Sul2 showed a significant cytotoxicity with LC₅₀ equal to 18.29 and 18 μg/ml respectively, and a genotoxic effect against TA100 and TA1535 Salmonella strains. Only compounds Sul3 , Sul4 and Sul5 with an interesting antibacterial activity, no cytotoxicity and no genotoxic effects, could be exploited against resistant pathogens as new drugs.     

Novel Cytotoxic Sesquiterpene Ester Derivatives from the Roots of Ferula mervynii

This study is the first chemical investigation of Ferula mervynii M. Sağıroğlu & H. Duman, an endemic species to Eastern Anatolia. The isolations of nine compounds including six previously undescribed sesquiterpene esters, 8-trans-cinnamoyltovarol ( 1 ), 8-trans-cinnamoylantakyatriol ( 3 ), 6-acetyl-8-trans-cinnamoyl-3-epi-antakyatriol ( 5 ), 6-acetyl-8-trans-cinnamoylshiromodiol ( 6 ), 6-acetyl-8-trans-cinnamoylfermedurone ( 7 ), and 6-acetyl-8-trans-cinnamoyl-(1S),2-epoxyfermedurone ( 8 ), were described along with three known sesquiterpene esters, 6-acetyl-8-benzoyltovarol ( 2 ), 6-acetyl-8-trans-cinnamoylantakyatriol ( 4 ), and ferutinin ( 9 ). The structures of novel compounds were elucidated through extensive spectroscopic analyses and quantum chemistry calculations. The putative biosynthetic pathways for compounds 7 and 8 were discussed. The extracts and isolated compounds were tested for cytotoxic activity against the COLO 205, K-562, MCF-7 cancer cell lines, and Human Umbilical Vein Endothelial Cell (HUVEC) lines using MTT assay. Compound 4 showed the highest activity against the MCF-7 cell lines with an IC₅₀ value of 16.74±0.21 μM.