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International audience; Colchicine, the main active alkaloid from Colchicum autumnale L., is a potent tubulin binder and represents an interesting lead structure for the development of potential anticancer chemotherapeutics. We report on the synthesis and investigation of potentially reactive colchicinoids and their surprising biological activities. In particular, the previously undescribed colchicinoid PT-100, a Bring contracted 6-exomethylene colchicinoid, exhibits extraordinarily high antiproliferative and apoptosis-inducing effects on various types of cancer cell lines like acute lymphoblastic leukemia (Nalm6), acute myeloid leukemia (HL-60), Burkitt-like lymphoma (BJAB), human melanoma (MelHO), and human breast adenocarcinoma (MCF7) cells at low nanomolar concentrations. Apoptosis induction proved to be especially high in multidrug-resistant Nalm6derived cancer cell lines, while healthy human leukocytes and hepatocytes were not affected by the concentration range studied. Furthermore, caspase-independent initiation of apoptosis via an intrinsic pathway was observed. PT-100 also shows strong synergistic effects in combination with vincristine on BJAB and Nalm6 cells. Cocrystallization of PT-100 with tubulin dimers revealed its (noncovalent) binding to the colchicine-binding site of β-tubulin at the interface to the α-subunit. A pronounced effect of PT-100 on the cytoskeleton morphology was shown by fluorescence microscopy. While the reactivity of PT-100 as a weak Michael acceptor toward thiols was chemically proven, it remains unclear whether this contributes to the remarkable biological properties of this unusual colchicinoid.

Fluorescent lipid probes are widely used as tools for studying the properties of biological membranes and for studies of such biological functions of lipids as metabolic pathways and the molecular nature of diseases. In this report, we propose the new Cy5-labeled phosphatidylcholine (Cy5-PC) fluorescent lipid probe and describe its geometrical parameters, its synthesis, its spectral characteristics, and data on its mobility in a lipid membrane. Су5-PC is an excellent probe for bioimaging, because the intensity of its fluorescence retains a linear dependence up to high concentrations. However, the use of Су5-PC in studies of membrane dynamics is impossible, since the probe is insensitive even to the phase transition in a lipid membrane.

Photodynamic therapy (PDT) is a treatment modality where light-mediated activation of photosensitizers in a patient's body leads to the generation of cytotoxic reactive oxygen species (ROS), eliminating cancer cells. One direction that has been firmly established over past years is the conjugation of photosensitizers with various molecules that demonstrate their own cytotoxic activity. As a result, improved selectivity and treatment outcomes are observed compared to those of unconjugated drugs. The attractiveness of such an approach is due to the variability of cytotoxic warheads and specific linkers available for the construction of conjugates. In this review, we summarize and analyze data concerning these inventions with the ultimate goal to find a promising conjugation partner for a porphyrinoid-based photosensitizer. The current challenges toward successful conjugation are also outlined and discussed. We hope that this review will motivate researchers to pay closer attention to conjugates and possibilities hidden in these molecules for the PDT of cancer.

To assess the stability and efficiency of liposomes carrying a phospholipase A2-sensitive phospholipid-allocolchicinoid conjugate (aC-PC) in the bilayer, egg phosphatidylcholine and 1-palmitoyl-2-oleoylphosphatidylglycerol-based formulations were tested in plasma protein binding, tubulin polymerization inhibition, and cytotoxicity assays. Liposomes L-aC-PC10 containing 10 mol. % aC-PC in the bilayer bound less plasma proteins and were more stable in 50% plasma within 4 h incubation, according to calcein release and FRET-based assays. Liposomes with 25 mol. % of the prodrug (L-aC-PC25) were characterized by higher storage stability judged by their hydrodynamic radius evolution yet enhanced deposition of blood plasma opsonins on their surface according to SDS-PAGE and immunoblotting. Notably, inhibition of tubulin polymerization was found to require that the prodrug should be hydrolyzed to the parent allocolchicinoid. The L-aC-PC10 and L-aC-PC25 formulations demonstrated similar tubulin polymerization inhibition and cytotoxic activities. The L-aC-PC10 formulation should be beneficial for applications requiring liposome accumulation at tumor or inflammation sites.

New water soluble conjugates of chlorin e6 derivative–zinc complex with β- d -galactose or β- d -glucose have been synthesized as potential agents for the photodynamic therapy of cancer. They exhibit photoinduced cytotoxicity at low micromolar concentrations with IC50(dark)/IC50(light) ratio of ∼50.

A new water-soluble conjugate, consisting of a chlorin-e6 photosensitizer part, a 4-arylaminoquinazoline moiety with affinity to epidermal growth factor receptors, and a hydrophilic β-d-maltose fragment, was synthesized starting from methylpheophorbide-a in seven steps. The prepared conjugate exhibited low levels of dark cytotoxicity and pronounced photoinduced cytotoxicity at submicromolar concentrations in vitro, with an IC50(dark)/IC50(light) ratio of ∼368 and a singlet oxygen quantum yield of about 20%. In tumor-bearing Balb/c nude mice, conjugate 1 preferentially accumulates in the tumor tissue. Irradiation of the nude mice bearing A431 xenograft tumors after intravenous administration of the prepared conjugate with a relatively low light dose (50 J/cm2) produced an excellent therapeutic effect with profound tumor regression and low systemic toxicity.

Aiming at the development of novel protease-triggered CO-releasing molecules (PT-CORMs) we designed a series of oxycyclohexadiene-Fe(CO)(3) complexes, which are connected through a self-immolative linker with a plasmin-specifying peptide unit. The challenging synthesis of these compounds was elaborated employing a combination of solid-phase peptide synthesis and solution chemical synthesis. Late-stage attachment of the organometallic unit and Pd-catalyzed cleavage of an alloc-protected lysine side chain afforded the target compounds in good yields and high purity.

We report the crystal structure and crystallization conditions of a first hydrated form of metacetamol (a hemihydrate), C8H9NO2·0.5H2O. It crystallizes from metacetamol-saturated 1:1 (v/v) water–ethanol solutions in a monoclinic structure (space group P21/n) and contains eight metacetamol and four water molecules per unit cell. The conformations of the molecules are the same as in polymorph II of metacetamol, which ensures the formation of hydrogen-bonded dimers and R 2 2(16) ring motifs in its crystal structure similar to those in polymorph II. Unlike in form II, however, these dimers in the hemihydrate are connected through water molecules into infinite hydrogen-bonded molecular chains. Different chains are linked to each other by metacetamol–water and metacetamol–metacetamol hydrogen bonds, the latter type being also present in polymorph I. The overall noncovalent network of the hemihydrate is well developed and several types of hydrogen bonds are responsible for its formation.

In crystals, molecules are linked by different types of non-covalent interactions (NCIs). Sometimes it can be an intricate task to define without resorting to calculations what type of NCIs is mainly responsible for maintaining the structure. One of such examples is meloxicam in the polymorphic form I, for which two controversial models describing NCIs are known to date. These models proposed by Cheney et al. (2010), and Tumanov et al. (2012), differ in structural motifs and a presence of particular types of interactions therein. However, they both rely on geometrical parameters only and were not confirmed quantitatively. Here we show the final model of NCIs within the crystal structure of meloxicam polymorph I supported by DFT calculations, Hirshfeld surface analysis and reduced density gradient (RDG) investigation. We found that both types of weak van der Waals interactions described in the previously proposed models (namely, S⋯O and O H⋯O contacts) are actually present in the structure and take part in linking the N H⋯O-bonded meloxicam dimers with each other. These dimers are formed by medium-strength H-bonds and represent the main building blocks of the structure. Our study demonstrates how a model of NCIs can be unambiguously revealed by means of different computational tools. We hope that the results obtained in the present work will be useful for further studies of meloxicam, its co-crystals and analogous compounds.

A (series) range of potential dimorpholinoquinazoline-based inhibitors of the PI3K/Akt/mTOR cascade was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound 7c with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound 7c inhibited the phosphorylation of Akt, mTOR, and S6K at 125–250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of 7b 50 µM and of 7c 500 µM and higher, that can indicate minority PI3Kα as a target among other kinases in the titled cascade for 7c. In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib (8) by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform.

The aim of this study was to compare the biodistribution in mice of functionalized rhodamine B (Rh) labeled colchicine derivative furano-allocolchicinoid (AC, 6) either conjugated to 40 kDa chitosan (AC-Chi, 8) or encapsulated into chitosan nanoparticles (AC-NPs). AC-NPs were formed by ionotropic gelation and were 400–450 nm in diameter as estimated in mice by dynamic light scattering and confocal microscopy. AC-Chi and AC-NPs preserved the specific colchicine activity in vitro. AC preparations were once IV injected into C75BL/6 mice, muscles, spleen, kidney, liver, lungs, blood cells and serum were collected at 30 min, 2, 5, 10, and 20 h post injection. To analyze the distribution of the furano-allocolchicinoid preparations in body liquids and tissues, Rh was measured directly in sera or extracted by acidic ethanol from tissue homogenates. Preliminary Rh extraction rate was estimated in vitro in tissue homogenates and was around 25–30% from total quantity added. After in vivo injection, AC-NPs were accumulated more in liver and spleen, while less in kidney and lungs in comparison with free AC and AC-Chi. Therefore, incorporation of colchicine derivatives as well as other hydrophobic substances into nano/micro sized carriers may help redistribute the drug to different organs and, possibly, improve antitumor accumulation.

Simple Summary Inorganic polyphosphate, a linear polymer of orthophosphoric acid, plays an important role in microorganisms’ stress resistance. Vtc4 protein synthetizes inorganic polyphosphate in yeast. Here we show that yeast lacking this protein exhibit very low polyphosphate level, decreased resistance to alkaline stress, but increased resistance to oxidative and heavy metal stresses. We suggest the increased stress resistance is achieved by constitutive up-regulation of oxidative stress-response genes and decreased expression of Pho84 that is responsible for manganese uptake. Abstract Inorganic polyphosphate (polyP) is an important factor of alkaline, heavy metal, and oxidative stress resistance in microbial cells. In yeast, polyP is synthesized by Vtc4, a subunit of the vacuole transporter chaperone complex. Here, we report reduced but reliably detectable amounts of acid-soluble and acid-insoluble polyPs in the Δvtc4 strain of Saccharomyces cerevisiae, reaching 10% and 20% of the respective levels of the wild-type strain. The Δvtc4 strain has decreased resistance to alkaline stress but, unexpectedly, increased resistance to oxidation and heavy metal excess. We suggest that increased resistance is achieved through elevated expression of DDR2, which is implicated in stress response, and reduced expression of PHO84 encoding a phosphate and divalent metal transporter. The decreased Mg2+-dependent phosphate accumulation in Δvtc4 cells is consistent with reduced expression of PHO84. We discuss a possible role that polyP level plays in cellular signaling of stress response mobilization in yeast.

In this study, the dependence of the catalytic activity of highly oriented pyrolytic graphite (HOPG)-supported bimetallic Pd-Au catalysts towards the CO oxidation based on the Pd/Au atomic ratio was investigated. The activities of two model catalysts differing from each other in the initial Pd/Au atomic ratios appeared as distinctly different in terms of their ignition temperatures. More specifically, the PdAu-2 sample with a lower Pd/Au surface ratio (~0.75) was already active at temperatures less than 150 °C, while the PdAu-1 sample with a higher Pd/Au surface ratio (~1.0) became active only at temperatures above 200 °C. NAP XPS revealed that the exposure of the catalysts to a reaction mixture at RT induces the palladium surface segregation accompanied by an enrichment of the near-surface regions of the two-component Pd-Au alloy nanoparticles with Pd due to adsorption of CO on palladium atoms. The segregation extent depends on the initial Pd/Au surface ratio. The difference in activity between these two catalysts is determined by the presence or higher concentration of specific active Pd sites on the surface of bimetallic particles, i.e., by the ensemble effect. Upon cooling the sample down to room temperature, the reverse redistribution of the atomic composition within near-surface regions occurs, which switches the catalyst back into inactive state. This observation strongly suggests that the optimum active sites emerge under reaction conditions exclusively, involving both high temperature and a reactive atmosphere.

Inorganic polyphosphate (polyP) is an important factor of stress tolerance in microbial cells. In yeast, the major enzyme of polyP biosynthesis is Vtc4, a subunit of the vacuole transporter chaperone (VTC) complex. In this study, we demonstrated that Vtc4 knockout in Saccharomyces cerevisiae not only decreased polyP content but also caused shifts in the composition of the intracellular polyP pool and changed the stress tolerance profile. In the mutant S. cerevisiae, the level of short-chain acid-soluble polyPs was decreased nearly 10-fold, whereas that of longer acid-insoluble polyPs was decreased only 2-fold, suggesting the existence of other enzymes compensating the production of long-chain polyPs. The Δvtc4 mutant showed inhibition of Mg2+-dependent phosphate uptake and decreased resistance to alkaline stress but increased tolerance to oxidation and heavy metal ions, especially Mn2+. Quantitative PCR revealed the upregulation of the DDR2 gene implicated in multiple stress responses and downregulation of PHO84 encoding a phosphate and Mn2+ transporter, which could account for the effects on phosphate uptake and Mn2+-related stress response in the Δvtc4 mutant. Our study indicates that short-chain polyPs, plays an important role in the regulation of stress response in yeast.

We describe an attempt to apply the concept of covalent binding towards the highly active allocolchicinoids selected on the basis of SAR analysis of previously synthesized molecules. To achieve the irreversible binding of the agent to the cysteine residues of the colchicine site of tubulin protein, we synthesized a number of new allocolchicinoids bearing the acceptor moiety. Some of the new derivatives possess cytotoxic activity against COLO-357, BxPC-3, HaCaT, and HEK293 cell lines in a low nanomolar range of concentrations. A substoichiometric mode of microtubule assembly inhibition was demonstrated. The most active compounds possess close to colchicine general toxicity on mice.

A six-step semisynthetic approach towards chiral nonracemic pyrrolo-allocolchicinoids starting from naturally occurring colchicine was developed. The synthetic scheme includes an electrocyclic tropolone ring contraction to afford allocolchicinic acid followed by the Curtius reaction, giving the corresponding aniline. The Sandmeyer reaction and copper-mediated hydrazination gave hydrazine-substituted allocolchicine. This was introduced into the Fischer indole synthesis, affording libraries of regioisomeric indole-based allocolchicine congeners.

Based on the natural antimitotic agent colchifoline as a lead structure, a series of novel bifunctional allocolchicine congeners were synthesized from commercial colchicine. The new derivatives maintain good cytotoxicity against T3M4, MiaPaCa-2, and PANC-1 cell lines. The presence of functional groups simplifies further modifications of the prepared structures and the design of novel colchicine-derived antitumor compounds with desired pharmacological properties.

Two novel indole-containing allocolchicinoids were prepared from naturally occurring colchicine exploiting the Curtius rearrangement and tandem Sonogashira coupling/Pd-catalyzed cyclization as the key transformations. Their cytotoxic properties, apoptosis-inducing activity, tubulin assembly inhibition and short-time cytotoxic effects were investigated. Compound 7 demonstrated the most pronounced anti-cancer activity: IC 50

An efficient seven-step semisynthetic approach towards non-racemic bifunctional furano-allocolchicinoids, starting from naturally occurring colchicine is presented. The Pd-catalyzed domino Sonogashira coupling/5-endo-dig cyclization was employed as the key step. The prepared compounds exhibited substantial cytotoxicity against T3M4, MiaPaCa-2, Colo-357, and PANC-1 cell lines. The presence of two functionalities with different reactivity (hydroxyl and amino groups) in the target molecules allows for an easy conjugation of furano-allocolchicinoids with drug delivery carriers, and opens promising opportunities for their further exploitation in the search of therapeutics.

The review discusses the latest advances in the directed synthesis and application of macroheterocyclic compounds in science, engineering and technology, viz. as catalysts for various processes in photo- and electrocatalysis, optical chemosensors for metal cations, selective receptors of organic compounds, inductors and selectors, in nonlinear optics, organic electronics, as magnets, photosensitizers for PDT of a number of oncological diseases and for antimicrobial PDT, etc.

We present the results of an experimental and computational study of structural changes in two polymorphs of tolazamide {systematic name: 1-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide}, C14H21N3O3S, on cooling to 100 K and reverse heating. No phase transitions occurred in this temperature range. The anisotropy of the thermal expansion was different for the two polymorphs and differed from that reported previously for the hydrostatic compression. The changes in different intermolecular contacts responsible for the strain anisotropy were analysed. Relative shortening of the contacts was related directly to their initial length and reversely to the steric density around them. Increasing steric density is likely to be the driving force for the conformational ordering of the azepane ring under compression.

Enzyme-responsive liposomes release their cargo in response to pathologically increased levels of enzymes at the target site. We report herein an assembly of phospholipase A2-responsive liposomes based on colchicinoid lipid prodrugs incorporated into lipid bilayer of the nanosized vesicles. The liposomes were constructed to addresses two important issues: (i) the lipid prodrugs were designed to fit the structure of the enzyme binding site; and (ii) the concept of lateral pressure profile was used to design lipid prodrugs that introduce almost no distortions into the lipid bilayer packing, thus ensuring that corresponding liposomes are stable. The colchicinoid agents exhibit antiproliferative activity in subnanomolar range of concentrations.

A series of furan-based allocolchicinoids was prepared from commercially available colchicine via a nine-step reaction sequence. Cytostatic activity, cell cycle arrest, apoptosis, tubulin and F-actin expression were studied in vitro in 2D and 3D cultures of normal and tumor epithelial keratinocytes, endothelial and mesenchymal cells. Among the prepared furanoallocolchicine analogues, 14a and 7a displayed the most pronounced anti-cancer activity. These compounds induced two types of effects: (a) cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding (metaphase effect), and (b) pronounced cell stress (as evidenced by the overexpression of tubulin and F-actin), which was caused by the hyperpolarization of mitochondrial and lysosomal membranes (interphase effect).

A μ-oxo-Fe3+ complex of chlorin e6–thioctic acid conjugate was synthesized and explored as a new sensing material for nitric oxide. This conjugate can be used as a model for NO-binding potential biosensors.

A series of multifunctional conjugates each consisting of a fluorescent chlorin photosensitizer and an (arylamino)quinazoline-based epidermal growth factor receptor/vascular endothelial growth factor receptor ligand, potentially useful in site-selective photodynamic antitumor therapy, were prepared and their photochemical properties were investigated.

Based on the natural antimitotic agent allocolchicine as a lead structure, a series of novel indole-based allocolchicine congeners was synthesized and assessed in vitro for their cytostatic properties. Several compounds exhibited potent anti-proliferative and apoptosis-inducing activity towards lymphoma cells along with low unspecific cytotoxicity. The observed activity is supposed to result from the inhibition of microtubule assembly, as indicated by the tubulin polymerisation assay.

The dimethyl derivatives of the group 13 metals I–IV were synthesized by interaction of N-(1-(5,7-di-tert-butyl-2-methyl-2,3-dihydrobenzo[d]oxazol-2-yl)ethylidene)-2,6-diisopropylaniline (a) with Me3M (M = Al (I), Ga (II), In (III), Tl (IV)) in high yield. The obtained complexes were characterized by elemental analysis, 1H NMR and IR spectroscopy. The structures of II–IV were determined by X-ray single crystal analysis. The compounds II–IV were found to be monomeric in the solid state due to the bulkiness of the tert-butyl and iso-propyl groups in contrast to similar derivatives reported previously.

A new water-soluble conjugate, consisting of a chlorin-based photosensitizing part, and a 4-arylaminoquinazoline moiety with high potential affinity to an epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), suitable for photodynamic therapy (PDT), was synthesized starting from methylpheophorbide-a in seven steps. An increased accumulation of this compound in A431 cells with high level of EGFR expression, in comparison with CHO and HeLa cells with low EGFR expression was observed. The prepared conjugate exhibits dark and photoinduced cytotoxicity at micromolar concentrations with IC50dark/IC50light ratio of 11–18. In tumor-bearing mice, the conjugate preferentially accumulates in the tumor tissue.

The synthesis of several new heterocyclic structural analogs of the natural antimitotic agent allocolchicine is reported. As a key step an intramolecular Pd-catalyzed C–H arylation reaction was used to close the seven-membered ring fused with two electron-rich aryl fragments. The stereostructure of the target compounds was determined by X-ray crystal analysis. The primary biological assessment of the synthesized compounds was carried out on human lymphoma cells. Several allocolchicinoids were determined to possess antiproliferative and apoptosis-inducing activity in the micromolar concentration range.

A series of boron difluoride–3-acyl-4-hydroxycoumarin complexes were synthesized in good yields in three steps starting from 4-hydroxycoumarins. The boron complexes showed strong luminescence­ in the green–yellow region and are compatible with surface imaging applications.

Channel mismatch — i.e., swapped left and right views — can cause major visual discomfort when viewing stereoscopic content, but detecting it automatically remains a challenge. We present a novel method for detecting channel mismatch that significantly outperforms a prior approach when analyzing a dataset of 1,000 video clips. Moreover, this method enabled detection of 65 scenes exhibiting channel mismatch in 105 real S3D movies. Perceived discomfort can vary greatly between different scenes with channel mismatch depending on a number of factors. We conducted a study involving 59 participants to compute subjective discomfort scores for 56 scenes with channel mismatch. In this paper, we propose a model to predict these scores on the basis of scene characteristics.

A midthroughput screening follow-up program targeting the first bromodomain of the human BRD4 protein, BRD4(BD1), identified an acetylated-mimic xanthine derivative inhibitor. This compound binds with an affinity in the low micromolar range yet exerts suitable unexpected selectivity in vitro against the other members of the bromodomain and extra-terminal domain (BET) family. A structure-based program pinpointed a role of the ZA loop, paving the way for the development of potent and selective BET-BRDi probes.

A series of novel combretastatin A-4 analogues was synthesized in 36–64% yields by Negishi cross-coupling reaction under mild conditions. The prepared compounds exhibit good cytotoxicity against HBL100 epithelial cell lines (IC50 = 0.022–10.31 µМ).

A series of coumarin triazolylglycosides were synthesized in good yields using copper-mediated 1,3-dipolar cycloaddition reactions of carbohydrate azides and 4-alkynyl-substituted coumarins. Several of the products show strong luminescence in the 490–560 nm region and are compatible with surface imaging applications.

A series of A-ring variously methoxylated 4-(3-hydroxy-4-methoxyphenyl)coumarins related to combretastatin A-4 was prepared by cross-coupling reactions. Cytotoxicity studies indicated a potent activity against HBL100 cell line. Substitution patterns on A-ring had only a slight effect on antiproliferative activity. For most cytotoxic compounds, the activity as potential modulators of P-gp and BCRP efflux pumps was evaluated. The results show that compounds 2 and 7 were able to restore mitoxantrone accumulation (BCRP) at concentrations similar to that of cyclosporine A. Compound 7 was the most efficient to reverse P-gp activity. All compounds were found to potently inhibit in vitro microtubule formation via a substoichiometric mode of action for the most part. Compounds 1 and 2 were found to have an apparent affinity binding constant similar to that of combretastatin A-4, i.e., 1 × 10 (6) M(-1). The molecular modeling of coumarin derivatives was performed on the basis of the molecular structure of 7, as determined by single-crystal X-ray crystallography. The calculations suggested that the presence of a methoxy group out of the plane of the chromenone moiety is an important steric hindrance factor embedding the accessibility of those molecules inside the binding pocket on tubulin.

Palladium-catalyzed reactions of 4-(trifluoromethylsulfonyloxy)coumarins with amides and NH-heterocycles afforded 4-amido- and 4-(N-hetaryl)coumarins in 60-96% yield.

Several 2-(azidomethyl)arylboronic acids were synthesized. Their involvement into organolead-mediated Pinhey arylation reaction with 4-hydroxycoumarins afforded 3-[2-(azidomethyl)aryl]-4-hydroxycoumarins or [4,3-c]isoquinolino-coumarins in reasonable yields via two- or four-step one-pot reaction sequence. Palladium-catalyzed cross-coupling of organoboron reagents with 4-trifluoromethylsulfonyloxycoumarins under Suzuki reaction conditions gave 4-[2-(azidomethyl)aryl]coumarins in good yields. 2-(Azidomethyl)arylboronic acid, as well as azide-containing iso- and neoflavonoid compounds underwent catalytic alkyne-azide cycloaddition in THF-water, providing 1,4-triazole compounds regioselectively in good to excellent yields.

A series of syn-restricted polymethoxylated 4-heteroarylcoumarins—the isostuctural analogs of combretastatin A-4—was synthesized by Suzuki–Miyaura cross-coupling reaction and evaluated for antiproliferative activity. The 4-(1-methyl-1H-indol-5-yl)chromen-2-ones exhibit a potent cytotoxicity against HBL100 epithelial cell line with an IC50 value amounting to 0.098 and 0.078 μM, respectively. The two compounds, having an indolyl moiety, potent inhibit in vitro microtubule assembly with a substoichiometric mode of action. A structure–activity relationship was discussed and the indolyl moiety was proved to be a good surrogate for the 3-hydroxy-4-methoxyphenyl ring of CA-4.

Colchicine irreversibly binds to tubulin, blocks microtubule formation, and inhibits cell division. However, its usage as an antitumor agent is limited due to its distribution to many tissues and low accumulation in the tumor. The increase in molecule weight can change colchicine biodistribution and decrease side effects. The aim of this work was to study in vivo and in vitro antitumor activity of colchicine-chitosan conjugate. A new allocolchicine derivative – furanoallocolchicinoid 3 was synthesized and conjugated to chitosan (4). Both 3 and 4 induced in vitro tubulin reorganization, cell cycle arrest, and inhibition of cell proliferation in 2D and 3D cultures. Antitumor effect of chitosan, 3, and 4 was studied in Wnt-1 breast tumor bearing mice. Conjugate 4 demonstrated significantly better tumor growth inhibition than 3 possibly as a result of a better accumulation in the tumor.

Key step in the synthesis of the structural analogues (III) and (VI) of the antimitotic agent allocolchicine is the formation of the polycyclic ring system under Pd catalysis in the presence of CsOPiv, generated in situ.

Tris-(polymethoxyphenyl)bismuth diacetate and dichloride derivatives react with C-nucleophiles in basic medium, as well as with N- and O-nucleophiles under copper catalysis to give good to high yields of the corresponding C-, N- and O-arylation products.

2-(3,3-Diphenylprop-2-enyloxy)phenyllead triacetate, an arylating reagent containing an internal free radical trap, was synthesised and its behaviour studied in base-catalysed C-arylation reactions and in copper-catalysed N-arylation reactions. The absence of benzofuran derivatives among the products of C- and N-arylation reactions excludes the involvement of radical species in these two processes. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)