Design, synthesis and biological evaluation of aloperine derivatives as potential anticancer agents.

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC50) of 1.43 µM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.

Facile synthesis and cytotoxicity of substituted uracil-1'(N)-acetic acid and 4-pyridone-1'(N)-acetic acid esters of 20(S)-camptothecins.

A series of novel substituted uracil-1'(N)-acetic acid esters (5-9) and 4-pyridone-1'(N)-acetic acid esters (10-11) of 20(S)-camptothecins (CPTs) have been synthesized by the acylation method. All of these new esters were assayed for in vitro cytotoxicity against five human cancer cell lines A549, Bel7402, BGC-823, HCT-8 and A2780. The in vitro bioassay results showed that all the synthesized compounds 5-11 had cytotoxities that were higher than TPT and comparable to CPT on these five tumor cell lines, some of them even showed comparable or superior cytotoxic activity to CPT. The in vitro data exhibited the cytotoxicity of the ester depended on that of its parent compound. The ester 5, 6, 8, 10, 11 even possessed the cytotoxity activity comparable to or even a little better than CPT on A549, HCT-8 and A2780. The compound 11 had the same level of cytoxity on Bel7402 as that of CPT. Here the synthesis and the in vitro antitumor evaluation of a series of novel 20-O-linked substituted uracil-1'(N)-acetic acid and 4-pyridone-1'(N)-acetic acid esters derivatives of CPTs are reported.

Blocking the major inflammatory pathways by newly synthesized thiadiazine derivatives via in-vivo, in-vitro and in-silico mechanism.

A series of new thiadiazine derivatives including 2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) propanoic acids (a) and 4-methyl-2-(5-alkyl/aryl-6-thioxo-1,3,5-thiadiazinan-3-yl) pentanoic acids (b) were synthesized by reacting primary alkyl/aryl amines with CS2, followed by reaction with formaldehyde and amino acids. The chemical structures of synthesized compounds were confirmed by 13C- NMR and 1H- NMR techniques. The inhibitory potential of major inflammatory enzymes, COX-2 and 5-LOX was examined. Moreover, anti-nociceptive and anti-inflammatory activities were evaluated in the in vivo thermally induced nociceptive, and carrageenan induced paw edema models in mice. The in-vitro results reflect that these compounds exhibited concentration dependent inhibition of COX-2 and 5-LOX. The tested compounds at 50 mg/kg showed significant effect on thermally induced pain, and reduced latency time (seconds) as compared to the vehicle treated animals. Moreover, tested compounds exhibited percent inhibition of paw edema in the carrageenan induced paw edema model in mice. Furthermore, the binding modes of the most active COX-2 and 5-LOX inhibitors were determined through computational methods. The computational study reflects that the docked compounds have high binding affinities for COX-2 and 5-LOX enzymes, which leads to inhibition of these enzymes.

Structure-activity relationship study of amidobenzimidazole derivatives as stimulator of interferon genes (STING) agonists.

Stimulator of interferon genes (STING) is a crucial adaptor protein that can regulate the innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. Due to the key role of STING in the innate immune system, the activation of STING pathway is expected to be an efficacious immunotherapeutic tactic to treat cancer. In this study, we performed a structure-activity relationship study of amidobenzimidazole monomer, led to a series of ABZI STING agonist derivatives with potent STING-activating effects. Among them, compound 72, as a representative compound, markedly activated the STING-TBK1-IRF3 signaling pathway and significantly increased the mRNA and protein levels of IFN-ß, CXCL10 and IL-6 in both WT THP-1 cells and human peripheral blood mononuclear cells (hPBMCs). In addition, it was confirmed that compound 72 was highly selective for human STING, specifically targeting human STING signaling and showing no activation of m-STING.

One pot domino synthesis of new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTTs) as anti-inflammatory and antinociceptive candidates: A proof from in-vivo to in-vitro and in-silico mechanistic studies.

A series of alkyl/aryl/aralkylamines or amino acids appended tetrahydro-2H-1,3,5-thiadiazine-2-thiones (4a-i, 5a-g, 6 and 7) were synthesized via one pot domino synthesis. The synthesis involved reacting alkyl/aryl/aralkylamines or amino acids with carbon disulfide employing basic aqueous medium and further cyclization with formaldehyde and alkyl/aryl/aralkylamines or amino acids. In addition, the carboxy-functionalized 1,3,5-thiadiazine-2-thione 6 was further subjected to esterification. All the structures were confirmed through spectral techniques i.e IR, 1H NMR, 13C NMR, and MS analysis. Furthermore, the newly synthesized compounds were biologically assessed via in vitro COX-2 and 5-LOX assays, in vivo anti-nociceptive and anti-inflammatory activities. Among the screened compounds, 6, 5f, and 7 exhibited highest inhibitory potency against COX-2 with IC50 values of 11.96, 13.54, and 13.93 µM, respectively. Moreover, compounds 6 and 7 exhibited excellent inhibitory potential against 5-LOX with IC50 values of 14.01 and 14.13 µM. The in-vivo anti-inflammatory bioassay studies showed that compounds 6, 7 and 5f dramatically reduced the paw edema size at 1 h and 3 h time intervals. In the anti-nociceptive activity, compound 6 showed pain protection comparative to Tramadol in all tested time intervals. In addition, studies of molecular docking revealed the compounds binding modes in the allosteric site of COX-2 and active site of 5-LOX, where these compounds exhibited higher binding scores and good binding interactions.

Research Progress on the Natural Product Aloperine and Its Derivatives.

In this review, an effort towards presenting an all-around account of the recent progress on the natural product, aloperine, is made, and the antivirus structure-activity relationship of its derivatives is also summarized comprehensively. In addition, the principal pharmacological effects and corresponding molecular mechanisms of aloperine are discussed. Some new structural modifications of aloperine are also given, which might provide brief guidance for further investigations on the natural product aloperine.

Design, synthesis and in vivo anticancer activity of novel parthenolide and micheliolide derivatives as NF-κB and STAT3 inhibitors.

Parthenolide and micheliolide have attracted great attention in anticancer research due to their unique activities. In this study, thirteen parthenolide derivatives and twenty-three micheliolide derivatives were synthesized. Most synthesized compounds showed higher cytotoxicity than parthenolide or micheliolide. The in vivo anticancer activity of several representative compounds was evaluated in mice. One micheliolide derivative, 9-oxomicheliolide (43), showed promising in vivo antitumor activity compared with clinical drugs cyclophosphamide or temozolomide. Compound 43 was particularly effective against glioblastoma, with its tumor inhibition rate in mice comparable to the drug temozolomide. The discovery of compound 43 also demonstrates the feasibility of developing anticancer micheliolide derivatives by modification at C-9 position. Anticancer mechanism studies revealed that 9-oxomicheliolide exhibited inhibition effect against NF-κB and STAT3 signaling pathways, as well as induction effects of cell apoptosis. It is postulated that 9-oxomicheliolide is likely to be a modulator of the immune system, which regulates the anticancer immune responses.

Synthesis and antiviral activity of lycorine derivatives.

There are no effective antiviral drugs to treat hand, foot, and mouth disease. In this study, a series of lycorine derivatives were synthesized and evaluated against enterovirus 71 and coxsackievirus A16 in vitro. Derivatives 7c-m with the phenoxyacyl group at the C-1 position showed higher efficacy and lower toxicity than lycorine. In addition, derivative 7e enhanced the survival rate to 40% in the mouse model of the lethal EV71 infection.

Evodiamine derivatives improve cognitive abilities in APPswe/PS1ΔE9 transgenic mouse models of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disease. Due to the complexity of its molecular pathogenesis and the interaction of the numerous factors involved, the etiology and pathogenesis of AD have not been fully elucidated. Therefore, effective treatment for AD remains to be developed. Evodiamine, a quinolone alkaloid, has been found to improve learning and memory ability to in the APPswe/PS1△E9 mouse model of dementia. However, the cytotoxicity and physicochemical properties of evodiamine have limited its use in the treatment of AD. METHODS: Evodiamine and its derivatives were effectively synthesized by EDCI-mediated condensation at room temperature. These target compounds contained 1 thio- and 21 oxo-evodiamine derivatives with different substituted groups. The cytotoxicity of evodiamine and its derivatives and the neuroprotective effects of the evodiamine derivatives against H2O2-induced cell loss in SH-SY5Y cells were investigated using the WST-8 assay. The Morris water-maze test was used to detect the effect of evodiamine and its derivatives on improving learning and memory in APPswe/PS1△E9 mice. RESULTS: In this study, a series of oxo- and thio-evodiamine derivatives was synthesized. Several derivatives showed lower cytotoxicity and stronger neuroprotective effects than evodiamine and elicited enhanced cognitive improvement, especially in the test of spatial memory in APPswe/PS1△E9 mice. CONCLUSION: Our study provides insights for developing novel evodiamine derivatives for chemical intervention and treatment of AD.

LiCl-promoted amination of ß-methoxy amides (γ-lactones).

An efficient and mild method has been developed for the amination of ß-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives by using lithium chloride in good yields. This reaction is applicable to a wide range of substrates with good functional group tolerance. Mechanism studies show that the reactions undergo a LiCl promoted MeOH elimination from the substrates to form the corresponding α,ß-unsaturated intermediates followed by the Michael addition of amines.

Lycorine Derivative LY-55 Inhibits EV71 and CVA16 Replication Through Downregulating Autophagy.

Hand, foot, and mouth disease (HFMD) is a global health concern, especially in the Asia-Pacific region. HFMD caused by Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) infection is usually self-limited but occasionally leads to severe pulmonary edema, neurological complications, and even death. Unfortunately, no effective drugs are currently available in clinical practice for the prevention and treatment of HFMD. Thus, anti-HFMD drugs must be urgently developed. A previous study had reported that lycorine could inhibit EV71 replication. In the present study, we found that LY-55, a lycorine derivative, inhibited the replication of EV71 and CVA16 in vitro and provided partial protection to mice from EV71 infection, as indicated by the decreased viral load and protein expression levels in muscles, clinical scores, and increased survival rates of infected mice. Mechanistically, LY-55 was not directly viricidal. Instead, the LY-55-mediated inhibition of EV71 and CVA16 was found to be mechanistically possible, at least in part, through downregulating autophagy, which plays an important role for EV71 and CVA16 replication. These findings suggest that LY-55 could be a potential lead or supplement for the development of anti-HFMD agents in the future.

Proanthocyanidins: A comprehensive review.

Proanthocyanidins are condensed tannins with various pharmacological properties. These phytochemicals are considered as 'offense and defense molecules because of their human health benefits. The validation of their diverse health aspects, namely, antioxidant, anticancer, antidiabetic, neuroprotective, and antimicrobial has earned them repute in thermochemistry. Proanthocyanidins are oligo- or polymers of monomeric flavan-3-ols produced as an end product of flavonoid biosynthetic pathway. Agricultural wastes and food processing wastes contain immense amount of proanthocyanidins, exploitation of which can be a sustainable source of dietary supplements and functional ingredients. The current review article discusses recent developments in the health promoting properties of proanthocyanidins and the associated hurdles.

Synthetic Optimization of Ellipticine and Antitumor Activity of Novel Hexacyclic Derivatives of Ellipticine.

BACKGROUND: For decades, a great deal of research work has been done to synthesize ellipticine and its derivatives because of their potential antitumor properties and anti-HIV activities. However, the resonance structures in different media, a low level of solubility at physiological pH and systemic toxicity have prevented the use of ellipticine as a therapeutic agent. Besides, the low yield and complex steps of ellipticine synthesis limit its application. METHODS: A high-yield synthetic procedure of ellipticine has been optimized, and the total yield was up to 50% without silica gel column chromatography. Novel hexacyclic ellipticine derivatives were synthesized by coupling ellipticine with o-aminobenzoic acid. Their cytotoxicities against HCT116, MGC803, HT29 and MCF-7 tumor cells were evaluated. RESULTS: The synthesis process of ellipticine was optimized, and the total yield of the synthetic route was increased to 50% through several operation steps optimization. Fourteen ellipticine hexacyclic derivatives were synthesized. The synthetic compounds were screened for anti-tumor activity in vivo and in vitro, and some of the derivatives had good anti-tumor activity. CONCLUSION: Compared with ellipticine, the compound 1l showed higher antitumor activity and better tolerance to tumor models. The compound 1l treatment increased the percentage of late apoptotic cells from 3.1% (DMSO) to 21.6% (20.0 µM) in NCI-H460 cells. It also was observed the effect of 1l on G2 phase arrest was similar as that of ellipticine. The mechanism of action indicated compound 1l could be a topoisomerase IIα poison. These studies provided the basis for the pharmacodynamics and toxicology of ellipticine, and further clarifies the structureactivity relationship of antitumor activity of ellipticine.

Synthesis of High Purified Tulobuterol and Its Study of the Organic Impurities.

The synthetic condition of tulobuterol was optimized to gain lower impurity content. Two intermediates were analyzed, and three degradation impurities were isolated using preparative liquid chromatography for the first time and subsequently characterized by various techniques. Possible degradation impurities were deduced by an oxidative mechanism. Two intermediate impurities were detected: α-bromo-2-chloroacetophenone and 1-(2-chlorophenyl)-2-bromoethanol. Three unreported degradation impurities were found and characterized as N-tert-butyl glycine, o-chloro-benzoic acid and chlorobenzene. The single crystal structure of tulobuterol was firstly reported.

Titanium(III)-Oxo Clusters in a Metal-Organic Framework Support Single-Site Co(II)-Hydride Catalysts for Arene Hydrogenation.

Titania (TiO2) is widely used in the chemical industry as an efficacious catalyst support, benefiting from its unique strong metal-support interaction. Many proposals have been made to rationalize this effect at the macroscopic level, yet the underlying molecular mechanism is not understood due to the presence of multiple catalytic species on the TiO2 surface. This challenge can be addressed with metal-organic frameworks (MOFs) featuring well-defined metal oxo/hydroxo clusters for supporting single-site catalysts. Herein we report that the Ti8(µ2-O)8(µ2-OH)4 node of the Ti-BDC MOF (MIL-125) provides a single-site model of the classical TiO2 support to enable CoII-hydride-catalyzed arene hydrogenation. The catalytic activity of the supported CoII-hydride is strongly dependent on the reduction of the Ti-oxo cluster, definitively proving the pivotal role of TiIII in the performance of the supported catalyst. This work thus provides a molecularly precise model of Ti-oxo clusters for understating the strong metal-support interaction of TiO2-supported heterogeneous catalysts.

Synthesis and antitumor activity of novel substituted uracil-1'(N)-acetic acid ester derivatives of 20(S)-camptothecins.

A series of novel substituted uracil-1'(N)-acetic acid esters (6-20) of camptothecins (CPTs) were synthesized by the acylation method. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines, A549, Bel7402, BGC-823, HCT-8 and A2780. In vitro results showed that most of the derivatives exhibited comparable or superior cytotoxicity compare to CPT (1) and topotecan (TPT, 2), with 12 and 13 possessing the best efficacy. Four compounds, 9, 12, 13 and 16, were selected to be evaluated for in vivo antitumor activity against H22, BGC-823 and Bel-7402 in mice. In vivo testing results indicated that 12 and 13 had antitumor activity against mouse liver carcinoma H22 close to Paclitaxel and cyclophosphamide. 12 had similar antitumor activity against human gastric carcinoma BGC-823 in nude mice compared to irinotecan (3) and possessed better antitumor activity against human hepatocarcinoma Bel-7402 in nude mice than 2. It is also discovered that 12 showed a similar mechanism but better inhibitory activity on topoisomerase I (Topo I) compared to 2. These findings indicate that 20(S)-O-fluorouracil-1'(N)-acetic acid ester derivative of CPTs, 12, could be developed as an antitumor drug candidate for clinical trial.

Condensation of anthranilic acids with pyridines to furnish pyridoquinazolones via pyridine dearomatization.

The unprecedented carbodiimide-mediated condensation between pyridines and anthranilic acids via pyridine dearomatization at room temperature has been developed to provide a straightforward approach to pyridoquinazolones. The value of this approach has further been demonstrated by its application to one-step, gram-scale syntheses of a series of pyridoquinazolone-based natural products and their analogues from readily available starting materials.

Quinolizidine alkaloids reduced mortality in EV71-infected mice by compensating for the levels of T cells.

Recent outbreak of hand, foot and mouse disease caused by enterovirus 71 is a serious threat to infants and children in Asia-Pacific countries. No vaccines or antiviral therapies are available against this infection. In this study, we found that quinolizidine alkaloids could improve the levels of T cells in mice. The structure-activity relationships demonstrated that the oxidation and double bonds are important for the excellent potency. Oxysophocarpine, the most effective compound of six quinolizidine alkaloids, could also relieve symptoms and reduce mortality in lethal enterovirus 71-infected mice through compensating for the decreased levels of T cells. This work suggested that quinolizidine alkaloids have the potential against enterovirus 71 for further development of novel antiviral drugs.

Synthesis and cytotoxicity of novel 20-O-linked homocamptothecin ester derivatives as potent topoisomerase I inhibitors.

In an attempt to improve the antitumor activity of homocamptothecins (hCPTs), a series of novel 20-O-linked hCPT ester derivatives were first designed and synthesized based on a synthetic route, by which hCPTs are acylated with different substituted phenoxyacetic acid ester derivatives. Most of the derivatives were assayed for in vitro cytotoxicity against six human cancer cell lines KB, KB/VCR, A549, HCT-8, Bel7402, and A2780, and most of the assayed compounds exhibited good antiproliferative activity on these tumor cell lines especially on KB.

Synthesis and antiviral activity of novel 1,3,4-thiadiazine derivatives.

A series of novel 1,3,4-thiadiazine derivatives were synthesized via chemical optimization on phthiobuzone. Their anti-herpes simplex virus (HSV) activities in vitro were also tested. Several compounds exhibited more highly potent anti-HSV activity and much higher selectivity index (SI) values than those of phthiobuzone. The most potent anti-HSV compound was 4f, which showed marked inhibition against HSV-1 (IC50=77.04 µg/ml) and HSV-2 (IC50=30.00 µg/ml). Meanwhile it had low cytotoxicity (CC50=1000.00 µg/ml), resulting in high (SI(HSV-1)=12.98, SI(HSV-2)=33.33, respectively). Furthermore, a computational study for prediction of absorption, distribution, metabolism, excretion (ADME) properties of compound 4f was performed by determination of topological polar surface area, absorption and Lipinski parameters.