Thiadiazolidinone (TDZD) Analogs Inhibit Aggregation-Mediated Pathology in Diverse Neurodegeneration Models, and Extend C. elegans Life- and Healthspan.

Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer's disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aß1-42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and "healthspan" (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15-30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3ß, we used molecular-dynamic tools to assess whether these analogs may also target GSK3ß. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3ß as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality.

Structural modeling of GSK3ß implicates the inactive (DFG-out) conformation as the target bound by TDZD analogs.

Glycogen synthase kinase-3ß (GSK3ß) controls many physiological pathways, and is implicated in many diseases including Alzheimer's and several cancers. GSK3ß-mediated phosphorylation of target residues in microtubule-associated protein tau (MAPTAU) contributes to MAPTAU hyperphosphorylation and subsequent formation of neurofibrillary tangles. Inhibitors of GSK3ß protect against Alzheimer's disease and are therapeutic for several cancers. A thiadiazolidinone drug, TDZD-8, is a non-ATP-competitive inhibitor targeting GSK3ß with demonstrated efficacy against multiple diseases. However, no experimental data or models define the binding mode of TDZD-8 with GSK3ß, which chiefly reflects our lack of an established inactive conformation for this protein. Here, we used metadynamic simulation to predict the three-dimensional structure of the inactive conformation of GSK3ß. Our model predicts that phosphorylation of GSK3ß Serine9 would hasten the DFG-flip to an inactive state. Molecular docking and simulation predict the TDZD-8 binding conformation of GSK3ß to be inactive, and are consistent with biochemical evidence for the TDZD-8-interacting residues of GSK3ß. We also identified the pharmacophore and assessed binding efficacy of second-generation TDZD analogs (TDZD-10 and Tideglusib) that bind GSK3ß as non-ATP-competitive inhibitors. Based on these results, the predicted inactive conformation of GSK3ß can facilitate the identification of novel GSK3ß inhibitors of high potency and specificity.

7-Azaindolequinuclidinones (7-AIQD): A novel class of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor ligands.

A series of N-benzyl-7-azaindolequinuclidinone (7-AIQD) analogs have been synthesized and evaluated for affinity toward CB1 and CB2 cannabinoid receptors and identified as a novel class of cannabinoid receptor ligands. Structure-activity relationship (SAR) studies indicate that 7-AIQD analogs are dual CB1/CB2 receptor ligands exhibiting high potency with somewhat greater selectivity towards CB2 receptors compared to the previously reported indolequinuclidinone (IQD) analogs. Initial binding assays showed that 7-AIQD analogs 8b, 8d, 8f, 8g and 9b (1 µM) produced more that 50% displacement of the CB1/CB2 non-selective agonist CP-55,940 (0.1 nM). Furthermore, Ki values determined from full competition binding curves showed that analogs 8a, 8b and 8g exhibit high affinity (110, 115 and 23.7 nM, respectively) and moderate selectivity (26.3, 6.1 and 9.2-fold, respectively) for CB2 relative to CB1 receptors. Functional studies examining modulation of G-protein activity demonstrated that 8a acts as a neutral antagonist at CB1 and CB2 receptors, while 8b exhibits inverse agonist activity at these receptors. Analogs 8f and 8g exhibit different intrinsic activities, depending on the receptor examined. Molecular docking and binding free energy calculations for the most active compounds (8a, 8b, 8f, and 8g) were performed to better understand the CB2 receptor-selective mechanism at the atomic level. Compound 8g exhibited the highest predicted binding affinity at both CB1 and CB2 receptors, and all four compounds were shown to have higher predicted binding affinities with the CB2 receptor compared to their corresponding binding affinities with the CB1 receptor. Further structural optimization of 7-AIQD analogs may lead to the identification of potential clinical agents.

Oxone®-Mediated TEMPO-Oxidized Cellulose Nanomaterials form I and form II.

The 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) oxidation of cellulose, when mediated with Oxone® (KHSO5), can be performed simply and under mild conditions. Furthermore, the products of the reaction can be isolated into two major components: Oxone®-mediated TEMPO-oxidized cellulose nanomaterials Form I and Form II (OTO-CNM Form I and Form II). This study focuses on the characterization of the properties of OTO-CNMs. Nanoparticle-sized cellulose fibers of 5 and 16 nm, respectively, were confirmed through electron microscopy. Infrared spectroscopy showed that the most carboxylation presented in Form II. Conductometric titration showed a two-fold increase in carboxylation from Form I (800 mmol/kg) to Form II (1600 mmol/kg). OTO-CNMs showed cellulose crystallinity in the range of 64-68% and crystallite sizes of 1.4-3.3 nm, as shown through XRD. OTO-CNMs show controlled variability in hydrophilicity with contact angles ranging from 16 to 32°, within or below the 26-47° reported in the literature for TEMPO-oxidized CNMs. Newly discovered OTO-CNM Form II shows enhanced hydrophilic properties as well as unique crystallinity and chemical functionalization in the field of bio-sourced material and nanocomposites.

Aggregate Interactome Based on Protein Cross-linking Interfaces Predicts Drug Targets to Limit Aggregation in Neurodegenerative Diseases.

Diagnosis of neurodegenerative diseases hinges on "seed" proteins detected in disease-specific aggregates. These inclusions contain diverse constituents, adhering through aberrant interactions that our prior data indicate are nonrandom. To define preferential protein-protein contacts mediating aggregate coalescence, we created click-chemistry reagents that cross-link neighboring proteins within human, APPSw-driven, neuroblastoma-cell aggregates. These reagents incorporate a biotinyl group to efficiently recover linked tryptic-peptide pairs. Mass-spectroscopy outputs were screened for all possible peptide pairs in the aggregate proteome. These empirical linkages, ranked by abundance, implicate a protein-adherence network termed the "aggregate contactome." Critical hubs and hub-hub interactions were assessed by RNAi-mediated rescue of chemotaxis in aging nematodes, and aggregation-driving properties were inferred by multivariate regression and neural-network approaches. Aspirin, while disrupting aggregation, greatly simplified the aggregate contactome. This approach, and the dynamic model of aggregate accrual it implies, reveals the architecture of insoluble-aggregate networks and may reveal targets susceptible to interventions to ameliorate protein-aggregation diseases.

A Novel Microtubule-Binding Drug Attenuates and Reverses Protein Aggregation in Animal Models of Alzheimer's Disease.

Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-Aß1-42 mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1ß to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic Caenorhabditis elegans (C. elegans) strains that express human Aß1-42 in muscle or neurons, PNR502 rescued Aß-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively. Moreover, in C. elegans with neuronal expression of Aß1-42, a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (P < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (P ≤ 0.001). Given that PNR502 can slow, prevent, or reverse Alzheimer-like protein aggregation in human-cell-culture and animal models, and that its principal predicted and observed binding targets are proteins previously implicated in Alzheimer's, we propose that PNR502 has therapeutic potential to inhibit cerebral Aß1-42 aggregation and prevent or reverse neurodegeneration.

A novel tetrazole analogue of resveratrol is a potent anticancer agent.

A series of novel tetrazole analogues of resveratrol were synthesized and evaluated for their anti-leukemic activity against an extensive panel of human cancer cell lines and against the MV4-11 AML cell line. These molecules were designed as drug-like derivatives of the resveratrol analogue DMU-212 and its cyano derivatives. Four compounds 8g, 8h, 10a and 10b exhibited LD50 values of 4.60 µM, 0.02 µM, 1.46 µM, and 1.08 µM, respectively, against MV4-11 leukemia cells. The most potent compounds, 8h and 10b, were also found to be active against an extensive panel of human hematological and solid tumor cell lines; compound 8h was the most potent compound with GI50 values <10 nM against more than 90% of the human cancer cell lines in the 60-cell panel. Analogues 8g, 8h, 10a and 10b were also tested for their ability to inhibit the polymerization of tubulin, and compound 8h was found to be the most potent analogue. Molecular modeling studies demonstrated that 8h binds to the colchicine binding site on tubulin. Thus, compound 8h is considered to be a lead druglike molecule from this tetrazole series of compounds.

Identification of resveratrol analogs as potent anti-dengue agents using a cell-based assay.

Dengue virus (DENV) causes a variety of difficult-to-treat diseases that threaten almost half of the world's population. Currently, no effective vaccine or antiviral therapy is available. We have examined a series of synthetic resveratrol analogs to identify potential anti-DENV agents. Here, we demonstrate that two resveratrol analogs, PNR-4-44 and PNR-5-02, possess potent anti-DENV activity with EC50 values in the low nanomolar range. These two resveratrol analogs were shown to mainly target viral RNA translation and viral replication, but PNR-5-02 is also likely to target cellular factors inside host cells. Although the precise molecular mechanism(s) mediating anti-DENV activities have not been elucidated, further structure-guided design might lead to the development of newer improved resveratrol derivatives that might have therapeutic value. J. Med. Virol. 89:397-407, 2017. © 2016 Wiley Periodicals, Inc.

N-[11CH3]Dimethylaminoparthenolide (DMAPT) uptake into orthotopic 9LSF glioblastoma tumors in the rat.

The aim of this study was to determine the uptake of intravenously administered N-[11CH3]-dimethylaminoparthenolide (DMAPT) into orthotopic 9LSF glioblastoma brain tumors in Fisher 344 rats from positron emission tomography (PET) imaging studies. [11C]methyl iodide (11CH3I) was utilized as a [11C]-labeling reagent to label the precursor methylaminoparthenolide (MAPT) intermediate. From PET imaging studies it was found that brain uptake of N-[11CH3]DMAPT into brain tumor tissue was rapid (30min), and considerably higher than that in the normal brain tissue.

Crystal structures of (Z)-5-[2-(benzo[b]thio-phen-2-yl)-1-(3,5-di-meth-oxy-phen-yl)ethen-yl]-1H-tetra-zole and (Z)-5-[2-(benzo[b]thio-phen-3-yl)-1-(3,4,5-tri-meth-oxy-phen-yl)ethen-yl]-1H-tetra-zole.

(Z)-5-[2-(Benzo[b]thio-phen-2-yl)-1-(3,5-di-meth-oxy-phen-yl)ethen-yl]-1H-tetrazole methanol monosolvate, C19H16N4O2S·CH3OH, (I), was prepared by the reaction of (Z)-3-(benzo[b]thio-phen-2-yl)-2-(3,5-di-meth-oxy-phen-yl)acrylo-nitrile with tri-butyl-tin azide via a [3 + 2]cyclo-addition azide condensation reaction. The structurally related compound (Z)-5-[2-(benzo[b]thio-phen-3-yl)-1-(3,4,5-tri-meth-oxy-phen-yl)ethen-yl]-1H-tetra-zole, C20H18N4O3S, (II), was prepared by the reaction of (Z)-3-(benzo[b]thio-phen-3-yl)-2-(3,4,5-tri-meth-oxy-phen-yl)acrylo-nitrile with tri-butyl-tin azide. Crystals of (I) have two mol-ecules in the asymmetric unit (Z' = 2), whereas crystals of (II) have Z' = 1. The benzo-thio-phene rings in (I) and (II) are almost planar, with r.m.s deviations from the mean plane of 0.0084 and 0.0037 Šin (I) and 0.0084 Šin (II). The tetra-zole rings of (I) and (II) make dihedral angles with the mean planes of the benzo-thio-phene rings of 88.81 (13) and 88.92 (13)° in (I), and 60.94 (6)° in (II). The di-meth-oxy-phenyl and tri-meth-oxy-phenyl rings make dihedral angles with the benzo-thio-phene rings of 23.91 (8) and 24.99 (8)° in (I) and 84.47 (3)° in (II). In both structures, mol-ecules are linked into hydrogen-bonded chains. In (I), these chains involve both tetra-zole and methanol, and are parallel to the b axis. In (II), mol-ecules are linked into chains parallel to the a axis by N-H⋯N hydrogen bonds between adjacent tetra-zole rings.

Dimers of Melampomagnolide B Exhibit Potent Anticancer Activity against Hematological and Solid Tumor Cells.

Novel carbamate (7a-7h) and carbonate (7i, 7j, and 8) dimers of melampomagnolide B have been synthesized by reaction of the melampomagnolide-B-triazole carbamate synthon 6 with various terminal diamino- and dihydroxyalkanes. Dimeric carbamate products 7b, 7c, and 7f exhibited potent growth inhibition (GI50 = 0.16-0.99 µM) against the majority of cell lines in the NCI panel of 60 human hematological and solid tumor cell lines. Compound 7f and 8 exhibited anticancer activity that was 300-fold and 1 × 10(6)-fold more cytotoxic than DMAPT, respectively, at a concentration of 10 µM against rat 9L-SF gliosarcoma cells. Compounds 7a-7j and 8 were also screened against M9-ENL1 and acute myelogenous leukemia (AML) primary cell lines and exhibited 2- to 10-fold more potent antileukemic activity against M9-ENL1 cells (EC50 = 0.57-2.90 µM) when compared to parthenolide (EC50 = 6.0) and showed potent antileukemic activity against five primary AML cell lines (EC50 = 0.76-7.3 µM).

1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1).

In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolylmethylene barbituric acid analogs (7a-7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogs (7 i-7 l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogs 7 i, 7 j, and 7 k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values <2 µM. Compound 7 k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22-0.35 µM. Analog 7 i also exhibited GI50 values <0.35 µM against three of the leukemia cell lines in the sub-panel. Analogs 7 i, 7 j, 7 k and 7 l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7 k and 7 l were found to cause dose-dependent apoptosis (AP50 = 1.75 µM and 3.3 µM, respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: that is, A498 renal cancer (GI50 = 0.19 µM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 µM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 µM, respectively), CNS cancer SF-539 (GI50 = 0.22 µM), melanoma MDA-MB-435 (GI50 = 0.22 µM), and breast cancer HS 578T (GI50 = 0.22 µM) cell lines. Molecular docking studies suggest that compounds 7 k and 7 l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7 i, 7 j, 7 k, and 7 l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors.

Comparison of the crystal structures of 4,4'-bis-[3-(4-methyl-piperidin-1-yl)prop-1-yn-1-yl]-1,1'-biphenyl and 4,4'-bis-[3-(2,2,6,6-tetra-methyl-piperidin-1-yl)prop-1-yn-1-yl]-1,1'-biphen-yl.

As part of a comprehensive program to discover α9α10 nicotinic acetyl-choline receptor antagonists, the title compounds C30H36N2, (I), and C36H48N2, (II), were synthesized by coupling 4,4'-bis-(3-bromo-prop-1-yn-1-yl)-1,1'-biphenyl with 4-methyl-piperidine and 2,2,6,6-tetra-methyl-piperidine, respectively, in aceto-nitrile at room temperature. In compound (I), the biphenyl system has a twisted conformation with a dihedral angle of 26.57 (6)° between the two phenyl rings of the biphenyl moiety, while in compound (II), the biphenyl moiety sits on a crystallographic inversion centre so the two phenyl rings are exactly coplanar. The terminal piperidine rings in both compound (I) and compound (II) are in the chair conformation. In compound (I), the dihedral angles about the ethynyl groups between the planes of the phenyl rings and the piperidine ring N atoms are 37.16 (16) and 14.20 (17)°. In compound (II), the corresponding dihedral angles are both 61.48 (17)°. There are no noteworthy inter-molecular inter-actions in (I), but in (II) there is a small π-overlap between inversion-related mol-ecules (1 - x, 1 - y, 1 - z), with an inter-planar spacing of 3.553 (3) Šand centroid-to-centroid separation of 3.859 (4) Å.

Comparison crystal structure conformations of two structurally related biphenyl analogues: 4,4'-bis-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]-1,1'-biphenyl and 4,4'-bis-{3-[(S)-2-methyl-pyrrolidin-1-yl]prop-1-yn-1-yl}-1,1'-biphen-yl.

The title compounds, C26H28N2, (I), and C28H32N2, (II), were designed based on the structure of the potent α9α10 nicotinic acetyl-choline receptor antagonist ZZ161C {1,1'-[[1,1'-biphen-yl]-4,4'-diylbis(prop-2-yne-3,1-di-yl)]bis-(3,4-di-methyl-pyridin-1-ium) bromide}. In order to improve the druglikeness properties of ZZ161C for potential oral administration, the title compounds (I) and (II) were prepared by coupling 4,4'-bis-(3-bromo-prop-1-yn-1-yl)-1,1'-biphenyl with pyrrol-idine, (I), and (S)-2-methyl-pyrrolidine, (II), respectively, in aceto-nitrile at room temperature. The asymmetric unit of (I) contains two half mol-ecules that each sit on sites of crystallographic inversion. As a result, the biphenyl ring systems in compound (I) are coplanar. The biphenyl ring system in compound (II), however, has a dihedral angle of 28.76 (11)°. In (I), the two independent mol-ecules differ in the orientation of the pyrrolidine ring (the nitro-gen lone pair points towards the biphenyl rings in one mol-ecule, but away from the rings in the other). The torsion angles about the ethynyl groups between the planes of the phenyl rings and the pyrrolidine ring N atoms are 84.15 (10) and -152.89 (10)°. In compound (II), the corresponding torsion angles are 122.0 (3) and 167.0 (3)°, with the nitro-gen lone pairs at both ends of the mol-ecule directed away from the central biphenyl rings.

Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents.

Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI50 values <1 µM. Interestingly, trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212.

Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents.

A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and ß-tubulin that is occupied by colchicine, and were stabilized by van der Waals' interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs.

Synthesis and anti-cancer screening of novel heterocyclic-(2H)-1,2,3-triazoles as potential anti-cancer agents.

trans-Cyanocombretastatin A-4 (trans-CA-4) analogues have been structurally modified to afford their more stable CA-4-(2H)-1,2,3-triazole analogues. Fifteen novel, stable 4-heteroaryl-5-aryl-(2H)-1,2,3-triazole CA-4 analogues (8a-i, 9 and 11a-e) were evaluated for anti-cancer activity against a panel of 60 human cancer cell lines. These analogues displayed potent cytotoxic activity against both hematological and solid tumor cell lines with GI50 values in the low nanomolar range. The most potent compound, 8a, was a benzothiophen-2-yl analogue that incorporated a 3,4,5-trimethoxyphenyl moiety connected to the (2H)-1,2,3-triazole ring system. Compound 8a exhibited GI50 values of <10 nM against 80% of the cancer cell lines in the panel. Three triazole analogues, 8a, 8b and 8g, showed particularly potent growth inhibition against the triple negative Hs578T breast cancer cell line with GI50 values of 10.3 nM, 66.5 nM and 20.3 nM, respectively. Molecular docking studies suggest that these compounds bind to the same hydrophobic pocket at the interface of α- and ß-tubulin that is occupied by colchicine and cis-CA-4, and are stabilized by Van der Waals' interactions with surrounding amino acid residues. Compound 8a was found to inhibit tubulin polymerization in vitro with an IC50 value of 1.7 µM. The potent cytotoxicity of these novel compounds and their inhibition of tubulin dynamics make these triazole analogues promising candidates for development as anti-cancer drugs.

Crystal structure of (E)-13-{4-[(Z)-2-cyano-2-(3,4,5-tri-meth-oxy-phen-yl)ethen-yl]phen-yl}parthenolide methanol hemisolvate.

The title compound, C33H35NO6 [systematic name: (Z)-3-(4-{(E)-[(E)-1a,5-dimethyl-9-oxo-2,3,7,7a-tetra-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2-b]furan-8(1aH,6H,9H,10aH,10bH)-yl-idene]meth-yl}phen-yl)-2-(3,4,5-tri-meth-oxy-phen-yl)acrylo-ni-trile methanol hemisolvate], C33H35NO6·0.5CH3OH, was prepared by the reaction of (Z)-3-(4-iodo-phen-yl)-2-(3,4,5-tri-meth-oxy-phen-yl)acrylo-nitrile with parthenolide [systematic name: (E)-1a,5-dimethyl-8-methyl-ene-2,3,6,7,7a,8,10a,10b-octa-hy-dro-oxireno[2',3':9,10]cyclo-deca-[1,2-b]furan-9(1aH)-one] under Heck reaction conditions. The mol-ecule is built up from fused ten-, five- (lactone) and three-membered (epoxide) rings with a {4-[(Z)-2-cyano-2-(3,4,5-tri-meth-oxy-phen-yl)ethen-yl]phen-yl}methyl-idene group as a substituent. The 4-[(Z)-2-cyano-2-(3,4,5-tri-meth-oxy-phen-yl)ethen-yl]phenyl group on the parthenolide exocyclic double bond is oriented in a trans position to the lactone ring to form the E isomer. The dihedral angle between the benzene ring of the phenyl moiety and the lactone ring mean plane is 21.93 (4)°.

Crystal structure of 4,5-bis-(3,4,5-tri-meth-oxy-phen-yl)-2H-1,2,3-triazole methanol monosolvate.

The title compound, C20H23N3O6·CH3OH, was synthesized by [3 + 2] cyclo-addition of (Z)-2,3-bis-(3,4,5-tri-meth-oxy-phen-yl)acrylo-nitrile with sodium azide and ammonium chloride in DMF/water. The central nitro-gen of the triazole ring is protonated. The dihedral angles between the triazole ring and the 3,4,5-tri-meth-oxy-phenyl ring planes are 34.31 (4) and 45.03 (5)°, while that between the 3,4,5-tri-meth-oxy-phenyl rings is 51.87 (5)°. In the crystal, the mol-ecules, along with two methanol solvent mol-ecules are linked into an R (4) 4(10) centrosymmetric dimer by N-H⋯O and O-H⋯N hydrogen bonds.

Comparison of crystal structures of 4-(benzo[b]thio-phen-2-yl)-5-(3,4,5-tri-meth-oxy-phen-yl)-2H-1,2,3-triazole and 4-(benzo[b]thio-phen-2-yl)-2-methyl-5-(3,4,5-tri-meth-oxy-phen-yl)-2H-1,2,3-triazole.

The title compound, C19H17N3O3S (I), was prepared by a [3 + 2]cyclo-addition azide condensation reaction using sodium azide and l-proline as a Lewis base catalyst. N-Methyl-ation of compound (I) using CH3I gave compound (II), C20H19N3O3S. The benzo-thio-phene ring systems in (I) and (II) are almost planar, with r.m.s deviations from the mean plane = 0.0205 (14) in (I) and 0.016 (2) Šin (II). In (I) and (II), the triazole rings make dihedral angles of 32.68 (5) and 10.43 (8)°, respectively, with the mean planes of the benzo-thio-phene ring systems. The trimeth-oxy phenyl rings make dihedral angles with the benzo-thio-phene rings of 38.48 (4) in (I) and 60.43 (5)° in (II). In the crystal of (I), the mol-ecules are linked into chains by N-H⋯O hydrogen bonds with R (2) 1(5) ring motifs. After the N-methyl-ation of structure (I), no hydrogen-bonding inter-actions were observed for structure (II). The crystal structure of (II) has a minor component of disorder that corresponds to a 180° flip of the benzo-thio-phene ring system [occupancy ratio 0.9363 (14):0.0637 (14)].