Discovery of Chemokine CXCL12 Inhibitors by Tandem Application of Virtual Screening and NMR Spectrometry.

The CXC chemokine ligand CXCL12 and its receptor CXCR4 play critical roles in stem-cell homing, infectious diseases, and cancer, which led the CXCL12/CXCR4 signaling axis to attract much attention in drug discovery. CXCR4 is regarded as the primary target while CXCL12 is considered too small to be a druggable target. In this paper, we employed virtual screening approaches and ligand-based NMR screening methods from a SPECS library and in-house natural products to discover new CXCR12 inhibitors.

Discovery of 1,2,4-triazole derivatives as novel neuroprotectants against cerebral ischemic injury by activating antioxidant response element.

Acute ischemic stroke is an important cause of death and long-term disability worldwide. In this work, we have synthesized a series of derivatives with 3,5‑diaryl substituent triazole scaffolds. The derivatives showed favorable protective effective in SNP-induced oxidative stress model, of which compound 5 was the most active.

Design and Discovery of Natural Cyclopeptide Skeleton Based Programmed Death Ligand 1 Inhibitor as Immune Modulator for Cancer Therapy.

Blockade of immune checkpoint PD-1/PD-L1 facilitates the rescue of immune escapes of tumor cells. Though various monoclonal antibodies have been approved for clinical therapy, the development of small molecular inhibitors lags behind antibodies partially owing to the challenges of protein-protein interaction (PPI) blocker design. In this work, we adopted the skeleton of natural cyclopeptidic antibiotics gramicidin S as the start point for PD-1/PD-L1 inhibitor exploring and discovered a series of novel cyclopeptides that could interfere with the PPI of PD-1/PD-L1 based on several rounds of structural design and optimization.

Co-delivery of terbinafine hydrochloride and urea with an in situ film-forming system for nail targeting treatment.

Onychomycosis is a chronic nail disorder consisting of a fungal infection that causes physical and psychosocial discomfort to patients. However, its treatment remains challenging owing to the barrier of the highly keratinized nail plate and the short time that conventional formulations reside on nails. In this work, we developed an in situ film-forming system(IFFS) based on Eudragit® RLPO to co-deliver terbinafine hydrochloride (TBH) and urea, i.

Raloxifene alleviates amyloid-β-induced cytotoxicity in HT22 neuronal cells via inhibiting oligomeric and fibrillar species formation.

Raloxifene, a selective estrogen receptor modulator, displays benefits for Alzheimer's disease (AD) prevention in postmenopausal women as hormonal changes during menopause have the potential to influence AD pathogenesis, but the underlying mechanism of its neuroprotection is not entirely clear. In this study, the effects of raloxifene on amyloid-β (Aβ) amyloidogenesis were evaluated. The results demonstrated that raloxifene inhibits Aβ aggregation and destabilizes preformed Aβ fibrils through directly interacting with the N-terminus and middle domains of Aβ peptides.

Synergetic skin targeting effect of hydroxypropyl-β-cyclodextrin combined with microemulsion for ketoconazole.

The objective was to develop a ternary skin targeting system for ketoconazole (KET) using a combined strategy of microemulsion (ME) and cyclodextrin (HP-β-CD), i.e., KET-CD-ME, which exploits both virtues of cyclodextrin complex and ME to obtain the synergetic effect.

2a, a novel curcumin analog, sensitizes cisplatin-resistant A549 cells to cisplatin by inhibiting thioredoxin reductase concomitant oxidative stress damage.

(1E,4Z,6E)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-7-(5-methylfuran-2-yl)hepta-1,4,6-trien-3-one (2a), a novel curcumin analog, was previously synthesized in our laboratory as a potential thioredoxin reductase (TrxR) inhibitor with excellent growth inhibitory effects on several TrxR over-expressed cancer cells. In this study, our further studies show that 2a is able to inhibit the growth of cisplatin-resistant A549 (A549/CDDP) cells much more effectively in a dose-dependent manner than that of A549 cells in antiproliferative activity experiments. Moreover, 2a-pretreated A549/CDDP cells are sensitive to cisplatin treatment, which is accompanied by the inhibition of TrxR activity in A549/CDDP cells.

Novel sorbicillin analogues from the marine fungus Trichoderma sp. associated with the seastar Acanthaster planci.

Two novel sorbicillinoid analogues, (4'Z)-sorbicillin (1) and (2S)-2,3-dihydro-7-hydroxy-6-methyl-2-[(E)-prop-1-enyl]-chroman-4-one (2), together with three known compounds, (2S)-2,3-dihydro-7-hydroxy-6,8-dimethyl-2-[(E)-prop-1-enyl]-chroman-4-one (3), sorbicillin (4), and 2',3'-dihydrosorbicillin (5), were isolated from the culture broth of the fungus Trichoderma sp. associated with the seastar Acanthaster planci. Their structures were determined by analysis of the NMR and MS data.

Synthesis, cytotoxicity of new 4-arylidene curcumin analogues and their multi-functions in inhibition of both NF-κB and Akt signalling.

A series of new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized and found to be potent antiproliferative agents against a panel of cancer cell lines at submicromolar to low micromolar concentrations by SRB assay. Their inhibitory abilities against NF-κB was evaluated by High Content Analysis (HCA) based immunofluorescence assay; and the Akt signalling inhibition was determined by fluorescence polarization assay and western blot respectively. The Structure-Activity Relationship was discussed.

Synthesis and cytotoxicity evaluation of biaryl-based chalcones and their potential in TNFα-induced nuclear factor-κB activation inhibition.

A series of biaryl-based chalcones were designed as a combination of the natural chalcone and biphenyl moieties, and synthesized by two step chemistry involving Knoevenagel reaction and microwave assistant Suzuki coupling. Sulforhodamine B (SRB) assay was performed to evaluate the cell viability inhibitory abilities of these compounds against five cancer cell lines (A549, CNE2, SW480, MCF-7, and HepG2) from different tissues. Their Nuclear Factor-κB (NF-κB) nuclear translocation inhibitory activities were further investigated by High Content Analysis (HCA) based assay.

Synthesis and identification of new 4-arylidene curcumin analogues as potential anticancer agents targeting nuclear factor-κB signaling pathway.

A series of curcumin analogues including new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogues can effectively decrease the growth of a panel of lung cancer cells at submicromolar and low micromolar concentrations. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogues exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogues also reduced the tumorigenic potential of cancer cells in a clonogenic assay.

Potential therapeutic effects of curcumin: relationship to microtubule-associated proteins 2 in Aβ1-42 insult.

Curcumin can bind senile plaques and promote disaggregation of existing amyloid deposits and prevent aggregation of new amyloid deposits. Curcumin can also reverse distorted and curvy neurites around senile plaques and repair the neuritic abnormalities. We hypothesized whether altered neurite morphologies resulting from Aβ production had anything to do with the changes of expression of microtubule-associated protein 2 (MAP2), but curcumin could reverse damaged neurites by upregulation of MAP2 expression.

New fluorescent trans-dihydrofluoren-3-ones from aldol-Robinson annulation-regioselective addition involved one-pot reaction.

An unexpected discovery of new trans-4-acetyl-1,9-dimethyl-4,4a-dihydro-3H-fluoren-3-ones from one pot reactions of benzaldehydes and acetylacetone is described. The synthetic mechanism and stereochemistry were discussed. These new derivatives exhibit good fluorescent properties in solutions.

5-N-methylated quindoline derivatives as telomeric g-quadruplex stabilizing ligands: effects of 5-N positive charge on quadruplex binding affinity and cell proliferation.

A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies.

Synthesis and evaluation of curcumin analogues as potential thioredoxin reductase inhibitors.

Series of curcumin derivatives were synthesized; the inhibitory activities on thioredoxin reductase (TrxR) of all analogues were evaluated by DTNB assay in vitro. It is found that most of the analogues can inhibit TrxR in the low micromolar range; Structure-activity relationship analysis reveals that analogues with furan moiety have excellent inhibitory effect on TrxR in an irreversible manner, indicating that the furan moiety may serve as a possible pharmacophore during the interaction of curcumin analogues with TrxR. The effect of selected curcuminoids on growth of different TrxR overexpressed cancer cell lines was also investigated and discussed.

Alpha-glucosidase inhibition of natural curcuminoids and curcumin analogs.

Natural curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) isolated from Curcuma longa (turmeric), and synthetic curcumin analogs (A(1-7), B(1-7), C(1-6) and D(1-7)) were evaluated in vitro for the alpha-glucosidase inhibitory activity via UV and circular dichroism (CD) spectroscopy. The results indicated that natural curcuminoid compound 3 showed a remarkable inhibitory effect with IC(50) of 23.0 microM, and the synthetic compounds A(2), B(2), C(2) and D(2) showed potent inhibitory effects with IC(50) of 2.