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A series of novel 1,2,3-triazole-linked isosteviol derivatives were designed and synthesized via Huisgen-click reaction. Their cytotoxicities in vitro against HCT-116 and JEKO-1 cells were screened. The preliminary bioassays indicated that most of the title compounds exhibited noteworthy cytotoxic activities. Particularly, the compound 10b revealed the most potent inhibitory activities against HCT-116 cells with IC 50 value of 2.987 ± 0.098 μM, which was better than that (3.906 ± 0.261 μM) of positive control cisplatin. On the basis of these bioactivity data, hologram quantitative structure–activity relationship (HQSAR) was performed, and a statistically reliable model with good predictive power ( r 2 = 0.848, q 2 = 0.544 and R 2 pred = 0.982) was achieved. Additionally, the contribution maps derived from the optimal model explained the individual atomic contributions to the activity for each molecule. [ABSTRACT FROM AUTHOR]

[Display omitted] Heme oxygenase-1 (HO-1) has been involved in the pathogenesis of Alzheimer's disease (AD), thus constituting a promising target for AD drug development. Positron emission tomography (PET) is a fully translational imaging technology, which will help us understand the role of HO-1 in the progression of AD, facilitating to validate promising HO-1 inhibitors in clinical trials. To our knowledge, there is no report on PET imaging probe targeting HO-1 in animals and humans. We report herein the synthesis and characterization of a 11C-labeled imidazole-based alcohol derivative ([11C]QC-33) for imaging of HO-1 in the brain. The desired product [11C]QC-33 was afforded with a radiochemical yield of 16 ± 9% (n = 3, decay corrected). The radiochemical purity was greater than 99%, and the molar radioactivity was greater than 185 GBq/μmol. In vitro autoradiography studies indicated specific binding of [11C]QC-33 in the HO-1 rich regions, showing 75%, 75%, and 69% radioactivity binding reductions in cerebellum, brain stem, and midbrain, respectively. PET/CT scanning in C57BL/6 mice showed low brain uptake and poor blood–brain barrier (BBB) penetration of [11C]QC-33. These results suggested that [11C]QC-33 can serve as a lead compound to advance the development of next generation PET tracer with the potential to monitor HO-1 in AD progression. [ABSTRACT FROM AUTHOR]

Abstract: Fifteen novel hybrids containing diterpene skeleton and nitric oxide (NO) donor were prepared from isosteviol. All the compounds were tested on preliminary cytotoxicity, and the results showed that six target compounds (8c, 10b, 14a, 14c, 18c, and 18d) exhibited anti-proliferation activity on HepG2 cells, with 8c (IC50 =4.24μM) and 18d (IC50 =2.75μM) superior to the positive control CDDO-Me (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid methyl ester, IC50 =4.99μM); eleven target compounds (8a–c, 9a–c, 10a–b, 14a, 14c, 18d) exhibited anti-proliferation activities on B16F10 cells at different levels, among them, seven compounds were more potent than comptothecin (IC50 =2.78μM) and CDDO-Me (IC50 =5.85μM), particularly, 10b (IC50 =0.02μM) presented the strongest effect, which was selected as a candidate for further study. [Copyright &y& Elsevier]

[Display omitted] • 41 novel FAK covalent inhibitors were synthesized. • Compound 11w displayed highest inhibition of FAK and tumor cells. • 11w inhibited the clone formation and migration of tumor cells, inducing apoptosis. • 11w covalently inhibited the autophosphorylation of FAK in a dose-dependent manner. • 11w showed adequate oral bioavailability and significant antitumor efficacy in vivo. Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC 50 value of 35 nM and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC 50 values of 0.41, 0.01 and 0.11 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G 2 /M phase, inducing tumor cell apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK. [ABSTRACT FROM AUTHOR]

Abstract: A series of substituted bis[(para-methoxy)benzyl] (bisPMB) esters of 1-naphthalenemethylphosphonate (NMPA) were synthesized and evaluated as phosphonate prodrugs. BisPMB NMPA esters (4b and 4c) with significantly improved aqueous stability were identified that also resulted in increased intracellular levels of NMPA following prodrug incubation with primary rat hepatocytes. [Copyright &y& Elsevier]

Abstract: Novel bioreductive and long-wavelength fluorescent markers for hypoxic cells in solid tumor, 9-isocyano-8H-acenaphtho[l,2-b]pyrrol-8-one with the side chain of 2-nitroimidazole, were designed, synthesized, and evaluated in V79 379A Chinese hamster cells in vitro. Compounds A 2 and A 4 showed good hypoxic–oxic fluorescence differential in vitro (V79 cells) by using fluorescence scan ascent. [Copyright &y& Elsevier]

• Novel pyrazolo[1,5- a pyrimidine derivatives were designed and synthesized. • TrkA, TrkB and TrkC inhibitory activity were evaluated. • Compounds 8a , 8f , 9a , 9b and 9f (IC 50 < 5 nM) showed significant inhibitory potency against Trk. Tropomyosin receptor kinases (Trks), a transmembrane receptor tyrosine kinases, have attracted more and more attention as a drug target. Here we reported the structure-based synthesis and biological evaluation of novel pyrazolo[1,5- a pyrimidine derivatives as Trk inhibitors, which exhibited potent Trk inhibitory activities. Particularly, compounds 8a , 8f , 9a , 9b and 9f (IC 50 < 5 nM) showed significant inhibitory potency against Trk. [ABSTRACT FROM AUTHOR]

[Display omitted] Natural plant-derived baicalein which is extracted from Chinese herb Scutellaria baicalensis Georgi belongs to the flavonoid compounds and possesses multiple pharmacological activities. In this study, we designed and synthesized new series of derivatives of baicalein (BE) through catalytic coupling reactions, and screened for their antiviral activity against arboviruses including Chikungunya virus (CHIKV), West Nile virus (WNV) or Zika virus (ZIKV). Our results revealed for the first time that BE and its derivatives had potent anti-CHIKV, anti-WNV and anti-ZIKV effects. And modification of 8 or 4′ position could lead to obtain potent antiviral compounds against CHIKV, WNV and ZIKV with lower cytotoxicity. Among the baicalein derivatives, C3 and F3 showed the most potent antiviral activities against CHIKV, WNV and ZIKV, which were 5–10 times more potent than baicalein. Our findings will provide research basis for the development of baicalein derivatives as effective antiviral agents. [ABSTRACT FROM AUTHOR]

[Display omitted] Natural plant-derived baicalein which is extracted from Chinese herb Scutellaria baicalensis Georgi belongs to the flavonoid compounds and possesses multiple pharmacological activities. In this study, we designed and synthesized new series of derivatives of baicalein (BE) through catalytic coupling reactions, and screened for their antiviral activity against arboviruses including Chikungunya virus (CHIKV), West Nile virus (WNV) or Zika virus (ZIKV). Our results revealed for the first time that BE and its derivatives had potent anti-CHIKV, anti-WNV and anti-ZIKV effects. And modification of 8 or 4′ position could lead to obtain potent antiviral compounds against CHIKV, WNV and ZIKV with lower cytotoxicity. Among the baicalein derivatives, C3 and F3 showed the most potent antiviral activities against CHIKV, WNV and ZIKV, which were 5–10 times more potent than baicalein. Our findings will provide research basis for the development of baicalein derivatives as effective antiviral agents. [ABSTRACT FROM AUTHOR]

Five new phorbol esters, (four phorbol diesters, 1 – 4 , and one 4-deoxy-4α-phorbol diester, 5 ), as well as four known phorbol esters analogues ( 6 – 9 ) were isolated and identified from the branches and leaves of Croton tiglium . Their structures were elucidated mainly by extensive NMR spectroscopic, and mass spectrometric analysis. Among them, compound ( 1 ) was the first example of a naturally occurring phorbol ester with the 20-aldehyde group. Compounds 2 – 5 , and 7 – 9 showed potent cytotoxicity against the K562, A549, DU145, H1975, MCF-7, U937, SGC-7901, HL60, Hela, and MOLT-4 cell lines, with IC 50 values ranging from 1.0 to 43 μM, while none of the compounds exhibited cytotoxic effects on normal human cell lines 293T and LX-2, respectively. In addition, compound 3 exhibited moderate COX-1 and COX-2 inhibition, with IC 50 values of 0.14 and 8.5 μM, respectively. [ABSTRACT FROM AUTHOR]

[Display omitted] • New pyrido[1,2- α ]pyrazole derivatives were designed and synthesized. • Wild-type TrkA, TrkAG595R and Alk inhibitory activity in vitro were evaluated. • Compound 14h and 14j behaved as excellent Second-generation inhibitor against Trk, and 14j was a selective inhibitor for Trk. As a receptor tyrosine kinase (RTK), tropomyosin receptor kinase (Trk) is a key drug target in solid tumors. However, the use of the First-generation Trk inhibitors was greatly restricted due to mutant drug resistance. Fortunately, the emergence of the Second-generation of Trk inhibitors has brought an effective solution to this mutant resistance, such as TPX-0005 (Repotrectinib). Here, we reported a series of pyrizolo[1,5- a ]pyrimidine derivatives as the second-generation Trk inhibitors, and carried out the subsequent biological activity evaluation. Among them, the best compound 14h (IC 50 = 1.40, 1.80 nM, against TrkA, TrkAG595R, respectively) and 14j (IC 50 = 0.86, 6.92 nM, against TrkA, TrkAG595R, respectively) has a kinase activity comparable to TPX-0005, and 14j (IC 50 = 350 nM against ALK) has a higher selectivity of Trk inhibition than TPX-0005, which may be of great significance for reducing toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Transferrin has shown potential in the delivery of anticancer drugs into primarily proliferating malignant cells that over-express transferrin receptors. Constructing transferrin receptor targeted drug delivery system has been widespread concerned. In this study, whether transferrin could transport noncovalent binding drugs into cancer cells has been investigated. Two representative compounds, doxorubicin hydrochloride (Dox) and vanadocene dichloride (Cp2VCl2), have been chosen to study the interactions with h-Tf and apo-Tf, and the influences in the presence of h-Tf and apo-Tf by using fluorescence spectroscopy, circular dichroism (CD) spectroscopy and MTT assay. The results have shown that both doxorubicin and Cp2VCl2 could bind to h-Tf and apo-Tf but with different binding modes. The results of MTT assay demonstrate that the presence of both h-Tf and apo-Tf has enhanced the antiproliferative activity of Cp2VCl2. However, the anticancer activity of the mixture of doxorubicin and h-Tf is basically the same as that of doxorubicin does. Our studies indicate that transferrin plays an important role in the transport and targeted delivery of Cp2VCl2 into cancer cells. [Copyright &y& Elsevier]

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5- f ]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model. [ABSTRACT FROM AUTHOR]

[Display omitted] Chikungunya fever is an acute infectious disease caused by Chikungunya virus (CHIKV) and transmitted by Aedes mosquito. It is characterized by fever, rash and arthralgia with no effective drugs. Lomerizine (Lom) is a new generation calcium antagonist, which is mainly used in the treatment of migraine. Certain antiviral function of Lom was shown by some research. In our study, a series of new derivatives of Lom were designed and synthesized, and their in-vitro anti-CHIKV activity was tested. The results showed that Lom and its derivatives had potent anti-CHIKV activity and low cytotoxicity. Among them, compounds B1 and B7 showed most potent antiviral activity. Besides, structure–activity relationships, in-silico ADMET properties were also analyzed. Molecular docking study was performed to rationalize the SAR and analyze the possible binding modes between B1 and amino acid residues in the active site of nsP3 protein to enhance the understanding of their action as antiviral agents. These finding provides research basis for the design and synthesis of effective anti-CHIKV drugs with Lom as the lead compound. [ABSTRACT FROM AUTHOR]

The increasingly acquired resistance to vemurafenib and side effects of known inhibitors motivate the search for new and more effective anti-melanoma drugs. In this Letter, virtual screening and scaffold growth were combined together to achieve new molecules as BRAF V600E inhibitors. Along with docking simulation, a primary screen in vitro was performed to filter the modifications for the lead compound, which was then substituted, synthesized and evaluated for their inhibitory activity against BRAF V600E and several melanoma cell lines. Out of the obtained compounds, derivative 3l was identified as a potent BRAF V600E inhibitor and exerted an anticancer effect through BRAF V600E inhibition. The following biological evaluation assays confirmed that 3l could induce cell apoptosis and marked DNA fragmentation. Furthermore, 3l could arrest the cell cycle at the G0/G1 phase in melanoma cells. The docking simulation displayed that 3l could tightly bind with the crystal structure of BRAF V600E at the active site. Overall, the biological profile of 3l suggests that this compound may be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Polycomb repressive complex 2 (PRC2) acts as a primary writer for di- and tri-methylation of histone H3 at lysine 27. This protein plays an essential role in silencing gene expression. Enhancer of zeste 2 (EZH2), the catalytic subunit of PRC2, is considered as a promising therapeutic target for cancer. GSK126, a specific inhibitor of EZH2, is undergoing phase I trials for hypermethylation-related cancers. In addition, many derivatives of GSK126 are also commonly used in laboratory investigations. However, studies on the mechanism and drug development of EZH2 are limited by the absence of structural diversity of these inhibitors because they share similar SAM-like scaffolds. In this study, we generated a pharmacophore model based on reported EZH2 inhibitors and performed in silico screenings. Experimental validations led to the identification of two novel EZH2 inhibitors, DCE_42 and DCE_254, with IC 50 values of 23 and 11 μM, respectively. They also displayed significant anti-proliferation activity against lymphoma cell lines. Thus, we discovered potent EZH2 inhibitors with novel scaffold using combined in silico screening and experimental study. Results from this study can also guide further development of novel specific EZH2 inhibitors. [ABSTRACT FROM AUTHOR]

A novel sesquiterpene with an unprecedented epoxy lactone skeleton, named tatarinolactone, together with two new amides, a new biphenylpropanoid and two known lignans were isolated from the rhizomes of Acorus tatarinowii Schott. Their structures were identified as 6,7,8-trihydroxy-4α-isobutyl-4,7-dimethylhexahydro-6,8α-epoxychromen-2(3 H )-one ( 1 ), ( E )-methyl 4-[3-(4-hydroxy-3-methoxyphenyl)acrylamido]butanoate ( 2 ), ( Z )-methyl 4-[3-(4-hydroxy-3-methoxyphenyl)acrylamido]butanoate enol isomer ( 3 ), ( R )-4-hydroxy-3-[1-hydroxy-3-(4-hydroxy-3-methoxyphenyl)propan-2-yl]-5-methoxybenzoic acid ( 4 ), (2 S ,3 R )-ceplignan ( 5 ), and (2 R ,3 S )-ceplignan ( 6 ), respectively, based on extensive spectroscopic analysis and by comparison to the known compounds. To test their effects on serotonin transporters, a high content assay using hSERT-HEK293 cell line was adopted. Results indicated that compounds 1 and 4 significantly inhibited SERT activity, while compounds 2 , 3 , 5 , and 6 significantly enhanced SERT activity, which partly explain the traditional uses of the rhizomes of Acorus tatarinowii Schott in treatments of neuropsychiatric and digestive disorders. [ABSTRACT FROM AUTHOR]

Investigation of the bark of Zanthoxylum simulans afforded six new dimeric lignans zanthpodocarpins C–H ( 1 – 6 ) bearing an unusual α,β-unsaturated ketone group. The new structures of 1 – 6 were determined by using detailed spectroscopic analysis. All of the isolated compounds were examined for their inhibitory effects against rat joint synovial cell and splenocyte proliferation. Compounds 1 – 6 showed potent anti-inflammatory activities with IC 50 values ranging from 18.6 to 36.1 μM, and 13.8 to 74.3 μM. [ABSTRACT FROM AUTHOR]

Abstract: Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. [Copyright &y& Elsevier]

Abstract: Tuberculosis (TB) is a major health problem worldwide. A series of novel sansanmycin derivatives were designed, semi-synthesized and evaluated for their activity against drug-susceptible Mycobacterium tuberculosis strain H37Rv with sansanmycin A (SSA) as the lead. Among these analogs tested, compound 1d possessing an isopropyl group at the amino terminal afforded an increased antimycobacterial activity with a MIC value of 8μg/mL in comparison with SSA. Importantly, it was active for rifampicin- and isoniazid-resistant M. tuberculosis strain isolated from patients in China. These promising results offer an opportunity for further exploration of this novel class of analogs as antitubercular agents. [Copyright &y& Elsevier]

Abstract: Currently, there is no approved antiviral drug for the infection caused by enteroviruses. A series of novel N-arylethyl isoquinoline derivatives defined with substituents on the ring A and C were designed, synthesized and evaluated in vitro for their activities against Coxsackievirus B3 (CVB3). The primary structure–activity relationship revealed that substituents on the ring A were not beneficial for the activity. Among these analogs synthesized, compound 7f bearing a methylenedioxy at the R4 and R5 positions afforded an anti-CVB3 activity and a reasonable selectivity index (SI=26.8); furthermore, 7f exhibited a moderate activity against enterovirus 71 (EV71) with SI value of 9.0. Thus it has been selected as an anti-enteroviral lead compound for further investigation. [Copyright &y& Elsevier]

Abstract: Oxymatrine (1) is a natural anti-hepatitis B virus (HBV) drug that down-regulates host heat-stress cognate 70 (Hsc70) expression through a mechanism different from that of nucleosides. Taking Hsc70 as a target against HBV, 26 novel N-substituted matrinic acid analogs were designed, synthesized and evaluated for their regulation of Hsc70 mRNA expression with 1 as the lead. The SAR analysis revealed that (i) the carboxyl group at the 11-position was required for activity; (ii) introducing of a substituent on the nitrogen atom at the 12-position of 3, especially substituted benzyl, might significantly improve the activity. Among these analogs, compound 9p possessing N-p-methoxylbenzyl afforded an increased anti-HBV effect in comparison with 1. We consider 9p a promising anti-HBV candidate. [Copyright &y& Elsevier]

Abstract: A series of novel 2′,3′-dideoxy-2′,3′-diethanethioribonucleosides and those modified with a triazole ring were prepared in excellent yields and their antitumor activity was evaluated. Nucleosides with a triazole ring, 16a–16c, showed significantly improved activity towards a broad range of tumor cell lines. [Copyright &y& Elsevier]

Abstract: A series of nonsteroidal glucocorticoid receptor (GR) ligands based on a 6-indole-1,2,3,4-tetrahydroquinoline scaffold are reported. Structure–activity relationship (SAR) of the pendent indole group identified compound 20 exhibiting good GR binding affinity (K i =1.5nM) and 100- to 1000-fold selectivity over MR, PR, and AR while showing activity in an E-selectin repression assay. [Copyright &y& Elsevier]

Thio-heterocyclic fused naphthalimides with aminoalkyl side chains were designed, synthesized and evaluated. These compounds have long wavelength absorptions and binding affinities to Calf thymus DNA. They could photodamage supercoiled pBR322 DNA from form I (closed) to II (nicked) at a concentration as low as 0.5 μM and to form III (linear) at a concentration of 50 μM. A possible mechanism of superoxide anion was provided. [Copyright &y& Elsevier]

We report herein the discovery of a positron emission tomography (PET) tracer for the (NOD)-like receptor protein 3 (NLRP3). Our recent medicinal chemistry campaign on developing sulfonamide-based NLRP3 inhibitors led to an analog, 1 , with a methoxy substituent amenable to labeling with carbon-11. PET/CT imaging studies indicated that [11C]1 exhibited rapid blood–brain barrier (BBB) penetration and moderate brain uptake, as well as blockable uptake in the brain. [11C]1 , thus suggesting the potential to serve as a useful tool for imaging NLRP3 inflammasome in living brains. [ABSTRACT FROM AUTHOR]