Antimitotic Activity Research Articles

Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells.

Background and PurposeCD22 and CD79b are cell‐surface receptors expressed on B‐cell‐derived malignancies such as non‐Hodgkin's lymphoma (NHL). An anti‐mitotic agent, monomethyl auristatin E, was conjugated to anti‐CD22 and anti‐CD79b antibodies to develop target‐specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody‐drug conjugates (ADCs) were investigated in cynomolgus monkeys.Experimental ApproachAnimals were administered anti‐CD22 or anti‐CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro.Key ResultsDepletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti‐human CD22 and anti‐human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity.Conclusions and ImplicationsThe findings support the proposed MOA: initial depletion of total B cells by antibody‐mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti‐mitotic action. Delivering potent anti‐mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk–benefit profiles over traditional chemotherapeutics.

Approach to ferrocenyl-podophyllotoxin analogs and their evaluation as anti-tumor agents

Podophyllotoxin is a natural product endowed of a high antimitotic activity and a high affinity for tubulin. Its action results in the cessation of cell division, inducing cell death. However, its high toxicity restrains its use as drug. To overcome this drawback, several chemical modifications of the native podophyllotoxin have been made. However, to date, no reports have so far been directed toward incorporation of a metallocene moiety. The search for new organometallic drugs is a central field in drug discovery, including the domain of cancer therapy. In particular, metallocenyl moieties are known to increase or decrease, depending on the degree of conjugation in the organometallic motif, the selectivity of drugs toward cancer cells. The conjugate organometallic compound reduces the damage of healthy tissues, yet permitting the selective desired antimitotic and cytotoxic effects of the active principle. We report here the synthesis of ferrocene-containing podophyllotoxin analogs and preliminary antiproliferative tests.

Cytotoxic, Antimitotic, and Antiproliferation Studies on Rasam: A South Indian Traditional Functional Food.

Background:Rasam is a traditional South Indian food, prepared using tamarind juice as a base, with a variety of spices. Rasam, with all its ingredients medicinally claimed for various ailments, is a functional food. Systematic consumption of traditional functional food provides an excellent preventive measure to ward off many diseases.Objective:To study rasam for cytotoxic, antimitotic, and antiproliferation potential beyond its culinary and nutritional effect.Materials and Methods:Brine shrimp lethality assay, onion root tip inhibition assay, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in Calu-6, HeLa, MCF-7 cell lines for four stage-wise samples in the preparation of rasam (RS1, RS2, RS3, and RS4) were studied.Results:RS4, the end product of rasam showed high lethality with an LC50 value of 38.7 μL/mL. It showed maximum antimitotic activity in a dose-dependent manner compared to other samples with an IC50 value of 189.86 μL/mL. RS4 also showed an IC50 value of 350.22 and 410.15 μL/mL in MCF-7 and Calu-6 cell lines, respectively.Conclusion:From this study, we suggest that rasam is a classic example of traditional functional food and it can treat breast and lung cancer on chronic use.SUMMARY Rasam, a South Indian traditional functional food, showed high lethality (LC50 = 38.7 mL/mL) against brine shrimpsRasam also showed potential antimitotic activity (IC50 = 189.86 mL/mL) by inhibiting the onion root tipsRasam showed an IC50 value of 350.22 and 410.15 mL/mL against MCF-7 and Calu-6 cell lines respectivelyRasam, when consumed on daily dietary basis, can treat breast and lung cancer. Abbreviations used: SS 316: Stainless Steel 316 grade; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DMEM: Dulbecco's modified Eagle medium; FBS: Fetal bovine serum media; TPVG: Trypsin phosphate versene glucose; EDTA: Ethylene diamine tetra acetic acid; PBS: Phosphate buffered saline; DMSO: Dimethyl sulfoxide.

Morita-Baylis-Hillman Adducts Display Anti-Inflammatory Effects by Modulating Inflammatory Mediator Expression in RAW264.7 Cells.

Inflammatory response plays an important role not only in the normal physiology but also in pathologies such as cancers. The Morita-Baylis-Hillman adducts (MBHA) are a novel group of synthetic molecules that have demonstrated many biological activities against some parasitic cells such as Plasmodium falciparum, Leishmania amazonensis, and Leishmania chagasi, and antimitotic activity against sea urchin embryonic cells was also related. However, little is known about the mechanisms induced by MBHA in inflammatory process and its relation with anticancer activity. The present work investigated the cytotoxicity of three MBHA derivatives (A2CN, A3CN, and A4CN), on human colorectal adenocarcinoma, HT-29 cells, and their anti-inflammatory activities were examined in lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells, being these derivatives potentially cytotoxic to HT-29 cells. Coincubation with A2CN, A3CN, or A4CN and LPS in RAW264.7 cells inhibited NO production, as well as the production of reactive oxygen species (ROS) was also repressed. The mRNA expressions of IL-1β and IL-6 were significantly downregulated by such MBHA compounds in RAW264.7 cells, but only A2CN was able to inhibit the COX-2 gene expression. We also showed that MBHA compounds decreased almost to zero the production of IL-1β and IL-6. These findings display that such MBHA compounds exhibit anticancer and anti-inflammatory activities.

Synthesis and Molecular docking for Anti-Inflammatory and Anti Mitotic activities of (S)-(2-Methyl-4-(1-Phenyl-1h-Thieno/Furan [3, 2-C] Pyrazol-3yl) Piperazin-1-yl)(Pyridin-2-yl) Methanone

Synthesis and Molecular docking for Anti-Inflammatory and Anti Mitotic activities of (<i>S</i>)-(2-Methyl-4-(1-Phenyl-1h-Thieno/Furan [3, 2-C] Pyrazol-3yl) Piperazin-1-yl)(Pyridin-2-yl) Methanone

Synthesis and Characterization of In2s3 Nanoparticles by Electrochemical Method, Evaluation of its Performance in Photo-Assisted Degradation of Indigo Carmine Dye, Antibacterial and Antimitotic Activity Studies

Synthesis and Characterization of In2s3 Nanoparticles by Electrochemical Method, Evaluation of its Performance in Photo-Assisted Degradation of Indigo Carmine Dye, Antibacterial and Antimitotic Activity Studies

High-performance Thin-layer Chromatographic-densitometric Quantification and Recovery of Bioactive Compounds for Identification of Elite Chemotypes of Gloriosa superba L. Collected from Sikkim Himalayas (India).

Background:Gloriosa superba L. (Colchicaceae) is used as adjuvant therapy in gout for its potential antimitotic activity due to high colchicine(s) alkaloids.Objective:This study aimed to develop an easy, cheap, precise, and accurate high-performance thin-layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L. and to identify its elite chemotype(s) from Sikkim Himalayas (India).Methods:The HPTLC chromatographic method was developed using mobile phase of chloroform: acetone: diethyl amine (5:4:1) at λmax of 350 nm.Results:Five germplasms were collected from targeted region, and on morpho-anatomical inspection, no significant variation was observed among them. Quantification data reveal that content of colchicine (Rf: 0.72) and gloriosine (Rf: 0.61) varies from 0.035%–0.150% to 0.006%–0.032% (dry wt. basis). Linearity of method was obtained in the concentration range of 100–400 ng/spot of marker(s), exhibiting regression coefficient of 0.9987 (colchicine) and 0.9983 (gloriosine) with optimum recovery of 97.79 ± 3.86 and 100.023% ± 0.01%, respectively. Limit of detection and limit of quantification were analyzed, respectively, as 6.245, 18.926 and 8.024, 24.316 (ng). Two germplasms, namely NBG-27 and NBG-26, were found to be elite chemotype of both the markers.Conclusion:The developed method is validated in terms of accuracy, recovery, and precision studies as per the ICH guidelines (2005) and can be adopted for the simultaneous quantification of colchicine and gloriosine in phytopharmaceuticals. In addition, this study is relevant to explore the chemotypic variability in metabolite content for commercial and medicinal purposes.SUMMARY An easy, cheap, precise, and accurate high performance thin layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L.Five germplasms were collected from targeted region, and on morpho anatomical inspection, no significant variation was observed among themQuantification data reveal that content of colchicine (Rf: 0.72) and gloriosine (Rf: 0.61) varies from 0.035%–0.150% to 0.006%–0.032% (dry wt. basis)Two germplasms, namely NBG 27 and NBG 26, were found to be elite chemotype of both the markers.

An Investigation on Kinetics of Photo Catalysis, Characterization, Antibacterial and Antimitotic Property of Electrochemically Synthesized ZnS and Nano Photocatalysts

Zinc sulphide is one of the commercially important II-VI semiconductors having a wide band gap, rendering it a very attractive material for optical application especially in nanocrystalline form. Nanocomposites of ZnS and ZrS2/ZnS were prepared by simple electrochemical method; their photocatalytic properties had been investigated. The structure, composition and optical property of the product were characterized by X-ray diffraction (XRD), FE-SEM (EDAX), UV-VIS and IR techniques. The UV-VIS spectra exhibited a blue-shift with respect to that of bulk material due to quantum confinement effect. Kinetics of photocatalytic degradation of Indigo Carmine dye has been studied. The photocatalytic decolourization of the dye follows first order kinetics. The antimitotic and antibacterial activity of these nanoparticles was investigated.

Xanthium strumarium extract inhibits mammalian cell proliferation through mitotic spindle disruption mediated by xanthatin

Ethnopharmacological relevanceXanthium strumarium L. is a member of the Asteraceae family popularly used with multiple therapeutic purposes. Whole extracts of this plant have shown anti-mitotic activity in vitro suggesting that some components could induce mitotic arrest in proliferating cells. Aim of the sudyAim of the present work was to characterize the anti-mitotic properties of the X. strumarium whole extract and to isolate and purify active molecule(s). Materials and methodsThe capacity of the whole extract to inhibit mitotic progression in mammalian cultured cells was investigated to identify its anti-mitotic activity. Isolation of active component(s) was performed using a bioassay-guided multistep separation procedure in which whole extract was submitted to a progressive process of fractionation and fractions were challenged for their anti-mitotic activity. ResultsOur results show for the first time that X. strumarium whole extract inhibits assembly of the mitotic spindle and spindle-pole separation, thereby heavily affecting mitosis, impairing the metaphase to anaphase transition and inducing apoptosis. The purification procedure led to a fraction with an anti-mitotic activity comparable to that of the whole extract. Chemical analysis of this fraction showed that its major component was xanthatin. ConclusionsThe present work shows a new activity of X. strumarium extract, i.e. the alteration of the mitotic apparatus in cultured cells that may be responsible for the anti-proliferative activity of the extract. Anti-mitotic activity is shown to be mainly exerted by xanthatin.

CWF-145, a novel synthetic quinolone derivative exerts potent antimitotic activity against human prostate cancer: Rapamycin enhances antimitotic drug-induced apoptosis through the inhibition of Akt/mTOR pathway

CWF-145, a synthetic 2-phenyl-4-quinolone derivative exerted potent cytotoxicity against prostate cancer. CWF-145 inhibited prostate cancer cell lines PC-3, DU-145 and LNCap. It had a very low IC50 about 200 nM against castrate-resistant prostate cancer (CRPC) PC-3. We found that CWF-145 had a similar effect to clinical trial antimitotic agents in cancer cells and normal cells. CWF-145 arrested cell cycle at G2/M phase by binding to the β-tubulin at the colchicine-binding site then disrupted microtubule polymerization. Furthermore, the damaged microtubule affected the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Our data showed that CWF-145 activated Akt and mTOR expression to increase emi1 accumulation and inhibit APC. The increased cyclin B1 and securin arrested cell cycle at G2/M phase. Moreover, we showed that Akt activation markedly increased resistance to microtubule-directed agents, including CWF-145, colchicine, and paclitaxel. Interestingly, rapamycin inhibited Akt-mediated therapeutic resistance, indicating that these effects were dependent on mTOR. Taken together, these observations suggest that activation of the Akt/mTOR signaling pathway can promote resistance to chemotherapeutic agents that do not directly target metabolic regulation. These data may provide insight into potentially synergistic combinations of anticancer therapies.

Synthesis and anti-mitotic activity of 6,7-dihydro-4H-isothiazolo[4,5-b]pyridin-5-ones: In vivo and cell-based studies

A series of 3,7-diaryl-6,7-dihydroisothiazolo [4,5-b]pyridin-5(4H)-ones 8 and 9 was synthesized by multicomponent condensation of 3-aryl-5-isothiazolecarboxylic acid esters 4a–f with aromatic (or thienyl) aldehydes 7 and Meldrum's acid in an acidic medium. The targeted compounds were evaluated for their antimitotic microtubule destabilizing activity using in vivo phenotypic sea urchin embryo model and in vitro human cancer cell-based assays. Selected dihydroisothiazolopyridinones altered sea urchin egg cleavage in 2–10 nM concentrations together with significant cytotoxicity against cancer cells including chemoresistant cell lines (IC50 in submicromolar – low nanomolar concentration range). Both approaches confirmed antimitotic microtubule destabilizing mechanism of action of the izothiazole derivatives. Structure-activity relationship study determined the importance of p-methoxybenzene A-ring for the antiproliferative effect. The most potent compound 9b containing p-methoxybenzene A-ring and thiophene B-ring caused mitotic arrest and disintegration of cell microtubules.

One-pot Synthesis and Antitumor Activity of Unsymmetrical Terphenyls.

In this paper a simple and efficient method for the unsymmetrical terphenyls via sequential one-pot Suzuki coupling reactions using Pd(OAc)2 without isolation of the intermediate is described. The prepared terphenyls were found to possess potent anticancer properties against a panel of cancer cells which includes A549, HeLa, MCF7, DU145, HT29 and BxPC-3. Structural similarity with combretastatin A4, these terphenyls disrupted the tubulin polymerization in vitro and destabilized the microtubules in cells. Flow cytometry studies indicated growth arrest of cells in the G2/M phase of the cell cycle corresponding to antimitotic action. Furthermore, compound 4c showed potent anti-mitotic activity even in zebrafish model and could likely be a potential therapeutic compound as it is active both in in vitro and in vivo.

Antimitotic Activity of Cayratia trifolia Ethanol Extract on Zygote Cells of Tripneustes gratilla

Cancer is a devastating disease characterized by abnormal cell growth. Due to several safety issues associated with current cancer treatment, identification of new strategies for cancer therapy is considered necessary. Natural substances in plants m and fruits have the potentials to be developed as anticancer drugs. One of them is Cayratia trifolia (C. trifolia). This study was aimed to determine the cytotoxic activity of stem and leaf ethanol extract of C. trifolia against zygote cells of sea urchin or Tripneustes gratilla (T. gratilla). Extraction of stem and leaf of C. trifolia was conducted using maceration method in ethanol solvent. Thin layer chromatography was performed to screen phytochemicals contained in the extract. Zygote of T. gratilla was used to conduct antimitotic activity test. We found that stem and leaf ethanol extract had IC50 of 169.82 μg/ml and 208.92 μg/ml, respectively. In comparison with positive control of vincristine which had IC50 value of 3.23x10-3 μg/ml (very strong category), this extract showed moderate antimitotic activity. In conclusion, C. trifolia is potential to be developed as anticancer treatment. Keywords: cancer, Cayratia trifolia, antimitotic

Prenylated Chalcone 2 Acts as an Antimitotic Agent and Enhances the Chemosensitivity of Tumor Cells to Paclitaxel.

We previously reported that prenylated chalcone 2 (PC2), the O-prenyl derivative (2) of 2′-hydroxy-3,4,4′,5,6′-pentamethoxychalcone (1), induced cytotoxicity of tumor cells via disruption of p53-MDM2 interaction. However, the cellular changes through which PC2 exerts its cytotoxic activity and its antitumor potential, remain to be addressed. In the present work, we aimed to (i) characterize the effect of PC2 on mitotic progression and the underlying mechanism; and to (ii) explore this information to evaluate its ability to sensitize tumor cells to paclitaxel in a combination regimen. PC2 was able to arrest breast adenocarcinoma MCF-7 and non-small cell lung cancer NCI-H460 cells in mitosis. All mitosis-arrested cells showed collapsed mitotic spindles with randomly distributed chromosomes, and activated spindle assembly checkpoint. Live-cell imaging revealed that the compound induced a prolonged delay (up to 14 h) in mitosis, culminating in massive cell death by blebbing. Importantly, PC2 in combination with paclitaxel enhanced the effect on cell growth inhibition as determined by cell viability and proliferation assays. Our findings demonstrate that the cytotoxicity induced by PC2 is mediated through antimitotic activity as a result of mitotic spindle damage. The enhancement effects of PC2 on chemosensitivity of cancer cells to paclitaxel encourage further validation of the clinical potential of this combination.

Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity.

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity toward the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The antitumor activities of leiodermatolide, as well as the proven utility of antimitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research.

Abstract 344: Antimitotic effect and complex of nonmitotic effect on tumor biology of eribulin mesilate in soft tissue sarcoma model

Abstract Background and objectives: Eribulin mesilate (Eribulin), a first-in-class halichondrin B-based microtubule dynamics inhibitor, has been shown to have novel mechanism of actions (reversion of epithelial-mesenchymal transition of tumor cell and promotion of vascular remodeling) beyond its established antimitotic activity in breast cancer models, leading to decrease of tumor metastatic potency. Recently, eribulin showed trends towards greater overall survival compared to Dacarbazine in subjects with leiomyosarcoma and liposarcoma patients in phase 3 trial. The objective of this study was to investigate the effect of eribulin on tumor cell proliferation of soft tissue sarcoma (STS). Furthermore, the effects of eribulin on morphology and gene expression of differentiation markers against STS and tumor blood perfusion in a leiomyosarcoma xenograft model were examined. Methods: Anti-proliferation activity of eribulin was examined in 6 human STS cell lines. Anti-tumor activity of eribulin was examined in xenografts of A-673 (Ewing's sarcoma), SK-LMS-1 (leiomyosarcoma), SW 872 (liposarcoma), and HT-1080 (fibrosarcoma) at several doses. To analyze the effect of eribulin on in vitro morphological change, 3 human STS cell lines were treated with eribulin at 1, 3, and 10 nmol/L for 7 days. Gene expression change was analyzed by microarray and differentiation marker genes in 2 cell lines were confirmed by qPCR analysis. For tumor blood perfusion analysis, eribulin was administered at doses of 0.38, 0.75, and 1.5 mg/kg one shot in SK-LMS-1 xenografts, and tumor blood perfusion was calculated as Hoechst-positive areas in tumor cryosections 5 days after the administration. Results: Eribulin showed anti-proliferation activity in vitro against all 6 cell lines in a dose dependent manner with 50% inhibitory concentration values of around 1 nmol/L. Eribulin showed significant antitumor activity against 4 xenografts in a dose dependent manner. Eribulin treatment for 7 days induced apparent morphological change in 3 cell lines. Of these, expression level of smooth muscle differentiation marker gene CNN1 was 7.1-fold upregulated in SK-UT-1 and adipocyte differentiation marker genes MYLK, C/EBPβ, and KIF23 were 1.9-, 1.4-, and 1.3-fold upregulated in SW 872, respectively, by 10 nmol/L treatment compared to vehicle control. In addition, eribulin significantly enhanced tumor blood perfusion compared to vehicle control 5 days after the administration in SK-LMS-1 xenografts at all doses.Conclusions: Eribulin showed anti-proliferation activity against all of STS cell lines we tested in vitro and in vivo. Furthermore, eribulin might cause differentiation of STS cells and remodeling of tumor vasculature to enhance tumor blood perfusion. These data supported that eribulin showed mitotic effect and non-mitotic effect, which may decrease tumor metastatic potency in STS, as well in breast cancer. Citation Format: Satoshi Kawano, Makoto Asano, Yusuke Adachi, Junji Matsui. Antimitotic effect and complex of nonmitotic effect on tumor biology of eribulin mesilate in soft tissue sarcoma model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 344.

Synthesis and characterization of novel benzothiazole amide derivatives and screening as possible antimitotic and antimicrobial agents

A new series of benzothiazole amide derivatives (9a–l) were synthesized and characterized by Fourier-transform infrared (FT-IR), mass, and 1H and 13C nuclear magnetic resonance (NMR) spectroscopic techniques. The antimitotic activity of the newly synthesized compounds was determined by the Allium assay method, from which mitotic index values were calculated. Here, 9g (14.0 %) and 9l (14.5 %) showed mitotic index values most comparable to that of standard drug (14.4 %), while the remaining compounds showed lower mitotic index values; hence, these compounds inhibit the regular cell division process and are the most promising antimitotic agents. Based on the structural activity relationship, the maximum percentage inhibition was observed for compounds containing electron-withdrawing group, revealing enhanced antimitotic activity, while compounds with electron-donating groups such as furan (9g) and methyl (9l) were comparable to standard. The newly synthesized compounds were also screened for antimicrobial activity, with some of them showing remarkable activity.

Synthesis and characterization of tetralones as intermediates for podophyllotoxin analogues

Podophyllotoxin has captured the attention of chemists all over the world for its biological activity. It was isolated from many plants of Podophyllum species such as Podophyllum emodi , Podophyllum peltatum and others. It mainly exhibits anticancer, antimitotic, antimalarial, anti-aids and other activities. Its use is restricted due to its toxicity and unfavourable solubility. It was aimed to synthesize some new heterocyclic analogues of podophyllotoxin by changing the substituents by changing lactone ring with pyrazoline ring and substituents in ring C with hydrogen and methoxy group. Chalcones were prepared by Claisen-Schmidt reaction of 1,3-methylene dioxyacetophenone with benzaldehyde and p -anisaldehyde. The reaction of chalcone with trimethylsulphoxonium iodide in presence of sodium hydride gave cyclopropyl ketone. Intramolecular cyclization reaction of cyclopropyl ketone gave tetralone intermediates of podophyllotoxin. They are obtained in good yields. The structure of all the products was confirmed by spectral data.

Ivermectin exhibits potent anti-mitotic activity

Ivermectin (IVM) is a pharmaceutical used as an anti-parasitic drug in livestock, companion animals and humans. The primary site of action of IVM is believed to be glutamate-gated chloride channels (GluCls). However we have recently reported a direct interaction between IVM and nematode tubulin with micromolar affinity. Here we report that IVM also interacts with mammalian tubulin. To test this possibility, we used the tubulin polymerization assay and found that IVM increased the degree of polymerization of mammalian tubulin. Furthermore when HeLa cells were exposed to IVM it stabilized the mammalian tubulin against the depolymerizing effects of cold temperatures, and prevented the replication of the HeLa cells in vitro. However, the IVM-induced inhibition of HeLa cell division was reversible. The data suggests that mammalian microtubules bound IVM and were stabilized by IVM at micromolar concentrations. IVM may thus affect the dynamics of tubulin polymerization and depolymerization, which in turn can result in cell death. Given that IVM is already approved for use in humans, its development as an anti-mitotic is a potentially appealing option.

Synthesis and evaluation of anticancer activity of 6-pyrazolinylcoumarin derivatives

A series of novel 6-pyrazolinylcoumarins has been synthesized via multi-step protocol. The synthetic procedure was based on the acetylation of hydroxycoumarins; Fries rearrangement and Claisen–Schmidt condensation; the target 6-[5-aryl-4,5-dihydropyrazol-3-yl]-5-hydroxy-7-methylcoumarins (33–49) were obtained under reactions of hydrazine and 2-aryl-5-methyl-2,3-dihydropyrano[2,3-f]chromen-4,8-diones as the last phase of the protocol. Anticancer activity screening in NCI60-cell lines assay allowed identification of compound 47 with the highest level of antimitotic activity with mean GI50 value of 10.20μM and certain sensitivity profile toward the Leukemia cell lines CCRF-CEM and MOLT-4 (GI50/TGI values 1.88/5.06μM and 1.92/4.04μM respectively).