Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan’su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein α (FAPα) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAPα-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAPα (rhFAPα) and was activated in tumors. The LD50 of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAPα prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides.

A series of novel bivalent securinine mimetics incorporating different linkers between C-15 and C-15′ were synthesized and their topoisomerase I (Topo I) inhibitory activities evaluated. It was thus revealed that mimetic R2 incorporating a rigid m-substituted benzene linker exhibits Topo I inhibitory activity three times that of parent securinine. Comprehensive structure–activity relationship analyses in combination with docking studies were used to rationalize the potent activity of these bivalent mimetics. Mechanistic studies served to confirm the deductions arising from docking studies that the active bivalent mimetics not only inhibited complexation between Topo I and DNA but also stabilized the Topo I–DNA complex itself.

•Two series of 4-(4-substituted amido-benzyl)furan-2(5H)-one derivatives were synthesized.•Compounds bearing an exocyclic double bond showed significant Topo I inhibitory and potent anti-proliferative activity.•Dual action mechanisms were identified for this class of compounds.In this study, two series of novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives containing an α,β-unsaturated lactone fragment were synthesized and screened for Topo I inhibition and antitumor activity. The topoisomerase I inhibitory activities and cytotoxicities against three human cancer cell lines (MCF-7,Hela,A549) were evaluated. The results revealed that series 2, compounds bearing an exocyclic double bond on the furanone ring, generally showed more potent activity than series 1, compounds lacking an exocyclic double bond. Several compounds of series 2 possess significant Topo I inhibitory activity and potent antiproliferative activity against cancer cell lines. Further mechanism studies of the most active compound of series 2 (B-15) indicated that synthetic compounds can not only stabilize the drug-enzyme-DNA covalent ternary complex as well as camptothecin, but also interfere with the binding between Topo I and DNA. The binding patterns of these compounds with Topo I and structure-activity relationships are discussed.Download high-res image (259KB)Download full-size image

•Novel securinine derivatives bearing β′-hydroxy-α,β-unsaturated ketones were synthesized.•Two compounds with significant Topo I inhibitory activity and potent anti-proliferative activity were identified.•The interference in the interaction of Topo I with DNA is identified as their action mechanism.DNA topoisomerase I (Topo I) has been validated as a target for anticancer agents. In this study, a series of novel securinine derivatives bearing β′-hydroxy-α,β-unsaturated ketone moiety were designed and synthesized via a Baylis-Hillman reaction for screening as Topo I inhibitors and antitumor agents. Their topoisomerase I inhibitory activity as well as their cytotoxicity against four human cancer cell lines (A549, HeLa, HepG2, SH-SY5Y) were evaluated, and two pairs of diastereomers 4a-1 and 4a-6 with significant Topo I inhibitory activity and potent anti-proliferative activity against cancer cell lines were identified. The diastereomers were separated, and absolute configurations of five pairs of diastereomers were identified based on X-ray crystallographic analysis and circular dichroism (CD) spectra analysis. Further mechanism studies of the most active compounds 4a-1-R and 4a-1-S indicated that this kind of securinine derivative exhibits a different inhibitory mechanism from that of camptothecin, an established Topo I inhibitor. Unlike camptothecin, compounds 4a-1-R and 4a-1-S specifically inhibits the combination of Topo I and DNA rather than forming the drug-enzyme-DNA covalent ternary complex. In addition, molecular docking and molecular dynamic studies revealed the binding patterns of these compounds with Topo I.A series of novel securinine derivatives bearing β′-hydroxy-α, β-unsaturated ketone moiety were synthesized and their Topo I inhibitory and antitumor activities were evaluated. Among them, 4a-1 and 4a-6 exhibited significant Topo I inhibitory activity and potent anti-proliferative activity. Their Topo I inhibitory mechanism was identified as interference in the interaction of Topo I with DNA.

Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17–19, and 21–23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.Keywords: Bivalent analogue strategy; neurite; neuronal differentiation; securinine

Cajaninstilbene acid (CSA) is one of the active components isolated from pigeon pea leaves. In this study, anti-inflammatory effects of CSA and its synthesized derivatives were fully valued with regard to their activities on the production of nitric oxide (NO) and pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in vitro cell model, as well as their impacts on the migration of neutrophils and macrophages in fluorescent protein labeled zebrafish larvae model by live image analysis. Furthermore, the anti-inflammatory mechanism of this type of compounds was clarified by western-blot and reverse transcription-polymerase chain reaction (RT-PCR). The results showed that CSA, as well as its synthesized derivatives 5c, 5e and 5h, exhibited strong inhibition activity on the release of NO and inflammatory factor TNF-α and IL-6 in lipopolysaccharides (LPS)-stimulated murine macrophages. CSA and 5c greatly inhibited the migration of neutrophils and macrophages in injury zebrafish larvae. CSA and 5c treatment greatly inhibited the phosphorylation of proteins involved in nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Moreover, we found that peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662 could reverse partly the roles of CSA and 5c, and CSA and 5c treatment greatly resist the decrease of PPARγ mRNA and protein induced by LPS stimulation. Our results identified the promising anti-inflammatory effects of CSA and its derivatives, which may serve as valuable anti-inflammatory lead compound. Additionally, the mechanism studies demonstrated that the anti-inflammatory activity of CSA and its derivative is associated with the inhibition of NF-κB and MAPK pathways, relying partly on resisting the LPS-induced decrease of PPARγ through improving its expression.

•QSAR models for a series of 40 1-hydroxypyridin-2-one compounds as MIDH1 inhibitors were developed.•Possible interaction modes between MIDH1 and 1-hydroxypyridin-2-one compounds was analyzed.•A set of novel derivatives with better predicted activities were designed.Mutation of isocitrate dehydrogenase 1 (IDH1) which is frequently found in certain cancers such as glioma, sarcoma and acute myeloid leukemia, has been proven to be a potent drug target for cancer therapy. In silico methodologies such as 3D-QSAR and molecular docking were performed to explore compounds with better mutant isocitrate dehydrogenase 1 (MIDH1) inhibitory activity using a series of 40 newly reported 1-hydroxypyridin-2-one compounds as MIDH1 inhibitors. The satisfactory CoMFA and CoMSIA models obtained after internal and external cross-validation gave q2 values of 0.691 and 0.535, r2 values of 0.984 and 0.936, respectively. 3D contour maps generated from CoMFA and CoMSIA along with the docking results provided information about the structural requirements for better MIDH1 inhibitory activity. Based on the structure-activity relationship, 17 new potent molecules with better predicted activity than the most active compound in the literature have been designed.

Berberine, an isoquinoline alkaloid in many medicinal herbs, has been found to possess broad pharmacological activities. A series of novel C-9-O-substituted-berberine derivatives have been synthesized and their anti-inflammatory effects evaluated both in vitro and in vivo. Compared to berberine, the new synthetic berberine derivatives 3i and 5e exhibit significantly improved inhibitory activities against the release of NO, TNF-α and IL-6. Furthermore, derivatives 3i and 5e were found to inhibit more effectively the migration of neutrophils and primitive macrophage in transgenic zebrafish larvae with injury-provoked inflammation. Pre-treatment with derivatives 3i or 5e could lead to a concentration-dependent decrease in nuclear factor-κB (NF-κB) p65 and NF-κB inhibitor α (IκBα) phosphorylation and inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-induced RAW264.7 cells, which suggested that the anti-inflammatory activities of berberine derivatives 3i and 5e are related to their suppression of the NF-κB signal pathway.

Correction for ‘Design, synthesis and anti-inflammatory effects of novel 9-O-substituted-berberine derivatives’ by Mei-Yan Huang et al., MedChemComm, 2016, DOI: 10.1039/c5md00577a.

•A series of novel 5-benzylidene-3,4-dihalo-furan-2-one derivatives were designed and synthesized.•Two compounds (6i and 6k) with excellent anti-inflammatory activity were identified.•Anti-inflammatory mechanism of 6i and 6k was interaction with PPARγ.Rosiglitazone has shown promising anti-inflammation effect. To develop preferable anti-inflammatory agents, twenty-two rosiglitazone analogs were synthesized and their anti-inflammatory activity was evaluated. Among these compounds, 6i and 6k displayed excellent inhibitory activities on the production of inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Furthermore, 6i and 6k showed suppression effects on the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, and this suppression effects could be partially reversed by GW9662, which is a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Additionally, our docking results exhibited the well combination of 6i and 6k to PPARγ. So the anti-inflammation activity of 6i and 6k was due at least in part, to their interaction with PPARγ.A series of novel 5-benzylidene-3,4-dihalo-furan-2-one derivatives were synthesized, characterized and their anti-inflammatory activities were evaluated. Among these compounds, 6i and 6k exhibited excellent anti-inflammatory potential.

The trypanothione reductase (TryR) has been used as a key validated target to guide drug discovery for human African trypanosomiasis (HAT). 3D-QSAR and docking studies were performed on a series of 3,4-dihydroquinazolines as TryR inhibitors to establish a molecular model for new drug design. The CoMFA and CoMSIA models resulted from 53 molecules gave rcv2 values of 0.591 and 0.574, r2 values of 0.968 and 0.943, respectively. The external validation indicated that CoMSIA model with a valid rm2 value of 0.864 exhibited better predictive power than CoMFA model. 3D contour maps generated from CoMFA and CoMSIA along with the docking analyses have identified several key features responsible for the activity. A set of analogs were proposed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The results can be served as a useful guideline for designing novel 3,4-dihydroquinazoline derivatives with improved activity against human African trypanosomes.

Presently, an in silico modeling was carried out on a series of 63 phosphonic acid-containing thiazole derivatives as fructose-1,6-bisphosphatase (FBPase) inhibitors using CoMFA/CoMSIA and molecular docking methods. The CoMFA and CoMSIA models using 51 molecules in the training set gave rcv2 values of 0.675 and 0.619, r2 values of 0.985 and 0.979, respectively. The systemic external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r02 values of 0.995 and 0.994, rm(test)2 values of 0.887 and 0.860, respectively. The 3D contour maps of the CoMFA and CoMSIA provided smooth and interpretable explanation of the structure-activity relationship for the inhibitors. Molecular docking studies revealed that a phosphonic group was essential for binding to the AMP binding site, and some key features were also identified. The analyses of the 3D contour plots and molecular docking results permitted interesting conclusions about the effects of different substituent groups at different positions of the common scaffold, which might guide the design of novel FBPase inhibitors with higher activity and bioavailability. A set of 60 new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.

Based on structural modifications of the natural 23-hydroxybetulinic acid, a series of novel its derivatives had been synthesized. The new compounds were screened for in vitro antiproliferative activity against cancer cell lines HeLa, MCF-7, HepG2, B16 and A375 using doxorubicin as a reference. The vast majority of derivatives had exhibited potent tumor growth inhibitory activity than original compound. The derivatives 4, 5, 7, 20, 23, 26, 43 and 44 with IC50 values lower than 10 μM on all tested cell lines were regarded as the most promising compounds. The structure–activity relationships of 23-hydroxybetulinic acid derivatives were also discussed in the present investigations.A series of 23-hydroxybetulinic acid derivatives had been synthesized and evaluated for their antiproliferative activity. Their structure–activity relationships were revealedHighlights► A set of fifty-five 23-hydroxybetulinic acid derivatives were synthesized. ► A number of new compounds exhibited potent antiproliferative activities. ► Preliminary structure–activity relationships were revealed.

3D-QSAR and docking studies were performed on sixty imidazo[4,5-b]pyridine derivatives as Aurora A kinase inhibitors. The CoMFA and CoMSIA models using forthy-eight molecules in the training set, gave rcv2 values of 0.774 and 0.800, r2 values of 0.975 and 0.977, respectively. The external validation indicated that both CoMFA and CoMSIA models possessed high predictive powers with rpred2 values of 0.933 and 0.959, rm2 values of 0.883 and 0.915, respectively. 3D contour maps generated from the two models along with docking binding structures have identified several key structural requirements responsible for the activity. A set of thirty new analogues were proposed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models.Research highlights► CoMFA and CoMISA models were established based on 60 imidazo[4,5-b]pyridine derivatives as Aurora A inhibitors. ► Molecular docking was performed to explore the binding features between Aurora A kinase and inhibitors. Some new potential Aurora A inhibitors were designed.

3D-QSAR studies were performed on a series of betulinic acid and betulin derivatives with anti-HIV-1 activities. 3D-QSAR models of analysis A and analysis B, which were related to two activity indexes EC50 and TI, respectively, were built by using CoMFA and CoMSIA. The analysis A resulted from 41 molecules gave rcv2 values of 0.664 and 0.718, r2 values of 0.979 and 0.955, respectively. The analysis B also resulted from 41 molecules gave rcv2 values of 0.570 and 0.559, r2 values of 0.938 and 0.933, respectively. The contour maps generated from the two analyses provided the regions in space where interactive fields may influence the activity. The results could serve as a useful guide for the design of potential betulinic acid and betulin derivatives with better anti-HIV-1 activity.

Novel anti-HIV-1 agents derived from betulinic acid have been greatly concerned. 3D-QSAR and molecular docking studies were applied to rationalize the structural requirements responsible for the anti-HIV activity of these compounds. The CoMFA and CoMSIA models resulted from 28 molecules gave rcv2 values of 0.599 and 0.630, r2 values of 0.994 and 0.958, respectively. To estimate the predictive ability of the 3D-QSAR model, an external validation was employed. Based on the contour maps generated from both CoMFA and CoMSIA, we have identified some key features in the betulinic acid derivatives that are responsible for the anti-HIV activity. Molecular docking was used to explore the binding mode between these derivatives and HIV gp120. We have therefore designed a series of novel betulinic acid derivatives by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provide a valuable method to design new betulinic acid derivatives as anti-HIV-1 agents.

A set of 17 novel ketolides bearing an aryltetrazolyl-substituted alkyl side chain were synthesized and evaluated for their antibacterial activities, which the aryltetrazolyl group was selected to replace the hetero-aryl moiety of the side chain in telithromycin for designing new compounds. The synthesis of aryltetrazolyl alkylamines was reported in detail. The antibacterial activities of new ketolides were evaluated against a number of pathogens including macrolide-resistant organisms by using telithromycin as the reference. Many of the evaluated compounds exhibited remarkable activities against both erythromycin-susceptible and erythromycin-resistant organisms such as Staphylococcus aureus (except S. aureus AD-08), Pseudomonas aeruginosa and Escherichia coli. Among these, the compound 11e exhibited excellent antibacterial potency against all the strains in comparison with others.

A series of C-12 pyrazolinyl spiro ketolide derivatives were designed and synthesized. The C-12 modifications involved replacing the natural C-12 methyl group in clarithromycin core with different pyrazolinyl spiros via chemical synthesis. Potential anti-bacterial activities against both erythromycin-susceptible and erythromycin-resistant bacteria were reported.Research highlights►A series of C-12 pyrazolinyl spiro ketolide derivatives were synthesized. ►New ketolides were found to have the improved anti-bacterial activities than erythromycin A and clarithromycin against Staphylococcus aureus strains, Staphylococcus. pneumonia and Haemophilus influenza strains.

3D-QSAR and docking studies were performed on a series of pyrazolo[4,3-h  ]quinazoline-3-carboxamides as CDK2/CyA inhibitors. The CoMFA and CoMSIA models using 54 molecules in the training set, gave rcv2 values of 0.644 and 0.507, r2 values of 0.959 and 0.951, respectively. 3D contour maps generated from the two models were applied to identify features important for the activity and better understand the interaction between the inhibitors and the receptor. Molecular docking was employed to explore the binding mode between these compounds and the receptor, as well as help understanding the structure–activity relationship revealed by CoMFA and CoMSIA. The results provide a useful guideline for the rational design of novel CDKs inhibitors.3D-QSAR and docking studies were performed on a series of pyrazolo[4,3-h]quinazoline-3-carboxamides as CDK2/CyA inhibitors. The correlation of the results obtained from 3D-QSAR and docking studies can be served as a useful guideline for the further modification of pyrazolo[4,3-h]quinazoline-3-carboxamides that function as CDK2/CyA inhibitors.

Fructose-1,6-biphophatase has been regarded as a novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). 3D-QSAR and docking studies were performed on a series of [5-(4-amino-1H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. The CoMFA and CoMSIA models using thirty-seven molecules in the training set gave rcv2 values of 0.614 and 0.598, r2 values of 0.950 and 0.928, respectively. The external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r02 values of 0.994 and 0.994, rm2 values of 0.751 and 0.690, respectively. Molecular docking studies revealed that a phosphonic group was essential for binding to the receptor, and some key features were also identified. A set of forty new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.

The title compounds were synthesized via N-benzylmalonamic acid methyl ester (3). As the key intermediate, 3 was prepared from methyl malonyl chloride and benzylamine. Then, compound 3 was reacted with dimethyl-formamide dimethyl acetal yielding vinylogue amides 4 and 5. Isomers 4 and 5 were respectively treated with amidine and guanidine to afford the title compounds 2-substituted pyrimidinone-5-carboxylic acid benzylamides 6 and 7. All of the new compounds were characterized by 1H-NMR (nuclear magnetic resonance), 13C-NMR, MS and High Resolution Mass Spectrometer (HRMS). The antitumor activities of the compounds were tested in vitro against LoVo cells and Hep3B cells. Both compounds 6 and 7 show activity against these two cell lines.