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1

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.

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Aminokwasy, glikany, peptydy i białka w ścieżkach diagnostycznych i terapeutycznych chorób cywilizacyjnych XXI wieku : projektowanie i charakterystyka fizykochemiczna oraz strukturalna

Bylińska Irena, Dzierżyńska Maria, Giżyńska Małgorzata, Guzow Katarzyna, Jankowska Elżbieta, Jurczak Przemysław, Kaczyński Zbigniew, Karska Natalia, Kowalczyk Agnieszka, Kuncewicz Katarzyna, Orlikowska Marta, Sawicka Justyna, Spodzieja Marta, Szpakowska Nikola, Szymańska Aneta, Wieczerzak Ewa, Witkowska Julia, Rodziewicz-Motowidło Sylwia

Wiadomości Chemiczne

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2022

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[Z] 76, 5-6

393--431

EN

The civilization diseases of the 21st century are non-infectious disorders, affecting a large part of modern society. They are associated with the significant development of industry and technology, and hence with environmental pollution and an unhealthy lifestyle. These factors have led to the development of many civilization diseases, which currently include: cardiovascular diseases, respiratory diseases, diabetes, obesity, malignant tumors, gastrointestinal diseases, mental disorders and allergic diseases. The development of technologies, including modern therapies and new drugs, resulted in increase in life expectancy. This creates a global problem of an aging population with an increasing number of diseases of the old age, i.e. dementias. In addition, sedentary lifestyles and changing diets are the reasons why more and more people develop metabolic diseases, as well as neurological and cognitive disorders characterized by progressive damage to nerve cells and dementia. Currently, problem on a global scale is also the growing resistance to existing antimicrobial drugs. Therefore, the scientists face many challenges related to searching for the causes of these diseases, their diagnosis and treatment. Scientific research conducted at the Department of Biomedical Chemistry at the Faculty of Chemistry of the University of Gdańsk is part of this research trend. In this publication, we discuss various research topics with the long-term aim of solving the problems associated with the diseases mentioned above. The following chapters are dedicated to (i) looking for new effective fluorophores with diagnostic and anti-cancer activity; (ii) designing of new compounds with antibacterial and antiviral activity and their synthesis; (iii) investigating the mechanisms of amyloid deposit formation by human cystatin C and possibilities of inhibition of this process; (iv) designing and studies of compounds activating the proteasome with the potential to suppress the development of neurodegenerative diseases; (v) designing peptide fibrils and hydrogels as drug carriers; (vi) searching for peptide inhibitors of immune checkpoint as potential drugs for immunotherapy; (vii) studying the mechanism of action of selected herpesviruses by determining the structure of viral proteins and (viii) studying the composition of natural glycans and glycoconjugates in order to better understand the mechanisms of interaction of bacteria with the environment or with the host.

3

Synthesis, physicochemical studies, fluorescence behavior, and anticancer properties of transition metal complexes with the pyridyl ligand

Azam Mohammad, Al-Resayes Saud I.

Polish Journal of Chemical Technology

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2022

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Vol. 24, nr 3

35--40

EN

A novel series of complexes with the formula [MLCl] [M = Co(II) (1), Ni(II) (2), Cu(II) (3), Zn(II) (4)] arising from Pyridyl ligand, N,N’-bis(1-(2-pyridyl)ethylidene)-2,2-dimethylpropane-1,3-diamine), ligand, L, was synthesized and investigated by elemental analyses, FT-IR, 1H and 13C NMR, Powder XRD, and thermal analyses. TGA analysis indicated that all complexes degraded in three different steps, while the PXRD examination showed well-defined sharp crystalline peaks for the complexes, indicating significant crystallinity. The antiproliferative activity of the ligand and its complexes were also evaluated in vitro against the HeLa (Human Cervical Cancer Cells) and HCT116 (Colon Cancer Cells) cell lines. The findings suggested complex 4 to be potential anticancer agent against these cell lines. In addition, ligand and its complexes also exhibited considerable emission properties.

4

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.

5

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.

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A Comparison of Antioxidant, Antibacterial, and Anticancer Activity of the Selected Thyme Species by Means of Hierarchical Clustering and Principal Component Analysis

Orłowska M., Pytlakowska K., Mrozek-Wilczkiewicz A., Musioł R., Waksmundzka-Hajnos M., Sajewicz M., Kowalska T.

Acta Chromatographica

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2016

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Vol. 28, no. 2

207--221

EN

In this study, six numerical data sets are presented valid for eighteen thyme (Thymus L.) species and characterizing three biological properties of these herbs, i.e., antioxidant, antibacterial, and anticancer activity. Four data sets characterize antioxidant properties, one data set characterizes antibacterial property, and one data set characterizes anticancer activity. Antioxidant properties were measured with two free radical standards (DPPH and ABTS), two free radical scavenger standards (trolox and gallic acid), and three analytical techniques (EPR spectroscopy, ultraviolet–visible [UV–vis] spectrophotometry, and the dot blot test with bioautographic detection). Antibacterial activity was tested upon the Gram-positive Bacillus subtilis (ATCC 6633) strain, and anticancer activity was evaluated upon the human colon adenocarcinoma cells (HCT116). It was found out that the thyme extracts characterize with all three biological activities (yet with anticancer activity not very strongly pronounced) and that in quantitative terms, each activity strongly depends on the thyme species considered. An ultimate goal of this study was to investigate if any quantitatively confirmed correlation exists among these three biological activities, which might point out to a common mechanism of their action. To this effect, six sets of numerical data underwent hierarchical clustering and Principal Component Analysis. Based on the results obtained, no quantitative correlation was established among antioxidant, antibacterial, and anticancer activity of the thyme species, which seems indicative of different molecular mechanisms of these three actions.

7

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.

8

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.

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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.

10

Synthesis, Structure, and Pharmacological Screening of 2,7-Naphthyridine Derivatives

Wagner E., Wójcicka A., Bryndal I., Lis T.

Polish Journal of Chemistry

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2009

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Vol. 83, nr 2

207-215

EN

An attempt to rearrange pyrrolo[3,4-c]pyridine-1,3-diones to the 2,7-naphthyridine ring under the conditions, described in only one report [1], gave compounds 7-9, but did not yield the expected 2,7- or 2,6-naphthyridine isomers. Important for the synthesis of the naphthyridine ring from pyrrolo[3,4-c]pyridine was that, of the two possible isomers, only 2,7- not 2,6-naphthyridine was obtained. Ethyl (4-R'-1,3- dioxo- 6-phenyl-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)acetate (5, 6, 10) treated with sodium ethoxide was rearranged by the Claisen-Dieckmann reaction to ethyl 4-hydroxy-8-R'-1-oxo-6-phenyl-1,2-dihydro-2,7-naphthyridine-3-carboxylate (13, 14), where R' = methyl or ethoxy. The structures of the new compounds were confirmed by elemental analysis and NMR and IR spectra. The structure of 14 was also determined by X-ray crystallography to prove the presence of 2,7-naphthyridine isomer. The in vitro anticancer activities of the final 2,7-naphthyridines were tested at the US NCI (Bethesda, MD). Compound 13 exhibited cytostatic activity in vitro.

11

Syntheses of N,S-Substituted 4-Chloro-2-mercapto-5-methylbenzenesulfonamide Derivatives with Potential Biological Activity

Pomarnacka E., Kornicka A., Bednarski P. J., Charkiewicz A.

Polish Journal of Chemistry

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2009

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Vol. 83, nr 1

65-73

EN

The syntheses of N,S-substituted 4-chloro-2-mercapto-5-methylbenzenesulfonamide derivatives are described. The compounds 6-11, 14, 15 and 19-22 were tested for their in vitro anticancer activity against 9 human cancer cell lines. The most active compounds 6, 9 and 20 showed moderate cytotoxic activity and were approximately 5-fold less potent than cisplatin.

12

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.

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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.

14

Syntheses and In Vitro Antitumor Activity of 3-Amino-N-(4-chlorobenzenesulfonyl)guanidine Derivatives Containing N'-Arylidene Moiety

Sławiński J., Bednarski P., Reszka P.

Polish Journal of Chemistry

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2004

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Vol. 78 / nr 3

369-379

EN

The syntheses of new 3-arylideneamino-1-(2-alkythio-4-chloro-5-methylbenzenesulfonyl) guanidines 2-8 and 1-arylidene-2-(2-alkylthio-4-chloro-5-R3-benzenesulfonyl)- 3-methylaminoguanidines 9-16 are described. The in vitro antitumor screening of compounds 2, 3, 9 and 10 was evaluated at the Institute of Pharmacy, University of Greifswald. The remaining compounds 5, 11-14 and 16 were screened at the National Cancer Institute (NCI) for their activities against a panel of 55 human tumor cell lines, and relationships between structure and anticancer activity in vitro are discussed. The highest anticancer activity was found for 2-(2-benzylthio-4-chloro-5-methylbenzenesulfonyl)- 3-methylamino-1-(5-nitrothienylidene)guanidine (12) (GI50 in the range 0.3-0.6 _M), while other compounds exhibit reasonable (16) or moderate ( 9, 13) anticancer activities.