Esters 3a Research Articles

Unexpected small molecules as novel SIRT2 suicide inhibitors

A series of sirtuin inhibitor candidates were assembled based on an intermediate ester (1a) our accidently discovered. After screening and evaluation, several SIRT2 selective inhibitors were identified, which can inhibit all the deacetylation, defatty-acylation and debenzoylation of SIRT2. Among these inhibitors, compound 1e was the best SIRT2 selective inhibitors. The primary study on the inhibitory mechanism indicated that compound 1e may be a suicide inhibitor acting as an irreversible way. Given almost all reported sirtuin inhibitors are non-covalent, sirtuin covalent inhibitors are still need to be developed. These findings will facilitate for further development of SIRT2 selective and suicide inhibitors.

Synthesis and biological activity of fibrate-based acyl- and alkyl-phenoxyacetic methyl esters and 1,2-dihydroquinolines

A series of highly potent antihyperlipidemic agents constituted by a fibrate-based structure was recently reported by our group, whose synthesis started from isovanillin derivatives. In the interest of evaluating the bioisosteric effect of the vanillin-based isomers on their antihyperlipidemic activity, the present study focuses on the synthesis of 5-acyl-1-phenoxyacetic methyl esters 5a–c and their saturated side-chain 5-alkyl-1-phenoxyacetates 6a–c. Their strong in vivo effect was associated with the inhibition of HMG-CoA reductase. Since 1,2-dihydroquinolines inhibit this enzyme, a series of such heterocycles (9a–d) was prepared by our efficient regioselective, one-step, solvent-free method. Apart from showing hypolipidemic activity in vivo, some of the compounds displayed antifungal, antioxidant and cytotoxic activity in vitro. The binding mode of four compounds at the active site of HMGRh was examined with docking simulations, observing an interaction with most of the amino acids targeted by simvastatin.

Synthesis of novel dimeric compounds containing triazole using click method and their selective antiproliferative and proapoptotic potential via mitochondrial apoptosis signaling

In this study, the main aim was synthesis of dimeric compounds, which contain lithocholic acid and a triazole structure to investigate the selective cellular and molecular antiproliferative and proapoptotic potential of these products in healthy embryonic fibroblast (MEF), cervix cancer (HeLa), and breast cancer (MCF-7) cells. Four ester (5a–d) and five dimeric (6a–d, 7) out of nine novel compounds were obtained. First of all, lithocholic acid was converted to methyl lithocholate and then it was reacted with certain alkynoic acids (a–d) to obtain its alkynoate derivatives (5a–d). Finally, these compounds were converted to dimers (6a–d) by using 2,6-bis(azidomethyl)pyridine via the click method. Our result indicate that, treatment with dimeric compounds can selectively decrease the cell viability and proliferation in cervix cancer HeLa and breast cancer MCF-7 cells, except 7 which caused a strong cytotoxicity on healthy MEF cells. According to MTT assay, Nucblue cell stain and Annexin V/Propodium iodide molecular probe staining, 100 µM concentrations of the dimeric compounds was sufficient in inducing death and apoptotic cell ratio in HeLa and MCF-7 breast cancer cells selectively. In brief, the present study indicates that most effective dimeric compounds are 6a and 6b, which have the highest IC50 (345.8–342.6 µM) value on healthy cell and the lowest IC50 value in both cervix (49.2–36.9 µM) and breast (23.0–66.1 µM) cancer cells especially long-term treatment and which triggers apoptosis pathway specifically.

Antimicrobial Activities of some Synthesized Cyclo (N<sup>α</sup>-dinicotinoyl) [L-phenylalanyl-L-leucine] Pentapeptide Candidates

Some of cyclo (Nα-di-nicotinoyl)[L-phenylalanyl-L-leucine]pentapeptides3-6 has been synthesized starting from bis-(1-carboxy-2-substituted)-3,5-diaminocarbonyl)pyridine 3 and N,N-bis-(1-hydrazonyl-2-substituted)-3,5 diaminocarbonyl) pyridine 2. Treatment of 1 or 2 afforded the corresponding bis-ester derivative 3, which was hydrolyzed with sodium hydroxideto give bis-acid 4. Cyclization of bis-acid 4 with L-dibasic amino acid methyl esters, afforded the corresponding macrocyclic methyl esters 5a,b, respectively. Finally, hydrazonolysis of 5a,b with hydrazine hydrated in refluxing methanol afforded macrocyclic pentapeptide hydrazides 6a,b, respectively. Some of these compounds exhibited antimicrobial activities comparable with Chloramphenicol and Fusidic acid as reference drugs.

Novel derivatives of plant monomeric phenolics: act as inhibitors of bacterial cell-to-cell communication

The aim of the present study was to synthesize novel active Anti-Quorum sensing derivatives from secondary metabolites viz. Gallic acid, Protocatechuic acid and Vanillic acid present in the plant Bergenia ciliata. Efficacy of all synthesized derivatives have been evaluated on the formation of bacterial biofilm and inhibition of cell-to-cell communication. Anti-Quorum Sensing activity and biofilm formation of all synthesized compounds was measured on biomonitor strain Chrobacterium violaceum, ATCC 12472 using standard paper disk-diffusion assay and quantification of violacein pigment. Among all derivatives, five derivatives 3,4,5-Trihydroxy-benzoic acid methyl ester (9a), 3,4-Dihydroxy-benzoic acid methyl ester (10a), 3,4,5-Tris-(2,4-dichloro-benzyloxy)-benzoic acid methyl ester (12), 3,4,5-Tris-(2,5-dichloro-benzyloxy)-benzoic acid methyl ester (13) and 4-(2,4-Dichloro-benzyloxy)-3-methoxy-benzoic acid methyl ester (15) has shown Anti-Quorum Sensing activity by inhibiting violacein pigment production and biofilm formation without interfering with its growth. The inhibitory effects in violacein pigment production were: positive control (C-30) 72%, (9a), (10a) 47.2%, (12) 27.3%, (13) 40.1% and (15) 22.7% at the concentration of 1 mg/mL and biofilm percent inhibition were found (C-30) 64% (9a) 46.2%, (10a) 40.3%, (12) 18.4%, (13) 35.2%, and (15) 17.3% when compared with the untreated control. Results reveal that synthesized derivatives seem to be good compounds for inhibition and formation of biofilm and AHL-mediated Quorum-sensing mechanism. The present article highlights the importance of derivatives derived from secondary metabolites as potent drug for biofilm formation and inhibition of cell-to-cell communication.

Synthesis of Novel 4‐Substituted Coumarins, Docking Studies, and DHODH Inhibitory Activity

Coumarins are the important class of naturally occurring heterocyclic compounds. Activities like antioxidant, antibacterial, anti‐inflammatory, and anticancer have been reported for coumarin derivatives. Present work details the synthesis of substituted coumarin‐4‐pyrrolones as well as coumarin‐4‐acetyl amino acids and their DHODH inhibitory activity, which is a dual target for malaria and cancer. Coumarin‐4‐acetic acids (2a–c) were coupled with different methyl esters of α‐amino acids (3) giving rise to corresponding coumarin‐4‐acetyl amino acid methyl esters (4a–o), which on hydrolysis under basic condition underwent cyclization forming substituted dihydropyrrole‐2‐ones (5a–i), dihydroindolizine‐3‐ones (5j–l), and dihydropyrrolizin‐3‐one (5m–o). Acidic hydrolysis of the compounds (4a–o) yielded corresponding coumarin‐4‐acetyl amino acids (6a–f). The docking study was performed with the protein 4IGH (obtained from PDB) using Surflex–Dock module. The newly synthesized compounds were tested for DHODH inhibitory activity using Brequinar as the standard. Compound 6b showed remarkable inhibition compared with the standard, and the other compounds with terminal COOH showed moderate inhibition.

Taicrypnacids A and B, a Pair of C37 Heterodimeric Diterpenoid Stereoisomers from Taiwania cryptomerioides.

Two uncommon C37 heterodimeric diterpenoids, taicrypnacids A (1) and B (2), and a known labdane-type diterpenoid (3) were isolated from the leaves of Taiwania cryptomerioides. Several techniques, such as comprehensive spectroscopic analysis, chemical conversion, X-ray crystallography, and ECD data, were employed to define the structures. The two new compounds displayed cytotoxicity against human breast cancer (MCF-7), osteosarcoma (U-2 OS), and human colon carcinoma (HCT-116) cell lines, while the methyl ester 1a showed no activity. Compound 1 induced Ca2+-ROS pathway-mediated endoplasmic reticulum stress, and excessive stress led to cell death by activating apoptosis and autophagy.

Synthesis and Biological Evaluation of Some Novel 2-Pyrazinoic Acidderived Esters

Pyrazine, a kojic acid having hydroxypyrone, and hydroquinone are the head compounds of different categories possessing a broad range of biological activities including anticancer and antioxidant activities, thus are interested in evaluating the cytotoxicity on K562 human leukemia cells and radical scavenging activities of these compounds in bonding together as ester compounds. Four hydroxypyrone containing-2-pyrazinoic esters along with hydroquinone containing-one were synthesized and characterized by spectral data. The cytotoxicity of these compounds on K562 human leukemia cells and free Radical scavenging activities were evaluated. The K562 cells were treated with various concentrations of each compound for a different time and cell viabilities were determined by MTT viability assay. It was observed that all compounds decreased the viability of the human leukemia K562 cells in a dose- and time-dependent manner. Hydroquinone pyrazinoate 4a with an IC50 value of 50±8.0 µM was the most active compound against the K562 cells. The compounds 4b and 4e showed higher cytotoxicity on K562 cells respectively after 72 h. Antioxidant activities of the compounds were evaluated by DPPH free radical scavenging assay. Hydroquinone ester 4a showed higher activity with an IC50 value of 0.82 mM than those of hydroxypyrone derivatives of which maltol pyrazinoate 4e showed the highest inhibition with IC50 value of 4.7 mM. Although free hydroxyl group of kojic acid was masked by ester group, 4b and 4e showed significant scavenging activities, as the same result was observed in the case of hydroquinone ester.

Secondary metabolites produced by the citrus phytopathogen Phyllosticta citricarpa.

The isolation and structure elucidation of one new fungal metabolite, phenguignardic acid butyl ester (1a), and four previously reported metabolites (1b, 2a, 3-4) from the citrus phytopathogen Phyllosticta citricarpa LGMF06 are described. The new dioxolanone phenguignardic acid butyl ester (1a) had low phytotoxic activity in citrus leaves and fruits (at dose of 100 µg), and its importance as virulence factor in citrus black spot disease needs to be further addressed. Beside the phytotoxic analysis, we also evaluated the antibacterial (against methicillin sensitive and resistant Staphylococcus aureus) and cytotoxic (A549 non-small cell lung cancer, PC3 prostate cancer and HEL 299 normal epithelial lung) activities of the isolated compounds, which revealed that compounds 1a, 1b and 2a were responsible for the antibacterial activity of this strain.

A Simple and Convenient Strategy for the Synthesis of Novel Ten, Twelve, and Fourteen‐membered Phosphorus Macrocyclic Compounds

Synthesis of the title compounds 4(a–i) was accomplished through a two‐step process. The synthetic route involves the cyclization of equimolar quantities of 2,2′‐methylene(methyl)bis(4,6‐di‐tert‐butyl‐phenol) (1) with tris‐(2‐chloro‐ethyl) phosphite (2a), tris‐(2‐bromo‐ethyl) phosphine (2b), and tris‐bromo methyl phosphine (2c) in the presence of sodium hydride in dry tetrahydrofuran at 45–50°C. They were further converted to the corresponding oxides, sulfides, and selenides under N2 atmosphere by reacting them with hydrogen peroxide, sulfur, and selenium, respectively (4a–c, 4d–f, and 4g–i). But the compounds 6a,b were prepared by the direct cyclocondensation of equimolar quantities of 1 with (2‐chloro‐ethyl)‐phosphonic acid dibromomethyl ester (5a) and (2‐chloro‐ethyl)‐phosphonic acid bis(2‐bromo‐ethyl) ester (5b) in the presence of sodium hydride in dry tetrahydrofuran at 45–50°C in moderate yields. All the newly synthesized compounds 4(a–i) and 6(a–b) exhibited moderate in vitro antibacterial and antifungal activities.

Indolenine – dibenzotetraaza [14] annulene Ni (II) complexes as sensitizers for dye - sensitized solar cells

A new series of macrocyclic Ni (II) complexes having indolenine and dibenzotetraaza [14] annulene (DBTAA) moieties were synthesized and tested for their application as sensitizers in dye - sensitized solar cells (DSSCs). The structures are furnished with anchoring groups of ethyl ester (8a, 8b, and 8c) or carboxylic acid (9c) on the indolenine moiety and hexyloxy (8b) or neopentyloxy (8c, 9c) groups on the DBTAA moiety. The best performance was exhibited by dye 9c, which under constant AM 1.5G solar simulation (100 mW cm−2) using I−/I3− electrolyte gave a short-circuit current Jsc = 0.43 mA cm−2, an open-circuit voltage Voc = 0.41 V and a fill factor FF = 0.528, corresponding to an overall conversion efficiency of η = 0.093%. This is the first investigation of macrocyclic DBTAA derivatives as sensitizers for DSSCs applications.

Friedel–Crafts Chemistry. Part 53. Divergent and Diversity-Oriented Synthesis of Condensed Indole Scaffolds via Friedel–Crafts Ring Closure Approach

A series of indole-fused medium-sized N-heterocyclic systems 10a–h were prepared from laboratory-synthesized indole-based esters 9a–h via intramolecular Friedel–Crafts cyclizations induced by both trifluoromethanesulfonic acid and AlCl3/CH3NO2 catalysts under suitable conditions. The synthetic sequence to precursors 9a–h that started from simple N-methylindole-2-carboxylic acid involved conversion to aminoindoles 2a, b, reaction with α,β-unsaturated acid chlorides to yield acyclic amides 5a–d, ring closure to tricyclic lactams 6a–d, and carbonyl reduction to respective pyrido and azepino tricyclic amines 7a–d, which finally underwent N-alkylations with α- or β-haloesters to produce the required ester precursors. The structures of synthesized compounds without stereochemical implications are established using both spectral and analytical data.

Novel dauricine derivatives suppress cancer via autophagy-dependent cell death

Eleven dauricine derivatives were synthesized and evaluated for their anti-cancer effect in different cancer cells and their autophagic activity in HeLa model cell. Among these newly synthesized compounds, carbamates 2a, 2b, carbonyl ester 3a and sulfonyl ester 4a exhibited potent cytotoxic effects on tested cancer cells with IC50 values ranged from 2.72 to 12.53 μM, which were more potent than that of dauricine (higher than 15.53 μM). The above four derivatives are validated to induce autophagy-dependent cell death in HeLa cancer cells. These findings offer us a promising source for generating novel autophagic enhancers for anti-cancer therapy.

Application of Lecitase® Ultra-Catalyzed Hydrolysis to the Kinetic Resolution of (E)-4-phenylbut-3-en-2-yl Esters

The possibility of using Lecitase® Ultra as a novel alternative biocatalyst for the kinetic resolution of model racemic allyl esters of (E)-4-phenylbut-3-en-3-ol: Acetate (4a) and propionate (4b) through their enantioselective hydrolysis was investigated. Reaction afforded (+)-(R)-alcohol (3) and unreacted (−)-(S)-ester (4a or 4b). Hydrolysis of propionate 4b proceeded with higher enantioselectivity than acetate 4a. (R)-Alcohol (3) with highest enantiomeric excess (93–99%) was obtained at 20–30 °C by hydrolysis of propionate 4b, while the highest optical purity of unreacted substrate was observed for (S)-acetate 4a (ee = 34–56%). The highest enantioselectivity was found for the hydrolysis of propionate 4b catalyzed at 30 °C (E = 38). Reaction carried out at 40 °C significantly lowered enantiomeric excess of produced alcohol 3 and enantioselectivity in resolution. Lecitase® Ultra catalyzed the enantioselective hydrolysis of allyl esters 4a,b according to Kazlauskas’ rule to produce (R)-alcohol 3 and can find application as a novel biocatalyst in the processes of kinetic resolution of racemic allyl esters.

Synthesis and antioxidant activities of novel N‐aryl (and N‐alkyl) γ‐ and δ‐imino esters and ketimines

Novel N‐aryl (and N‐alkyl) γ‐ and δ‐imino esters 2a–g (3a–g) and N‐aryl (and N‐alkyl) ketimines 2h–j (3h–j) were synthesized in high yields (80–99%) from their corresponding γ‐ and δ‐keto esters and ketones in this study. The structures of the synthesized compounds were clarified by Fourier transform infrared (FT‐IR), NMR (1H and 13C), mass spectrometry, and elemental analyses. Isomerizations [E/Z] were also determined by their 1H NMR spectra. The free‐radical scavenging activity of imines was evaluated using the 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH) method. The relationships between the structure and antioxidant activity of these compounds are discussed. Among these compounds, 2a–c (at the concentration 1000 μg/mL) exhibit high antioxidant activity similar to those of the standards (butylated hydroxyanisole [BHA], butylated hydroxytoluene [BHT], and ascorbic acid).

Synthesis of Some Di‐ and Tetraphosphonic Acids by Suzuki Cross‐Coupling

Five diphosphonic acids, namely, benzene‐1,4‐bis‐p‐phenylphosphonic acid (1), anthracene‐9,10‐bis‐p‐phenylphosphonic acid (2), benzene‐1,2‐bis‐p‐phenylphosphonic acid (3), benzene‐1,3‐bis‐p‐phenylphosphonic acid (4), and biphenyl‐4,4′‐bis‐p‐phenylphosphonic acid (5) as well as three tetraphosphonic acids, namely, benzene‐1,2,4,5‐tetrakis‐p‐phenylphosphonic acid (6), tetrabiphenylsilane tetrakis‐4‐phosphonic acid (7), and pyrene‐1,3,6,8‐tetrakis‐p‐phenylphosphonic acid (8) and their dimethyl esters 1a–8a were prepared via Suzuki cross‐coupling reactions involving p‐dimethylphosphonatophenylboronic acid and brominated aromatics. The Suzuki cross‐coupling occurs under milder conditions than the transition metal catalyzed Arbuzov reaction usually applied for the preparation of dialkyl phosphonates. For the same starting material both reactions are complementary and yield phosphonic acids with different spacer lengths, which was exemplified for tetrakis(4‐bromophenyl)silane. Suzuki cross‐coupling gives rise to 7, whereas the Arbuzov reaction produces tetraphenylsilane tetrakis‐4‐phosphonic acid.

Activity of steroid 4 and derivatives 4a–4f as inhibitors of the enzyme 5α-reductase 1

It is known that the growth of prostate metastatic bone tumor depends on androgens, and tumor formation can start from migratory malignant cells produced in that organ. These cells exhibit grater type 1 5α-reductase (5α-R1) activity than type 2 5α-reductase. Noteworthy, both isozymes convert testosterone (T) to the more active androgen dihydrotestosterone (DHT) in the target tissues.Thus, in order to potentially improve the prognosis of this disease, in this work, seven derivatives of 17-(1H-benzimidazol-1-yl)-16-formillandrosta-5,16-dien-3β-yl benzoate (4a–f) and 17-(1H-benzimidazol-1-yl)-3-hydroxy-16-formylandrost-5,16-diene (4) were synthesized, characterized and identified as inhibitors of type 1 5α-reductase (5αR1). These derivatives having the advantage of improved plasma half-life.The inhibitory activity of the compounds towards 5α-R1 isoenzyme was determined by conversion of T into DHT in the presence or absence of compounds 4, 4a–f. Further, in vivo experiments were also carried out, treating gonadectomized hamsters with T and/or 4, 4a–f and evaluating their effect on the diameter of hamster flank organs and on the weight of the prostatic and seminal vesicles. Results indicated that compounds 4, 4b, 4c, served as in vitro inhibitors of the enzyme 5α-R1 and pharmacological experiments showed that 4 and derivatives 4a–f decreased the diameter of the flank glands, the weight of the prostate and seminal vesicles of treated hamsters without any appreciable toxicity during observation. Noteworthy the fact that compound 4 is the product, in all cases, of the hydrolysis of the series of esters 4a–f, thus they can serve as precursors (prodrugs) of the active form 4.

One-pot Preparation and Characterisation of Five-membered Cyclic Alcohols

Background: Over the last few years, one of the primary focuses of our research group has been the synthesis and biological evaluation CANs featuring structural and/or configurationally alterations on the carbocyclic moiety. We previously reported an enlarged group of diversely functionalized amino cyclopentenols, cyclopentenols and cyclopentenones as useful precursors in the synthesis and pos-terior biological evaluation of CANs featuring structural and/or configurationally alterations on the carbo-cyclic moiety; moreover the five-membered carbocycles are common structural units in other natural products and bioactive compounds, for this reason, these compounds presented great interest for their use as building blocks in the development of compounds with potential pharmacological activities. Method: The conversion of benzyl cyclopent-3-enocarboxylate into a mixture of the corresponding hydroxy allylic esters 5a and 5b was efficiently achieved by the employed diphenyl diselenide, H2O2 in dry CH2Cl2 for the synthesis of phenylselenenic acid and electrophilic addition to double bond of 3, and 90% tert-butyl hydroperoxide subsequently being added. Results: The mixture of compounds 5 was obtained in good yields under these conditions, and this was readily separated by column chromatography. Isolated components were identified by1H and13C NMR spectral, as well as by its EI HRMS. The corresponding alcohols 5a or 5b were easily transformed in the corresponding 3,5-dinitrobenzoyl derivatives, 6a and 6b, from which single crystals were obtained, permitting unequivocal identification. Conclusion: Using a one-pot method, benzyl cyclopent-3-enecarboxylate was turned into a mixture of corresponding hydroxy allylic derivatives 5a and 5b, employing diphenyl diselenide, H2O2 and tert-butyl hydroperoxide for the formation and subsequent oxidation/elimination of the first-generated alkyl phenyl selenides. The use of these oxidants corresponds to modern trends in organic synthesis, because they are easily available and environmentally friendly reagents, which can be used at a large scale.

Synthesis of steroid analogs of tubuloclustin, their cytotoxicity and effect on microtubules of A549 carcinoma cells

Synthesis of analogs of tubuloclustin (N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine (1)) with the colchicine fragment replaced with 2-methoxyestradiol scaffold attached via phenolic hydroxy group was described. Esters 3a–c exhibit moderate cytotoxicity (EC50 = 5–6 μmol L–1) and exert a weak effect on the microtubule network in A549 human lung carcinoma cells similar to the clustering effect of tubuloclustin and its derivatives. Conjugates 6a–c and 7a–c with the phenolic ester bond are low stable and compounds 7a–c are inactive to the microtubules of A549 cells, while compounds 6a–c cause an unusual effect of curling of the microtubules.

Facile synthesis of stereoregular helical poly(phenyl isocyanide)s and poly(3-hexylthiophene)-block-poly(phenyl isocyanide) copolymer using chiral π-allylnickel complexes as initiators

Living polymerization of achiral phenyl isocyanide using a simply prepared chiral π-allylnickel complex as initiator was found to proceed in helix-sense-selective manner. The polymerization of achiral phenyl isocyanide, 4-isocyanobenzoyl-2-aminoisobutyric acid hexyl ester (1a) produced optically active helical poly-1am (L or D) whose chirality totally come from the helical conformation without containing any other chiral atoms. The monomer-structural effect on the helix-sense-selectivity was examined and indicated the long alkyl group in the monomer is not essential for the helix-sense-selective polymerization. The effect of chiral phosphine ligand was also investigated. The success of the helix-sense-selective polymerizations indicated the high activity of π-allylnickel complexes. Finally, polymerization of 2,5-dibromo-3-hexylthiophene (3HT) and subsequent addition of 1a in the presence of chiral π-allylnickel complex as a single catalyst afforded P3HTm-b-poly-1an with nonhelical P3HT and helical poly(phenyl isocyanide) (PPI) segments, which may be used as unique chiral organic materials in the future.