New protein tyrosine phosphatase inhibitors from fungus Aspergillus gorakhpurensis F07ZB1707

Twelve new compounds, aspergorakhins A–L (1–12) coupled with one known xanthone leptosphaerin D (13), were isolated from the extract of soil-derived fungus Aspergillus gorakhpurensis F07ZB1707. Their structures were elucidated by spectroscopic data analysis including UV, IR, NMR, and HRESIMS. The absolute configurations of 5 and 8–11 were identified using ECD and OR calculations. All compounds were tested by enzyme inhibitory activity assay in vitro. Aspergorakhin A (1) showed selective activities against PTP1B and SHP1 over TCPTP with IC₅₀ values 0.57, 1.19, and 22.97 μM, respectively. Compounds 1 and 2 exhibited modest cytotoxicity against tumor cell lines A549, HeLa, Bel-7402, and SMMC-7721 with IC₅₀ values in the range of 6.75–83.4 μM.

Twelve novel metabolites were isolated from Aspergillus gorakhpurensis F07ZB1707. Aspergorakhin A (1) showed selective activities against PTP1B and SHP1 over TCPTP with IC₅₀ values of 0.57, 1.19, and 22.97 μM, respectively.     

Synthesis of benzoin under supramolecular catalysis involving cyclodextrins in water: application for the preparation of the antiepileptic drug phenytoin

Among the cyclodextrins screened for the synthesis of 2-hydroxy-1,2-diphenylethanone (benzoin) in water, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) exhibited the highest yield in the benzoin condensation reactions, and HP-β-CD can be recycled several times with little loss of activity through the addition of fresh VB₁. As an example of supramolecular catalysis, the methodology was applied to the “green” synthesis of the antiepileptic drug phenytoin through benzoin condensation, oxidation, and cyclization reactions in the presence of HP-β-CD, without the use of any harmful organic solvent. Moreover, the complexation behaviors of HP-β-CD with benzaldehyde and intermediates were studied by UV-vis and 2D-ROESY NMR spectroscopies to reveal the plausible mechanisms of the reactions, and HP-β-CD did not act as a simple phase transfer agent.

Benzoin was synthesized using cyclodextrins as phase transfer catalysts. As an example of supramolecular catalysis, the methodology was applied to the “green” synthesis of the antiepileptic drug Phenytoin in the presence of HP-β-CD.     

The synthesis of imidazo[1,5-a]quinolines via a decarboxylative cyclization under metal-free conditions

An iodine-mediated decarboxylative cyclization was developed from α-amino acids and 2-methyl quinolines under metal-free conditions, affording a variety of imidazo[1,5-a]quinolines with moderate to good yields.

An iodine-mediated decarboxylative cyclization was developed from α-amino acids and 2-methyl quinolines under metal-free conditions, affording a variety of imidazo[1,5-a]quinolines with moderate to good yields.     

Discovery of mercaptopropanamide-substituted aryl tetrazoles as new broad-spectrum metallo-β-lactamase inhibitors

β-Lactam antibiotic resistance mediated by metallo-β-lactamases (MBL) has threatened global public health. There are currently no available inhibitors of MBLs for clinical use. We previously reported the ruthenium-catalyzed meta-selective C–H nitration synthesis method, leading to some meta-mercaptopropanamide substituted aryl tetrazoles as new potent MBL inhibitors. Here, we described the structure–activity relationship of meta- and ortho-mercaptopropanamide substituted aryl tetrazoles with clinically relevant MBLs. The resulting most potent compound 13a showed IC₅₀ values of 0.044 μM, 0.396 μM and 0.71 μM against VIM-2, NDM-1 and IMP-1 MBL, respectively. Crystallographic analysis revealed that 13a chelated to active site zinc ions via the thiol group and interacted with the catalytically important residues Asn233 and Tyr67, providing further structural information for the development of thiol based MBL inhibitors.

Compound 13a showed IC₅₀ values of 0.044 μM, 0.396 μM and 0.71 μM against VIM-2, NDM-1 and IMP-1 MBL, respectively. It binds to chelates via active site zinc ions and forms interactions with residues on the L1 and L3 loops of VIM-2.     

Continuous flow synthesis of diaryl ketones by coupling of aryl Grignard reagents with acyl chlorides under mild conditions in the ecofriendly solvent 2-methyltetrahydrofuran

An efficient continuous flow sequential synthesis of diaryl ketones was achieved by coupling of aryl Grignard reagents with acyl chlorides in the bio-derived “green” solvent 2-methyltetrahydrofuran (2-MeTHF) under mild reaction conditions (ambient temperature, 1 hour), allowing a safe and on-demand generation of 2-(3-benzoylphenyl)propionitrile with a productivity of 3.16 g hour⁻¹.

Continuous flow method for parallel synthesis of diaryl ketones using commercially available reagents.     

Synthesis and biological evaluation of novel artemisone–piperazine–tetronamide hybrids

For the first time, six novel artemisone–piperazine–tetronamide hybrids (12a–f) were efficiently synthesised from dihydroartemisinin (DHA) and investigated for their in vitro cytotoxicity against some human cancer cells and benign cells. All the targets showed good cytotoxic activity in vitro. Hybrid 12a exhibited much better inhibitory activity against human liver cancer cell line SMMC-7721 (IC₅₀ = 0.03 ± 0.04 μM for 24 h) than the parent DHA (IC₅₀ > 0.7 μM), and two references, vincristine (VCR; IC₅₀ = 0.27 ± 0.03 μM) & cytosine arabinoside (ARA; IC₅₀ = 0.63 ± 0.04 μM). Furthermore, hybrid 12a had low toxicity against human benign liver cell line LO2 (IC₅₀ = 0.70 ± 0.02 μM for 24 h) compared with VCR, ARA, and DHA in vitro. Moreover, the inhibitory activity of hybrid 12a was obviously enhanced when human liver cancer cell line MHCC97H absorbed Fe²⁺in vitro.

Six novel artemisone–piperazine–tetronamide hybrids were efficiently synthesised and investigated for their cytotoxicity against some human cancer cells.     

Triterpenoids with α-glucosidase inhibitory activity and cytotoxic activity from the leaves of Akebia trifoliata

Ten pentacyclic triterpenoids including a new multiflorane triterpene acid, 2α,3β,23-trihydroxymultiflor-7-en-28-oic acid (1), and a new lupane triterpene monoglucoside named akebiaoside C (2), were obtained from the leaves of Akebia trifoliata. Their structures were elucidated by extensive spectroscopic analysis, and they were all isolated from the leaves of A. trifoliata for the first time. These compounds, except 4 and 5, showed in vitro α-glucosidase inhibitory activity much stronger than acarbose. Especially, 2, 3, 6, 8 and 10 displayed in vitro α-glucosidase inhibitory activity with IC₅₀ values from 0.004 to 0.081 mM, which were close or even more potent than corosolic acid (IC₅₀ 0.06 mM). Triterpenoids 1, 8 and 10 were further revealed to show moderate in vitro cytotoxic activity against human tumor A549, HeLa and HepG2 cell lines, with IC₅₀ values ranging from 26.5 to 51.9 μM. Compound 9 selectively showed in vitro cytotoxicity toward HeLa and HepG2 cell lines, with IC₅₀ values of 81.49 and 73.47 μM, respectively. These findings provided new data to support that the leaves of A. trifoliata are a rich source in bioactive triterpenoids highly valuable to be developed for medicinal usage.

Ten pentacyclic triterpenoids including a new multiflorane triterpene acid, 2α,3β,23-trihydroxymultiflor-7-en-28-oic acid (1), and a new lupane triterpene monoglucoside named akebiaoside C (2), were obtained from the leaves of Akebia trifoliata.     

Diastereoselective approach to rationally design tetrahydro-β-carboline–isatin conjugates as potential SERMs against breast cancer

A series of tetrahydro-β-carboline–isatin conjugates, with varying substituents as well as stereochemistry at C-1 and C-5 position of tetrahydro-β-carboline (THβC) and isatin ring, were prepared and assayed for anti-proliferative efficacy on Estrogen Responsive ER(+) (MCF-7) and ER(−ve) MDA-MB-231 cell-lines. The synthesized scaffolds displayed selective anti-proliferative efficacy against MCF-7 cell-line with the most active conjugate 8b exhibiting an IC₅₀ value of 37.42 μM, comparable to that of peganumine A, a tetrahydro-β-carboline analogue, isolated from Peganum harmala. The synthesized compound 8b was also more potent than the standard drug tamoxifen (IC₅₀ = 50 μM against MCF-7). The observed activities were further corroborated via docking studies in ER-α (PDB ID: 3ERT).

A series of tetrahydro-β-carboline–isatin conjugates was prepared and assayed for anti-proliferative activities on Estrogen Responsive ER(+) and non-responsive ER(−ve) cell-lines.     

Newly synthesised oxime and lactone derivatives from Dipterocarpus alatus dipterocarpol as anti-diabetic inhibitors: experimental bioassay-based evidence and theoretical computation-based prediction

Dipterocarpus alatus-derived products are expected to exhibit anti-diabetes properties. Natural dipterocarpol (1) was isolated from Dipterocarpus alatus collected in Quang Nam province, Vietnam; afterwards, 20 derivatives including 13 oxime esters (2 and 3a–3m) and 7 lactones (4, 5, 6a–6e) were semi-synthesised. Their inhibitory effects towards diabetes-related proteins were investigated experimentally (α-glucosidase) and computationally (3W37, 3AJ7, and PTP1B). Except for compound 2, the other 19 compounds (3a–3m, 4, 5, and 6a–6d) are reported for the first time, which were modified at positions C-3, C-24 and C-25 of the dipterocarpol via imidation, esterification, oxidative cleavage and lactonisation reactions. A framework based on docking-QSARIS combination was proposed to predict the inhibitory behaviour of the ligand-protein complexes. Enzyme assays revealed the most effective α-glucosidase inhibitors, which follow the order 5 (IC₅₀ of 2.73 ± 0.05 μM) > 6c (IC₅₀ of 4.62 ± 0.12 μM) > 6e (IC₅₀ of 7.31 ± 0.11 μM), and the computation-based analysis confirmed this, i.e., 5 (mass: 416.2 amu; polarisability: 52.4 ų; DS: −14.9 kcal mol⁻¹) > 6c (mass: 490.1 amu; polarisability: 48.8 ų; DS: −13.7 kcal mol⁻¹) > 6e (mass: 549.2 amu; polarisability: 51.6 ų; DS: −15.2 kcal mol⁻¹). Further theoretical justifications predicted 5 and 6c as versatile anti-diabetic inhibitors. The experimental results encourage next stages for the development of anti-diabetic drugs and the computational strategy invites more relevant work for validation.

Dipterocarpus alatus-derived products are expected to exhibit anti-diabetes properties.     

Knecorticosanones C–H from the fruits of Knema globularia (Lam.) warb

Six undescribed polyketides, 1–6, were discovered from the fruits of Knema globularia (Lam.) warb. Two known polyketides and three known lignans were also isolated. Cytotoxicities against HepG2 and KKU-M156 cells of all polyketides were evaluated. Compound 1 displayed the most cytotoxic activity against HepG2 and KKU-M156 cell lines with IC₅₀ values of 1.57 ± 0.37 and 1.78 ± 0.14 μg mL⁻¹, respectively. The structure of all isolates was identified using spectroscopic methods including NMR, IR, MS and ECD.

Compound 1 displayed the most cytotoxic activity against HepG2 and KKU-M156 cell lines with IC₅₀ values of 1.57 ± 0.37 and 1.78 ± 0.14 μg mL⁻¹, respectively.     

An umpolung reaction of α-iminothioesters possessing a cyclopropyl group

An umpolung N-alkylation reaction of α-cyclopropyl α-iminothioesters with diethylaluminum chloride or ethylmagnesium bromide affords the corresponding N-ethylated α-aminothioesters in good yields. Subsequent oxidation and reaction of the N-ethylated product with a thiolate or a chloride anion proceed effectively to give the ring-opened products in good yields. In contrast, relatively “hard” nucleophiles did not give the ring-opened products but gave the addition products to the iminium carbon.

Tandem N-alkylation/oxidation/second addition reaction to α-cyclopropyl α-imino(thio)esters gave N-alkylated ring-opened products in good yields.     

Cipadessains A–K,eleven limonoids from the fruits of Cipadessa cinerascens

Eleven new mexicanolide-type limonoids, cipadessains A–K (1–11), were isolated from the fruits of Cipadessa cinerascens (Pellegr) Hand.-Mazz. Their planar structures were determined based on IR, UV, 1D and 2D NMR spectra and HRESIMS data. The absolute configuration of 1 was elucidated by single-crystal X-ray diffraction using mirror Cu Kα radiation, and that of compounds 2–8 were determined by ECD analysis. Two mexicanolides bearing methoxybutenolide moiety originated from the furan ring 3 and 6, showed significant cytotoxicity against HepG2 cell line with IC₅₀ values of 5.23 ± 0.12, 8.67 ± 1.02 μM, respectively; and NO inhibitory activities in LPS-activated RAW 264.7 macrophages at nontoxic concentration (IC₅₀ 5.79 ± 0.18, 6.93 ± 0.89 μM, respectively).

Eleven new mexicanolide-type limonoids, cipadessains A–K (1–11), were isolated from the fruits of Cipadessa cinerascens (Pellegr) Hand.-Mazz.     

Synthesis of quinolines via sequential addition and I2-mediated desulfurative cyclization

An efficient one-pot approach for the synthesis of quinolines from o-aminothiophenol and 1,3-ynone under mild conditions is disclosed. With the aid of ESI-MS analysis and parallel experiments, a three-step mechanism is proposed—a two-step Michael addition–cyclization condensation step leading to intermediate 1,5-benzothiazepine catalyzed by zirconocene amino acid complex Cp₂Zr(η¹-C₉H₁₀NO₂)₂, followed by I₂-mediated desulfurative step.

An efficient one-pot approach is proposed for the synthesis of quinolines through Lewis acid-catalyzed cyclization and iodine-mediated desulfurization reactions.     

Novel derivatives of eugenol as potent anti-inflammatory agents via PPARγ agonism: rational design,synthesis, analysis,PPARγ protein binding assay and computational studies

Eugenol is a natural product abundantly found in clove buds known for its pharmacological activities such as anti-inflammatory, antidiabetic, antioxidant, and anticancer activities. It is well known from the literature that peroxisome proliferator-activated receptors (PPARγ) have been reported to regulate inflammatory responses. In this backdrop, we rationally designed semi-synthetic derivatives of eugenol with the aid of computational studies, and synthesized, purified, and analyzed four eugenol derivatives as PPARγ agonists. Compounds were screened for PPARγ protein binding by time-resolved fluorescence (TR-FRET) assay. The biochemical assay results were favorable for 1C which exhibited significant binding affinity with an IC₅₀ value of 10.65 μM as compared to the standard pioglitazone with an IC₅₀ value of 1.052 μM. In addition to the protein binding studies, as a functional assay, the synthesized eugenol derivatives were screened for in vitro anti-inflammatory activity at concentrations ranging from 6.25 μM to 400 μM. Among the four compounds tested 1C shows reasonably good anti-inflammatory activity with an IC₅₀ value of 133.8 μM compared to a standard diclofenac sodium IC₅₀ value of 54.32 μM. Structure–activity relationships are derived based on computational studies. Additionally, molecular dynamics simulations were performed to examine the stability of the protein–ligand complex, the dynamic behavior, and the binding affinity of newly synthesized molecules. Altogether, we identified novel eugenol derivatives as potential anti-inflammatory agents via PPARγ agonism.

Rational design, synthesis, analysis, PPARγ protein binding assay and computational studies of novel eugenol derivatives.     

Photo-induced synthesis,structure and in vitro bioactivity of a natural cyclic peptide Yunnanin A analog

A cyclic analog of natural peptide Yunnanin A was synthesized via photoinduced single electron transfer reaction (SET) in the paper. The resulting compound exhibited potent bioactivity (with IC₅₀ values 29.25 μg mL⁻¹ against HepG-2 cell lines and 65.01 μg mL⁻¹ against HeLa cell lines), but almost have no toxicity to normal cells (with IC₅₀ values 203.25 μg mL⁻¹ against L929 cell lines), which may be served as a potential antitumor drug for medical treatment. The spatial structure was examined by experimental electronic circular dichroism (ECD) and quantum chemistry calculations. Moreover, the theoretical study suggested that special intramolecular hydrogen bonds and γ, β-turn secondary structures may be possible sources affecting cyclic peptide''s bioactivity.

The photo-induced synthesis, structure and in vitro bioactivity study of a Yunnanin A cyclopeptide analog was presented.     

Triarylethylene-indolin-2,3-dione molecular conjugates: design,synthesis, docking studies and anti-proliferation evaluation

A series of 1H-1,2,3-triazole-linked ospemifene-isatin and O-methylated ospemifene–isatin conjugates were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as estrogen-non-responsive cells. The non-cytotoxic conjugate 14e, with an optimal combination of bromo substituents at the C-5/C-7 positions of isatin, proved to be a promising hit with an IC₅₀ value of 31.62 μM against MCF-7 and 19.23 μM against MDA-MB-231. The observed anti-proliferative activities of active conjugates were further corroborated via docking studies carried out on estrogen receptor subtypes α and β.

A series of 1H-1,2,3-triazole-linked ospemifene–isatin and O-methylated ospemifene–isatin conjugates were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as estrogen-non-responsive cells.     

Structural transformation of methasterone with Cunninghamella blakesleeana and Macrophomina phaseolina

An anabolic-androgenic synthetic steroidal drug, methasterone (1) was transformed by two fungi, Cunninghamella blakesleeana and Macrophimina phaseclina. A total of six transformed products, 6β,7β,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-3-one (2), 6β,7α,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-3-one (3), 6α,17β-dihydroxy-2α,17α-dimethyl-5α-androstane-3,7-dione (4), 3β,6β,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-7-one (5), 7α,17β-dihydroxy-2α,17α-dimethyl-5α-androstane-3-one (6), and 6β,9α,17β-trihydroxy-2α,17α-dimethyl-5α-androstane-3-one (7) were synthesized. Among those, compounds 2–5, and 7 were identified as new transformed products. MS, NMR, and other spectroscopic techniques were performed for the characterization of all compounds. Substrate 1 (IC₅₀ = 23.9 ± 0.2 μg mL⁻¹) showed a remarkable anti-inflammatory activity against nitric oxide (NO) production, in comparison to standard LNMMA (IC₅₀ = 24.2 ± 0.8 μg mL⁻¹). Whereas, its metabolites 2, and 7 showed moderate inhibition with IC₅₀ values of 38.1 ± 0.5 μg mL⁻¹, and 40.2 ± 3.3 μg mL⁻¹, respectively. Moreover, substrate 1 was found to be cytotoxic for the human normal cell line (BJ) with an IC₅₀ of 8.01 ± 0.52 μg mL⁻¹, while metabolites 2–7 were identified as non-cytotoxic. Compounds 1–7 showed no cytotoxicity against MCF-7 (breast cancer), NCI-H460 (lung cancer), and HeLa (cervical cancer) cell lines.

Fungal transformation of methasterone resulted in six products (2–7). 2–5, and 7 were identified as new. Substrate 1 showed remarkable anti-inflammatory activity but was cytotoxic. Products 2 and 7 showed moderate activity but were non-cytotoxic.     

Microbial transformation of mestanolone by Macrophomina phaseolina and Cunninghamella blakesleeana and anticancer activities of the transformed products

The microbial transformation of anabolic androgenic steroid mestanolone (1) with Macrophomina phaseolina and Cunninghamella blakesleeana has afforded seven metabolites. The structures of these metabolites were characterized as 17β-hydroxy-17α-methyl-5α-androsta-1-ene-3,11-dione (2), 14α,17β-dihydroxy-17α-methyl-5α-androstan-3,11-dione (3), 17β-hydroxy-17α-methyl-5α-androstan-1,14-diene-3,11-dione (4), 17β-hydroxy-17α-methyl-5α-androstan-3,11-dione (5), 11β,17β-dihydroxy-17α-methyl-5α-androstan-1-ene-3-one (6), 9α,11β,17β-trihydroxy-17α-methyl-5α-androstan-3-one (7), and 1β,11α,17β-trihydroxy-17α-methyl-5α-androstan-3-one (8). All the metabolites, except 5 and 6, were identified as new compounds. Substrate 1 (IC₅₀ = 27.6 ± 1.1 μM), and its metabolites 2 (IC₅₀ = 19.2 ± 2.9 μM) and 6 (IC₅₀ = 12.8 ± 0.6 μM) exhibited moderate cytotoxicity against the HeLa cancer cell line (human cervical carcinoma). All metabolites were noncytotoxic to 3T3 (mouse fibroblast) and H460 (human lung carcinoma) cell lines. The metabolites were also evaluated for immunomodulatory activity, and all were found to be inactive.

The microbial transformation of anabolic androgenic steroid mestanolone (1) with Macrophomina phaseolina and Cunninghamella blakesleeana has afforded seven metabolites. Some of them have exhibited moderate cytotoxicity against HeLa cancer cell line.     

Decarboxylative aldol reaction of α,α-difluoro-β-ketocarboxylate salt: a facile method for generation of difluoroenolate

We developed a decarboxylative aldol reaction using α,α-difluoro-β-ketocarboxylate salt, carbonyl compounds, and ZnCl₂/N,N,N′,N′-tetramethylethylenediamine. The generation of difluoroenolate proceeded smoothly under mild heating to provide α,α-difluoro-β-hydroxy ketones in good to excellent yield (up to 99%). The α,α-difluoro-β-ketocarboxylate salt was bench stable and easy to handle under air, which realizes a convenient and environmentally friendly methodology for synthesis of difluoromethylene compounds.

A ZnCl₂/N,N,N′,N′-tetramethylethylenediamine complex promoted decarboxylative aldol reaction of α,α-difluoro-β-ketocarboxylate salt with carbonyl compounds has been developed.     

Semi-rational screening of the inhibitors and β-lactam antibiotics against the New Delhi metallo-β-lactamase 1 (NDM-1) producing E. coli

Bacteria containing bla_NDM-1 gene are a growing threat to almost all clinically β-lactam antibiotics. Especially, the New Delhi metallo-β-lactamase (NDM-1) has become a potential public survival risk. In this study, a novel and efficient strategy for inhibitors and β-lactam antibiotics screening using recombinant New Delhi metallo-beta-lactamase (NDM-1) was developed. First, the gene of bla_NDM-1 were identified and cloned from multi-drug resistance of Acinetobacter baumannii isolate; by the means of protein expression and purification, recombinant NDM-1 activity was up to 68.5 U ml⁻¹, and high purity NDM-1 protein with activity of 347.4 U mg⁻¹ was obtained. Finally, for NDM-1, the inhibitors (aspergillomarasmine A (AMA) and EDTA) with high affinity (HI) and the β-lactam antibiotics (imipenem) with low affinity (LA) were screened out. Surprisingly, the inhibition of the NDM-1 was enhanced by the use of inhibitor combinations (AMA–EDTA (1 : 2)), where the IC₅₀ of AMA–EDTA was reduced by 88% and 95%, respectively, comparing to the AMA and EDTA alone. More interesting, AMA–EDTA could restore the activity of imipenem when tested against NDM-1 expressing strains (E. coli and Acinetobacter baumannii), with a working time of 120 min and 330 min, respectively. This method is expected to be used in high-throughput screening, drug redesign (including new inhibitors and drugs) and “old drug new use”.

Bacteria containing bla_NDM-1 gene are a growing threat to almost all clinically β-lactam antibiotics. A semi-rational screening of the inhibitors and antibiotics against the New Delhi metallo-β-lactamase 1 has been developed in this study.