A facile and practical method for the synthesis of aromatic aldehydes by palladium-catalyzed reductive carbonylation starting from aryl iodides and HCOOH is described. Compared to the known formylation procedure, HCOOH serves not only as the most convenient and environmental-friendly C1 source but also as the reviving agent in the reductive elimination process of a Pd-catalyst. Furthermore, this procedure is also applied successfully to the modification of natural products, such as vindoline, tabersonin, and vincamine, to obtain the corresponding products in good yields.

A Pd(II)-catalyzed cascade Heck/intramolecular C(sp2)–H amidation reaction is described for the synthesis of 4-aryl-2-quinolinone derivatives. Substituted cinnamamide containing 2-(pyridin-2-yl)ethanamine unit reacts with aryl iodide to form intermediate by Heck reaction. Then, the intermediate takes place intramolecular amidation via C(sp2)–H activated process promoted by orientation group.

•The isoindolin-1-ones are synthesized from 2-formylbenzoic acid and amine under Pd(OAc)2/HCOOH system.•This procedure is green, efficient, and high yields.•This method is also suitable for the modification of natural products.A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives from 2-formylbenzoic acid and amine under Pd(OAc)2/HCOOH system has been described. The whole process is carried out in ligand-free conditions and furnished the desired products by reductive intramolecular cyclization. Furthermore, this procedure is applied successfully for the modification of natural products, such as vindoline and estrone.Download high-res image (41KB)Download full-size image

•Bioisosterism strategy was used to modify the carboxamide bond of sunitinib.•All the derivatives were evaluated in FLT3-dependent human AML cell line MV4-11.•The kinase and cellular inhibition assay experiments were also conducted.Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of acute myeloid leukemia (AML) patients, which has been proposed as a promising drug target for AML therapy. A series of indolin-2-one derivatives bearing different groups at the solvent interface position based on sunitinib as FLT3 inhibitors were designed, synthesized and evaluated in FLT3-dependent human AML cell line MV4-11. Structure-activity relationship (SAR)analysis showed that heterocyclic alkane at the solvent interface position could significantly increase the potency for the inhibition of proliferation of MV4-11 cell line. Compound 10a and 10d exhibited better efficacy (MV4-11, IC50: 14.7 nM for 10a and 24.8 nM for 10d) than positive control sunitinib (MV4-11, IC50: 38.5 nM). The kinase and cellular inhibition assay exhibited that 10d (FLT3, IC50: 5.3 nM) was a potent and selective FLT3 inhibitor. Furthermore, the pharmacokinetic experiments showed that 10d had good properties of oral bioavailability, Cmax, Tmax, T1/2 and AUC in mice, respectively. The in vivo study indicated that 10d could significantly suppress tumor growth in MV4-11 xenografts nude mice model and occupied with a commendable therapeutic window compared to sunitinib.Download high-res image (168KB)Download full-size image

A straightforward and efficient method has been developed for the synthesis of 2-benzylbenzaldehyde derivatives from 2-methylbenzaldehyde and iodobenzene via a C(sp3)–H activation process. In the course of the activation reaction, acetohydrazone is formed between 2-benzylbenzaldehyde and acetohydrazine as a transient directing group. As a new kind of transient directing group, acetohydrazone exhibits a remarkable directing effect to give corresponding products in good to excellent yields.

Kv2.1 as a voltage-gated potassium (Kv) channel subunit has a pivotal role in the regulation of glucose-stimulated insulin secretion (GSIS) and pancreatic β-cell apoptosis, and is believed to be a promising target for anti-diabetic drug discovery, although the mechanism underlying the Kv2.1-mediated β-cell apoptosis is obscure. Here, the small molecular compound, ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2–a]pyrimidine-6-carboxylate (SP6616) was discovered to be a new Kv2.1 inhibitor. It was effective in both promoting GSIS and protecting β cells from apoptosis. Evaluation of SP6616 on either high-fat diet combined with streptozocin-induced type 2 diabetic mice or db/db mice further verified its efficacy in the amelioration of β-cell dysfunction and glucose homeostasis. SP6616 treatment efficiently increased serum insulin level, restored β-cell mass, decreased fasting blood glucose and glycated hemoglobin levels, and improved oral glucose tolerance. Mechanism study indicated that the promotion of SP6616 on β-cell survival was tightly linked to its regulation against both protein kinases C (PKC)/extracellular-regulated protein kinases 1/2 (Erk1/2) and calmodulin(CaM)/phosphatidylinositol 3-kinase(PI3K)/serine/threonine-specific protein kinase (Akt) signaling pathways. To our knowledge, this may be the first report on the underlying pathway responsible for the Kv2.1-mediated β-cell protection. In addition, our study has also highlighted the potential of SP6616 in the treatment of type 2 diabetes.

A facile and efficient method for the synthesis of alkynones by a Pd-catalyzed carbonylative Sonogashira coupling reaction starting from aryl iodide, terminal alkyne and chloroform (CHCl3) as the CO source is described. This procedure proves that CHCl3 is a cheap and efficient CO source in the presence of CsOH·H2O as the base. Furthermore, it is applied successfully for the modification of natural products, such as vindoline and tabersonin, to obtain the corresponding products in good yields.

As a follow-up discovery of AMPK activators from natural products, 20S-dammar-24-en-2α,3β,12β,20-tetrol (GP, 1), a dammarane-type triterpenoid, was found to have some favorable metabolic effects on dyslipidemia in Golden Syrian hamsters, and activate AMPKα2β1γ1 by around 2.4 fold with an EC50 of 5.1 μM on molecular level. In order to enhance its potency at AMPK and structure–activity relationship study, GP derivatives were designed, synthesized, and evaluated in pharmacological AMPK activation assays. Structure–activity relationship analysis showed that amine at the 24-position (groups I–IV) effectively and significantly increased the potency and efficacy. GP derivatives 12 and 17–19 exhibited better potency (EC50: 0.3, 0.8, 0.8, and 1.0 μM) and efficacy (fold: 3.2, 2.7, 3.0, and 2.8) in the activation of AMPK heterotrimer α2β1γ1 than positive control (AMP, EC50: 1.6 μM, fold: 3.2). Furthermore, the most potent compounds 12 and 17 obviously inhibited glucose output through increasing the phosphorylation of AMPK, without affecting mitochondrial membrane potential or producing cytotoxicity.

A series of arctigenin-4-yl carbamate derivatives were synthesized and evaluated for potency in reducing β-amyloid (Aβ) content in HEK293-APPswe cells. Most of the arctigenin-4-yl aralkyl or aryl carbamate derivatives showed improved potency in reducing Aβ content. Among the synthesized compounds, arctigenin-4-yl (3-chlorophenyl)carbamate (20) exhibited the strongest potency with 78.7% Aβ content reduction at 20 μM. Furthermore, the effect of arctigenin-4-yl (4-chlorophenyl)carbamate (19) and arctigenin-4-yl (3-chlorophenyl)carbamate (20) on lowing Aβ content was better than arctigenin under the concentrations of 1, 10 and 20 μM.

3-(tert-Butyl)-4-hydroxyphenyl 2,4-dichlorobenzoate (1) was discovered in our in-house high throughput screening as a moderate FXR antagonist. To improve the potency and the stability of the hit 1, forty derivatives were synthesized and SAR was systematically explored. The results turn out that replacing the 2,4-dichlorophenyl with 2,6-dichloro-4-amidophenyl shows great improvement in potency, replacing the benzoate with benzamide shows improvement in stability and slight declining of potency and 3-(tert-butyl)-4-hydroxyphenyl unit is essential in obtaining the FXR antagonistic activity.

A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure–activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC50: 2.36 and 2.13 μM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 μM, respectively.

The natural product arctigenin (ATG) demonstrated preferential cytotoxicity to cancer cells under glucose starvation. A series of 4-amino-4-dehydroxylarctigenin derivatives based on lead compound ATG were designed and synthesized by bioisosteric modifications. Their cytotoxicities were evaluated in glucose-starved A549 tumor cells and the results indicated that the 4-amino-4-dehydroxylarctigenin showed more potent cytotoxicity than arctigenin, and the further substituent group on 4-amino would result in the cytotoxicities decreased significantly. 4-Substituted-arctigenin could selectively target on glucose-starved A549 tumor cells which provide an alternative strategy for anticancer drug development with minimal normal tissue toxicity.

•Gypenosides and their metabolites were quantified in rat plasma by LC–MS/MS.•Three MS transitions were selected to quantify six analytes.•Epimers can get baseline separation under this HPLC condition.•The PK profiles of these analytes in rat plasma were firstly studied and compared.Gypenoside LVI and gypenoside XLVI are the major bioactive dammarane saponins from Gynostemma pentaphyllum. Gypenoside LVI, gypenoside XLVI, and their metabolite 2α-OH-protopanaxadiol (2α-OH-PPD) possess potent non-small cell lung carcinoma A549 cell inhibitory activity. A sensitive liquid chromatography tandem mass spectrometry method was developed and validated to study the pharmacokinetics of gypenoside LVI and XLVI, 2α-OH-PPD, metabolite 1 (M1), and metabolite 2 (M2) after administration of gypenosides or 2α-OH-PPD. Plasma samples from rats were protein precipitated with methanol. Analytes were detected by triple quadrupole MS/MS with an electrospray ionization source in the positive multiple reaction monitoring mode. The transition m/z 441.4 → 109.2 was selected to quantify gypenoside LVI and XLVI, and 2α-OH-PPD, because of the extensive conversion of the gypenosides to aglycone in the ionization source. M1 and M2 are isomers that shared the transition m/z 493.4 → 143.1. To avoid interference, the baseline separation of each analyte was performed on a SunFire C18 column with a gradient of acetonitrile (0.1% formic acid, v/v) and water (0.1% formic acid, v/v). The chromatographic run time was 10 min. The linearity was validated over a plasma concentration range from 2.00 to 2000 ng/mL for M1 and M2, and from 10.0 to 2000 for gypenosides LVI and XLVI, and 2α-OH-protopanaxadiol. The lower limits of quantification were 10.0, 10.0, 10.0, 2.00, and 2.00 ng/mL for gypenoside LVI, gypenoside XLVI, 2α-OH-PPD, M1, and M2, respectively, with acceptable intra-/inter-day precision and accuracy. The extraction recovery rates were >86.9% for each compound. No apparent matrix effect or instability was observed during each step of the bioanalysis. After full validation, this method was proved to be simple, fast, and efficient in analyzing large batches of plasma samples for the analytes.

A facile and efficient method for the synthesis of 3,4-disubstituted-furan-2(5H)-one derivatives using PdCl2(dppf)2 as catalyst via the Suzuki–Miyaura reaction was reported. 3,4-Dibenzylfuran-2(5H)-ones were synthesized through the coupling reaction of 3,4-dibromo-furan-2(5H)-one and potassium benzyltrifluoroborates in the presence of PdCl2(dppf)2/Cs2CO3. However, regioselective product 4-benzyl-3-bromofuran-2(5H)-ones were obtained under PdCl2(dppf)2/K2CO3 conditions. Furthermore, 4-benzyl-3-bromofuran-2(5H)-ones could react with another molecule of potassium benzyltrifluoroborates or phenylboronic acids to form 3,4-asymmetric disubstituted furan-2(5H)-ones.

A series of 3-(1H-indol-3-yl)isoindolin-1-one derivatives were synthesized by the three-component reaction of a phthalaldehydic acid, primary amine, and 1H-indole in water under catalyst-free conditions. The reaction presented here has several advantages, such as clean, one-pot, and easy handling. The environmentally-friendly features make this procedure a sustainable method for the synthesis of 3-(1H-indol-3-yl)isoindolin-1-ones.

•SAR study of PPD has been reported.•Some derivatives showed potent AMPK activation.•12 and 13 exhibited potent inhibition of lipid synthesis.Adenosine 5′-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype α2β1γ1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated. Structure–activity relationship study showed that the amine derivatives at the 24-position (groups I–VI) can improve the potency (EC50: 0.7–2.3 μM) and efficacy (fold: 2.5–3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 μM) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model.

The natural product embelin was found to have PAI-1 inhibitory activity with the IC50 value of 4.94 μM. Based on the structure of embelin, a series of analogues were designed, synthesized, and evaluated for their ability to inhibit PAI-1. The SAR study on these compounds disclosed that the inhibitory potency largely depended on the hydroxyl groups at C2 and C5, and the length of the alkyl chains at C3 and C6. Compound 11 displayed the best PAI-1 inhibitory potency with the IC50 value of 0.18 μM.

Plasminogen activator inhibitor-1 (PAI-1), a serpin, is the physiological inhibitor of tissue-type and urokinase-type plasminogen activators and thus also an inhibitor of fibrinolysis and tissue remodeling. It is a potential therapeutic target in many pathological conditions, including thrombosis and cancer. Several types of PAI-1 antagonist have been developed, but the structural basis for their action has remained largely unknown. Here we report X-ray crystal structure analysis of PAI-1 in complex with a small-molecule antagonist, embelin. We propose a mechanism for embelin-induced rapid conversion of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1.Highlights► Identification of a small molecular PAI-1 antagonist, embelin ► Crystal structure of PAI-1 in complex with embelin ► Structural insight into the mechanism of PAI-1 inactivation by embelin

A series of new arctigenin and 9-deoxy-arctigenin derivatives bearing different ester and ether side chains at the phenolic hydroxyl positions are designed, synthesized, and evaluated for activating AMPK potency in L6 myoblasts. Initial biological evaluation indicates that some alkyl ester and phenethyl ether arctigenin derivatives display potential activities in AMPK phosphorylation improvement. Further structure–activity relationship analysis shows that arctigenin ester derivatives 3a, 3h and 9-deoxy-arctigenin phenethyl ether derivatives 6a, 6c, 6d activate AMPK more potently than arctigenin. Moreover, the 2-(3,4-dimethoxyphenyl)ethyl ether moiety of 6c has been demonstrated as a potential functional group to improve the effect of AMPK phosphorylation. The structural optimization of arctigenin leads to the identification of 6c as a promising lead compound that exhibits excellent activity in AMPK activation.Figure optionsDownload full-size imageDownload as PowerPoint slide

Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure–activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3–2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5 μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.Figure optionsDownload full-size imageDownload as PowerPoint slide

A simple and efficient method for the synthesis of 3-(1H-benzo[d]imidazol-1-yl)isoindolin-1-one derivatives by a one-pot, three-component condensation reaction of phthalaldehydic acid, primary amine, and 2-mercaptobenzimidazole or 2-hydroxybenzimidazole is described. By using EtOH–AcOH (v/v, 15:1) as the solvent system, the reaction proceeds smoothly to give corresponding products in good yields.

A facile and efficient one-pot synthesis of 4-[(2-hydroxynaphthalen-1-yl)(phenyl)methyl]-3-methyl-1H-pyrazol-5-ol derivatives catalyzed by ammonium acetate has been developed using the three-component reaction of β-naphthol, aldehyde, and 1H-pyrazol-5(4H)-one. The advantages of this method are the use of an inexpensive and readily available catalyst, easy workup, and improved yields.

A series of C4′-substituted oleandrin analogues were designed, synthesized and evaluated for their cytotoxicity towards human cervical carcinoma cell line (HeLa). The structure-activity relationships (SARs) of these compounds were summarized in this paper, and 4′-α-amino-4′-dehydroxyloleandrin 4a (IC50 = 21.7 nM) and 4′-β-amino-4′-dehydroxyloleandrin 4b (IC50 = 10.9 nM) exhibited stronger cytotoxicity compared with oleandrin (IC50 = 33.3 nM). Furthermore, the cytotoxicity of these two compounds towards another five human cancer cell lines (NCI-H266, A549, Jurkat, HL-60 and PC-3) was also evaluated and the IC50 values of β-amino derivative 4b were approximately 2–3 folds lower than that of oleandrin.Download high-res image (185KB)Download full-size image

Highlights•Six new cardenolides were isolated from the root bark of Calotropis gigantea.•Cardenolides were evaluated for their cytotoxicity against A549 and Hela cell lines.•Some cardenolides displayed potent cytotoxicity.Six new cardenolides (1, 2 and 11–14), along with ten known ones, were isolated from the root bark of Calotropis gigantea. The structural determination was accomplished by the 1D- and 2D-NMR spectrum as well as ESIMS analysis. The isolated compounds were evaluated for their in vitro growth inhibitory activity against human A549 and Hela cell lines. The results suggested that some of these cardenolides (compounds 1, 6, and 8) displayed potent cytotoxicities.Download full-size image

•Highly efficient method to synthesize bufalin-3-yl nitrogen-containing-carbamate derivatives.•Bufalin-3-yl nitrogen-containing-carbamate derivatives show significant cytotoxicity.•3i-HCl significantly inhibits tumor growth in vivo by 100% at the dose 2 mg/kg by iv, or 4 mg/kg by ig.A series of bufalin-3-yl nitrogen-containing-carbamate derivatives 3 were designed, synthesized, and evaluated for their proliferation inhibition activities against human cervical epithelial adenocarcinoma (HeLa) cell line. The structure–activity relationships (SARs) of this new series are described in this paper. Cytotoxicity data revealed that the C3 moiety had an important influence on cytotoxic activity. Compound 3i-HCl exhibited significant in vitro antiproliferative activity against the ten tested tumor cell lines, with IC50 values ranging from 0.30 to 1.09 nM. Furthermore, 3i-HCl can significantly inhibit tumor growth by 100% at the dose 2 mg/kg by iv, or 4 mg/kg by ig.Download full-size image

It is demonstrated that natural product vindoline can enhance the glucose-stimulated insulin secretion (GSIS) in MIN6 cells with the EC50 value of 50.2 μM. In order to improve the activities, a series of vindoline derivatives are synthesized and evaluated in MIN6 cells. Compounds 4, 8, 17 and 24 show about 4.5 times more effective stimulation insulin secretion ability (EC50: 10.4, 14.2, 11.0 and 12.7 μM, respectively) than vindoline.