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Zastosowanie chemii "klik" do syntezy biokoniugatów salinomycyny

Sulik Michał, Antoszczak Michał, Huczyński Adam

Wiadomości Chemiczne

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2022

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[Z] 76, 11-12

883--907

EN

Bioconjugation is a well-known method of designing new drug candidates for many different diseases, including cancer. The idea of the process is to join two or more bioactive molecules by means of a covalent bond. Thus, obtained hybrids often exhibit higher efficiency compared to that of the starting compounds. Recently, the use of click chemistry, especially Huisgen 1,3-dipolar cycloaddition, has attracted much attention for the synthesis of bioconjugates of natural compounds. The great advantage of this reaction is its high yield and enzymatic stability of the 1,2,3-triazole ring. Mild conditions of this reaction guarantee that it can be used to modify compounds with low stability, such as salinomycin – a representative of ionophore antibiotics. Salinomycin is a naturally occurring lipophilic compound isolated from Streptomyces albus. It is capable of forming complexes with metal cations and transport them across the lipid membranes. This process disturbs the intercellular Na+ /K+ concentration gradient and leads to apoptosis (programmed cell death). Salinomycin exhibits high anticancer activity, including efficiency against multidrug-resistant cancer cells and cancer stem cells of different origin. Chemical modification of the salinomycin skeleton to increase its biological activity is a very interesting research direction. Our review article is focused on the application of click chemistry for the synthesis of salinomycin bioconjugates with many different biologically active compounds (Cinchona alkaloids, nucleosides, triphenylphosphonium cation, betulinic acid and other ionophore antibiotics). Some of the obtained hybrids exhibit higher efficiency compared to that of the starting compounds, e.g., increased anticancer activity, the ability to overcome multi-drug resistance, or improved ionophoretic properties. These results are a good starting point for further research on the use of click chemistry in the synthesis of highly functional hybrids of natural compounds.

2

Wydzielanie, właściwości i aktywność przeciwnowotworowa polisacharydów ze strzykwy

Duan Kunfeng

Przemysł Chemiczny

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2019

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T. 98, nr 2

200--203

PL

Z surowego polisacharydu uzyskanego ze strzykwy (ogórka morskiego) metodą hydrolizy enzymatycznej wydzielono trzy rafinowane polisacharydy, które zastosowano jako inhibitory w leczeniu raka płuc (linia komórkowa A549), raka żołądka (linia komórkowa SGC-7901), raka piersi (linia komórkowa MCF-7) oraz raka trzustki (linia komórkowa PANC-1). Rafinacja poprawiła efekt hamowania wzrostu komórek nowotworowych, zwłaszcza przy zastosowaniu polisacharydów o większym stężeniu. Hamowanie było najskuteczniejsze w przypadku komórek raka piersi MCF-7, a najsłabsze dla komórek raka płuc A549.

EN

Three polysaccharides were prepd. by refining the crude polysaccharide of sea cucumber by enzymatic hydrolysis and studied as cancer inhibitors on human lung cancer cells A549, human gastric carcinoma cells SGC-7901, human breast cancer cells MCF-7 and pancreatic cancer cell PANC-1. The refining resulted in increasing the inhibition effects. They increased also with increasing the polysaccharide concn. The inhibition was strongest in respect to MCF-7 cells and weakest for A549 cells.

3

Biokoniugaty antybiotykow jonoforowych : cele, strategie syntezy i właściwości

Antoszczak M., Kordylas M., Huczyński A.

Wiadomości Chemiczne

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2018

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[Z] 72, 1-2

1--28

EN

Polyether ionophore antibiotics (ionophores) represent a large group of naturally- occurring lipophilic compounds which are able to form complexes with the metal cations and transport them across the lipid membranes. This process disturbs the intercellular Na+/K+ concentration gradient and intracellular pH, and leads to the mitochondrial damages, cell swelling, vacuolization and finally to apoptosis process. For this reason, ionophores are commonly used in veterinary medicine as the non-hormonal growth-promoting as well as coccidiostatic agents. In this group particularly interesting are monensin and salinomycin (Fig. 1) because of their proved anti-tumour activity, including efficiency against multidrug- -resistant cancer cells and cancer stem cells of different origin. Improved synthetic derivatives of both polyether ionophores are thus of considerable current interest. Selective derivatization of these structures whose display multiple reactive functional groups and, in the case of salinomycin, a sensitive tricyclic spiroketal ring system is however non-trivial. Even so, semi-synthetic analogs reported to date includes i.a. selective derivatization of the carboxyl group, the three hydroxyl groups, the ketone group, the alkene, and epimerization of the characteristic tricyclic salinomycin unit (for more details see: M. Antoszczak, A. Huczyński, B. Brzezinski, Wiad. Chem., 2017, 71, 629). On the other hand, as part of the original program to develop innovatory anti- -cancer pro-drugs and prompted by the idea that cancer cells may be individually effectively killed by monensin and salinomycin, a very interesting direction of research is bioconjugation of these ionophores. In this context, our review article is focused on the possible role of hybrids of both ionophore antibiotics with other biologically active substances (natural amino acids, Cinchona alkaloids, flavonoids, nucleosides) in anti-bacterial and anti-cancer treatment, and gives an overview of their properties.

4

Synteza i aktywność biologiczna pochodnych salinomycyny

Antoszczak M., Huczyński A., Brzezinski B.

Wiadomości Chemiczne

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2017

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[Z] 71, 7-8

629--661

EN

Polyether ionophore antibiotics (ionophores) represent a large group of naturally- occurring lipid-soluble compounds isolated from actinomycetes strains of Streptomyces genus. Ionophores are able to form complexes with the metal cations, especially sodium and potassium, and transport them across the lipid membranes according to electroneutral or electrogenic transport mechanism. This process disturbs the intercellular Na+/K+ concentration gradient and intracellular pH, leads to the mitochondrial injuries, cell swelling, vacuolization and finally to programmed cell death (apoptosis). For this reason, ionophore antibiotics found commercial use in veterinary medicine as coccidiostatic agents and non-hormonal growth promoters. In addition to the industrial use of ionophores, some of them effectively and selectively inhibit properties of different cancer cells as well as enhance the anti-cancer effects of radio- and/or chemotherapy. In this group, particularly interesting is salinomycin because of its potent anti-microbial and anti-cancer activity, including efficiency against multi-drug resistant cancer cells and cancer stem cells. A very interesting direction of research is the chemical modification of ionophore antibiotics, which can lead to obtaining various derivatives with better biological activity and lower toxicity than those of the starting substances. Because biological activity of ionophore antibiotics and their derivatives is strictly connected with the ability to form characteristic pseudocyclic structures around the complexed cations (host-guest complex), it is also important to establish the detailed information on these structures. In this context, our review article is focused on the possible role of salinomycin and its derivatives in anti-microbial as well as anti-cancer therapy, and gives an overview of the properties of this antibiotic.

5

Pochodne 1,2,3-triazolu. Potencjalne leki?

Bankowska E., Wróblewski A. E.

Wiadomości Chemiczne

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2012

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[Z] 66, 11-12

993-1022

EN

Recently, 1,2,3-triazoles have gained an increased attention in the field of drug discovery because several derivatives have already been marketed as medications (e.g. tazobactam, cefatrizine, rufinamide) [1, 2] and many of them appeared to be very active in diverse biological studies including plinambulin 69 currently in the last stage of the clinical trials [60]. In this review very recent investigations of antibacterial, antitubercular, antifungal, antipsychotic, antiepileptic, anti-inflammatory, hypoglycemic, anticancer and antiviral properties of 1,2,3-triazole derivatives are discussed. These studies allowed to select several compounds which were found to be more active in comparison to the already used drugs.

6

Izoksazolidynowe analogi nukleozydów

Kokosza K., Piotrowska D. G.

Wiadomości Chemiczne

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2012

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[Z] 66, 11-12

1041-1070

EN

Compounds having isoxazolidine moiety are of special interest since they show a broad spectrum of biological activity, including anticancer [1–5], antiviral [6], antibacterial [7–9] and antifungal activities [9–12]. Extensive studies on isoxazolidine moiety containing compounds resulted in discovery of several potentially antiviral and anticancer drugs (e.g. pyridemine-A 1 [2, 3], as well as isoxazolidines substituted with thymine and 5-fluorouracil 52a (AdT) [38–40] and 59 [(–)-AdFU] [41–43], respectively). In this review the most spectacular examples of the synthesis of isoxazolidine analogues of nucleosides are discussed and their biological activity is emphasized.

7

Naturalne i syntetyczne laktony o aktywności przeciwnowotworowej i przeciwdrobnoustrojowej

Mazur M.

Wiadomości Chemiczne

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2011

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[Z] 65, 1-2

135-149

EN

Medicine is one of the most developing branches of knowledge. But even now there are still some diseases which are impossible to cure. Different cancers, antibiotic resistant bacterial infections and fungal pathogenesis infections are still everlasting problems. Thus, two ways of solutions are proposed. First is the return to natural medicines. From the ancient times plants have been used in medicine and the natural products have been an important source of drugs. Nowadays isolation and identification of these compounds, together with the determination of their biological activity, also play an important role. Lactones are the cyclic esters with a wide range of carbon atoms in a lactone ring. They are a very interesting group of compounds which reveal a wide spectrum of biological activity. Terpenoid, especially sesquiterpene lactones and coumarin derivatives, are found in plants of the Asteraceae and Apiaceae families as well as in many others organisms. The naturally occurring lactones often possess anti-inflamatory [1, 2], phytotoxic [3, 4], antiprotozoal [5], and antiviral activities [6]. They are also well known for their anticancer [7, 8] and antimicrobial activities [9, 10]. The second way of obtaining new biologically active lactones is the chemical synthesis of new potent structural analogs of natural bioactive compounds. However, the complexity of natural products and their derivatives may lead to limited supplies, especially when they have the chiral centers which are one of the most important factors influencing their biological activity. It also causes difficulties to determine the mechanism of action. For those reasons, structural simplification plays an important role in the development of analog design. This review is focused on novel literature data about synthetic and natural lactones which reveal anticancer, antibacterial and antifungal activities. Presented compounds show potent biological activity and high selectivity with holding promises for further applications.

8

Kombretastatyna A-4 (CA-4) i jej analogi : synteza i aktywność biologiczna

Dzierzbicka K., Kubacka P., Renusz S., Kołodziejczyk A.M.

Wiadomości Chemiczne

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2008

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[Z] 62, 11-12

1037-1064

EN

This article described synthesis and biological activity of combretastatin A-4 (CA-4) and its analogues. Combretastatin A-4 (CA-4), a natural product isolated from the South African bush willow tree Combretum caffrum, binds to the colchicine binding site and inhibits the polymerization of microtubules. CA-4 exhibits potent cytotoxicity against a variety of human cancer cell lines including multidrug-resistant (MDR) cell lines [5-7]. The studies of structure-activity relationship (SAR) of CA-4 1 (Fig. 1) showed that 3,4,5-trimethoxy substitution on the A ring and the 4'-methoxy group on the B ring and the cis-olefin configuration are crucial for potent cytotoxicity, while the 3'-hydroxy group is optional [5-7]. A many of CA-4 analogues were synthesized where the double bond have been replaced by introduction of nonheterocyclic groups (e.g. ethers, olefins, ketones, sulfonates, sulfonamides, amide derivatives, amine, cyclopentanes) or heterocyclic groups containing five-membered rings (e.g. pyrazoles, thiazoles, triazoles, tetrazoles, oxazoles, furans, dioxolanes, thiophenes) and indoles [5, 7, 41, 56] (Fig. 9-12). Up to now, many CA-4 analogues and their biological activity have been extensively studied and three derivatives are currently in clinical trials: a water-soluble disodium phosphate derivative of CA-4 (CA-4P) 11c (Fig. 3); Oxi-4503, a water-soluble combretastatin A-1 (CA-1diP) 4a (Fig. 1); and AC7700 59e (Scheme 7) an aminocombretastatin prodrug developed in Japan in 1998 [5-10, 34].

9

Chemia i aktywność biologiczna czosnku (Allium sativum)

Kwiecień H.

Wiadomości Chemiczne

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2008

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[Z] 62, 9-10

901-942

EN

Garlic (Allium sativum) has historically been one of the most common vegetables to serve as a both spice and medical herb in many countries. One of the outstanding features of the chemical composition of garlic is the large amount of unique organosulfur compounds, which provide its characteristic flavor and odor and most of its potent biological activity. Two classes of primary organosulfur compounds are found in whole garlic cloves: γ-glutamyl-S-alk(en)yl-L-cysteines and S-alk(en)yl-L-cysteine sulfoxides (alliin, metiin, propiin, isallin) (Fig. 1, 2) [5-15]. When garlic is crushed or cut, S-alk(en)yl--L-cysteine sulfoxides are exposed to the enzyme alliinase and thiosulfinates, via intermediate sulfenic acids are formed (Fig. 6) [29-33]. The major thiosulfinate, allicin is a reactive intermediate species that can be transformed, into a variety of compounds including diallyl, methyl allyl and mono- di-, tri-, tetrasulfides, vinyldithiins and ajoenes (Fig. 7-9) [37-49]. Garlic belongs to the Allium species, which accumulate only fructans as their nonstructural carbohydrates [52-59]. Garlic is also known for its production of some unique furostanol saponins, e.g. proto-eruboside-B and sativoside-B1 (Fig. 10-12) [60-63]. The Allium species also contain high levels of flavonides, including apigenin, myricetin and quercetin (Fig. 13) [64, 65], moderate levels of vitamins as well as free amino acids (Arg, Gln, Asn, Glu, and Lys) [66-69]. It was found that the amino acid fraction of Aged Garlic Extract (AGE) contain Maillard reaction products, N-fructosyl glutamine (Fru-Glu), Nα-(1-deoxy-D-fructos-1-yl)-L-arginine (Fru-Arg) (Fig. 14, 15) [74-76], as well as tetrahydro-?-carboline derivatives (Fig. 16, 17) [77-82]. Recently, allixin (Fig. 18), a novel phytoalexin, with the structure 4H-pyran-4-one, as a novel substance with neurotrophic activity has been reported to by synthesized by garlic [83-85]. Garlic has the ability to accumulate the selenium from soil and the major selenium compound in both Se-enriched and unenriched garlic was identified as γ-glutamyl-Se-methyl selenocysteine along with lesser amounts of Se-methyl selenocysteine, selenocysteine, selenomethionine among other compounds (Fig. 19) [86-96]. Pharmacological investigations have shown that garlic has a wide spectrum of actions, not only it is antimicrobial [97], but it also has beneficial effects in regard to cardiovascular and cancer diseases [2, 3, 14, 42]. A number of organosulfur substances derived from garlic such as allicin, allicin-derived organosulfur compounds including sulfides, ajoene, steroidal saponins, flavonides, Fru-Arg, Fru-Glu, organic seleno-compounds and tetrahydro-?-carboline derivatives have been found to have strong antioxidant properties. It has been suggested that garlic can prevent cardiovascular disease, inhibit platelet aggregation, decrease the synthesis of cholesterol and prevent cancer. Thus it may either prevent or delay chronic diseases associated with aging.

10

Kompleksy platyny (IV) jako potencjalne związki przeciwnowotworowe

Ciołkowski M., Budzisz E.

Wiadomości Chemiczne

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2007

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[Z] 61, 1-2

43-60

EN

Cisplatin is an important anticancer drug. Unfortunately it does not bring satisfactory effects in all types of tumor. Other problems are its toxicity and intrinsic or acquired resistance of tumor cells. That is why new drugs based on this molecule are being searched. One of the promising group of chemical compounds are neutral platinum(IV) complexes. They are more inert than platinum(II) complexes. In consequence their reactivity in bloodstream is weaker and more molecules can reach their target. Many studies were done to establish the relation among the structure, lipophilicity, reduction potential and cytotoxicity of those complexes. It is believed that platinum(IV) complexes must be reduced to platinum(II) complexes to obtain cytotoxicity. The speed of reduction depends on the nature of axial ligands. The complexes with chloride ligands are reduced the most quickly and complexes with hydroxide ligands are reduced the most slowly. In vitro cytotoxic activity of those complexes was shown to depend on their reduction potential. However suggestions exist that this result can be misleading for their in vivo activity, as platinum(IV) complexes are pro-drugs and might be inactive before reaching cancer cells. In a study of group of platinum(IV) complexes, derivatives of cisplatin and dichloroethylenediamineplatinum(II), a tendency for an increase of cytotoxic activity when lipophilicity increased was observed. However in a study of tetrakis(carboxylato)(1,2-diaminocyclohexane)platinum(IV) complexes, different cytotoxic activity of complexes possessing similar lipophilicity was observed. Hence lipophilicity of complex is important but it is not the only factor that determines complex activity. In other studies complexes of general structure cis, trans, cis-[PtNH3(RNH2)Cl2(OCOR')2] were examined. The research showed an increased activity of compounds with longer carbon chains of carboxylate axial ligands. It was also revealed that complexes with alicyclic amine ligands were more cytotoxic than those with aliphatic or aromatic amine ligands. Hall et al. revealed that platinum(IV) complexes, derivatives of cisplatin and dichloroethylenediamineplatinum(II), are active against DLD-1 colon cancer cell line in hypoxic environment. An examination of trans-dichlorodihydroxo(dimethylamine)(isopropylamine)platinum(IV) revealed its greater cytotoxic activity against A2780, CH1 and 41M human ovarian cancer cell lines, in vitro. Moreover this complex was shown to be active against A2780cisR, CH1cisR and 41McisR human ovarian cell lines which are resistant to cisplatin. Two platinum(IV) complexes: iproplatin (cis, trans, cis-dichlorodihydroxobis(isopropylamine)platinum(IV)) and tetraplatin (tetrachloro(cyclohexane-1,2-diamine)platinum(IV)) have had entered clinical trials. However iproplatin occurred to be less active than cisplatin and tetraplatin turned out to be neurotoxic. Presently two other complexes seem to be very promising: satraplatin (bis(acetato)amminedichlorocyclohexylamineplatinum(IV)) and adamplatin (bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)). Both have entered clinical trials. There are some "nonstandard" approaches to investigating platinum complexes. For example platinum(IV) complexes with radioactive iodine isotope or with enzyme inhibitor were examined. Studies mentioned above present different approaches to searching for anticancer drugs among platinum(IV) complexes. Despite all encountered difficulties during researching platinum(IV) complexes, this group of compounds still seems to be potential source of new anticancer drugs.

11

Chemiczno-enzymatyczna strategia konstrukcji proleków nukleozydowych

Kaczmarek R., Kulik K., Baraniak J.

Wiadomości Chemiczne

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2007

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[Z] 61, 5-6

417-443

EN

Several nucleoside analogues have found successful application as antiviral and anticancer agents. Their mode of action differs, but in the most general terms they have been developed as inhibitors or competitors of natural 2'-deoxynucleosides in the process of their conversion to the corresponding nucleoside-5'-triphosphates. As such, they can be incorporated into a growing viral DNA strand by a DNA polymerase resulting in chain termination. In cancer therapy, modified nucleosides, after being phosphorylated to the corresponding monophosphates, block DNA biosynthesis by deactivating nucleoside syntheses. Hence biological activity of nucleoside analogues in most cases depends on the intracellular phosphorylation by viral and/or cellular kinases to their respective mono-, di-, and triphosphate derivatives. Among the three successive activating phosphorylation steps the first one has fundamental importance as the rate-limiting step. Several different enzymes can perform this initial phosphorylation, depending on the nature of the aglycone. Also, the presence and activity of the intracellular enzymes necessary for the activation of nucleoside analogues are highly dependent on the host species, the cell type, and the stage in the cell cycle. Moreover, in many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation. For all these reasons, intracellular nucleoside monophosphate (NMP) delivery has been considered for overcoming the first phosphorylation step. Unfortunately, NMPs themselves cannot be used as potential chemotherapeutic agents. Owing to their high polarity, these compounds are not able to penetrate cellular membrane or the blood-brain barrier easily. Therefore, in order to reduce the phosphate negative charge and enable the modified nucleotide to enter the cell, many nucleotides modified on the phos-phate moiety by so-called masking group have been synthesized. A suitable nucleotide prodrug (so-called pronucleotide) has to fulfill two requirements: i) it has to be lipophilic enough for passive diffusion of the membrane and the blood-brain barrier; ii) it should be able to deliver the nucleoside by chemical or enzymatic hydrolysis leaving a non-toxic masking group. Many strategies using various protecting groups for the phosphate moiety have been deve-loped to achieve this goal. The majority of strategies for unmasking pronucleotides that have been examined to date have involved substrate-nonspecific enzymes to remove one or more groups that are attached to the 5'MP moiety. Carboxylesterases (CEs) have attracted considerable attention, since they include bis(pivaloyloxymethyl) [(bis(POM)] and S-acyl-2-thioethyl (SATE) moieties which are initially unmasked by CE-mediated cleavage. A combination of aryl ester and amino acid phosphoramidate groups as a particular class of enzyme-labile protecting groups was developed for the delivery of antiviral nucleoside prodrugs. An endogenous phosphoramidase was responsible and necessary for the biological activity of those compounds in living cells. On the other side almost all approaches based on chemical hydrolysis reported so far were unable to deliver the nucleotide selectively exept the cycloSal approach. This review will predominantly concentrate on the different approaches to the design of nucleotide prodrugs. Keywords: prodrug, pronucleotide, nucleoside analogues, antiviral activity, anticancer acti-vity, masking groups.

12

Inhibitory mikrotubul w terapii przeciwnowotworowej

Dzierzbicka K., Kołodziejczyk A.M.

Wiadomości Chemiczne

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2006

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[Z] 60, 5-6

345-364

EN

Microtubule targeting drugs being in the late preclinical or early clinical development are described in this article. New semisynthetic paclitaxel analogues, natural compounds of diverse structure such as epothilones, combretastatins, colchino-ids or dolastatins and synthetic compounds of low molecular weight such as heterocombretastatins, sulfonamides, phenstatins, indoles and quinolones belong to this category of anticancer medicines. Microtubules are hollow tubes consisting of L- and B-tubulin heterodimer proteins that polymerize parallelly to a cylindrical axis. The targeting of microtubules is an important mechanism in cancer chemotherapy for such drugs as the vinca alkaloids (vincristine (1), vin-blastine (la)), podophilotoxin, their semisynthetic analogues and taxanes (paclitaxel (2), docetaxel (3)) known of their great usefulness in the anticancer therapy. These agents may stabilize microtubules, as the taxanes do, or destabilize them, as it is in the case of the vinca alkaloids. Today, more than 30 compounds targeting tubulin, either stabilizing or destabilizing microtubule dynamics, are in late preclinical or early clinical development. Despite of more than 30 years after the discovery of paclitaxel microtubule inhibitors they are still of the topic of interest of all over the world. In the end of 1990 and up to 2005 year survey articles on the microtubule inhibitors were published .We expect now that the paper which presents last results study may be useful.