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Natamycin is a macrolide polyene antibiotic, characterized by a potent broad spectrum antifungal activity and low toxicity. However, it is not used for the treatment of systemic mycoses due to its low bioavailability and low solubility in aqueous solutions. In order to create new semisynthetic antifungal agents for treatment of mycoses, a series of water-soluble amides of natamycin were synthesized. Antifungal activities of natamycin derivatives were investigated against

The review aims to draw attention to the latest advances in the organoboron chemistry and therapeutic use of organoboron compounds. The synthetic strategies towards boron-containing compounds with proven in vitro and/or in vivo biological activities, including derivatives of boronic acids, benzoxaboroles, benzoxaborines and benzodiazaborines, are summarized. Approaches to the synthesis of hybrid structures containing an organoboron moiety as one of the pharmacophores are considered, and the effect of this modification on the pharmacological activity of the initial molecules is analyzed. On the basis of analysis of the published data, the most promising areas of research in the field of organoboron compounds are identified, including the latest methods of synthesis, modification and design of effective therapeutic agents. The bibliography includes 246 references.

To ensure the uniformity of measurements and metrological traceability of measurement results in state regulation of ensuring the uniformity of measurements, including in healthcare and pharmaceuticals, reference materials of composition, properties and structure of substances are needed. Currently, the Federal Information Fund of the Russian Federation has approximately 9000 reference materials, among which only about 30 reference materials are intended for use in pharmaceuticals and medicine. This amount is clearly insufficient for full metrological support of these areas. This article describes the main stages and results of research and development of reference materials of starting pharmaceutical substances amphotericin B, natamycin, olivomycin A. The main substances of the created reference materials are identified. Mass fractions of related compounds, residual organic solvents and inorganic impurities (iron cations and heavy metals) were determined. The results of the work were used to confirm the reference material types of the starting pharmaceutical substances amphotericin B, natamycin, olivomycin A.

This microreview provides generalized information on the heterocyclization methods leading to derivatives of oxaborines, as well as considers some details of their biological activity. The provided material covers key studies published over the previous three years.

To ensure the uniformity of measurements and ensure metrological traceability of the measurement results in the field of ensuring the uniformity of measurements state regulation, including in the areas of healthcare and pharmaceuticals, reference materials of the composition, properties and structure of substances are needed. Currently, the Federal Information Fund of the Russian Federation has approximately 9000 reference materials, among which only about 30 reference materials are intended for use in pharmaceuticals and medicine. This amount is clearly not enough for full metrological support of these areas. This article describes the main stages and results of research and development of starting pharmaceutical substances reference materials of amphotericin B, natamycin, olivomycin A. The main substances of the created reference materials are identified. Mass fractions of related compounds, residual organic solvents and inorganic impurities (iron cations and heavy metals) were determined. The results of the work were used to confirm the reference materials types of the starting pharmaceutical substances amphotericin B, natamycin, olivomycin A.

Amphotericin B (AmB) remains a drug of first choice for treatment of most severe mycoses despite significant toxicity and solubility problems. Screening of a series of new semisynthetic polyene macrolide derivatives identified AmB N-(2-aminoethyl)amide (amphamide) as having several competitive advantages over the parent polyene. Aprototype parenteral amphamide dosage form in which the active ingredient was highly soluble and stable during storage was developed. Chronic toxicity of the finished amphamide dosage form was studied in rabbits. The amphamide dosage form displayed dose-dependent reversible toxicity.

The search for new antifungal agents with improved chemotherapeutic properties has produced the semisynthetic polyene macrolide amphotericin B derivative amphamide, which has a number of clear advantages over the starting antibiotic. The development of a medicinal formulation of amphamide for parenteral use is described, with high water solubility, good stability of the active ingredient, and high specific activity. The prototype composition has potential for a further full-scale set of clinical trials.

Methods for selective chemical modification of the antitumor antibiotic olivomycin A(OA) were developed at GINA. The compound olivamide with advantages over starting OA was selected from series of OA analogs. The goal of the present work was to develop a dosage form of the antitumor semi-synthetic antibiotic olivamide that guaranteed the stability and high specific activity of olivamide drug substance and was designed for further comprehensive preclinical studies.

Methods for selective chemical modification of the antibiotic olivomycin A (OA) were developed at G. F. Gause Institute of New Antibiotics. The compound with the highest activity against various tumor cell lines was selected from a series of OA analogs. The aim of the work was to study the antitumor activity and toxicity of a dosage form of this compound, i.e., olivamide. Antitumor activity was studied in four syngenic grafted murine tumors. Chronic toxicity was assessed in experiments with rats that determined the animal body mass, clinical and biochemical blood analysis, urinalysis, electrocardiography, and structures of internal organs. The preparation exhibited high antitumor activity and displayed dose-dependent nephro- and hepatotoxic properties.

For some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant Staphylococcus aureus (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of glycopeptide antibiotics is essentially the binding of peptidoglycan cell-wall fragments terminating in the d-Ala-d-Ala sequence to the carboxylate anion binding pocket of the antibiotic. Dimerization of these antibiotics in aqueous solution was shown to persist and even to enhance the antibacterial effect in a co-operative manner. Some works based on solid state (ss) Nuclear Magnetic Resonance (NMR) studies questioned the presence of dimers under the conditions of ssNMR while in a few cases, higher-order oligomers associated with contiguous back-to-back and face-to-face dimers were observed in the crystal phase. However, it is not proved if such oligomers persist in aqueous solutions. With the aid of 15N-labelled eremomycin using 15N relaxation and diffusion NMR methods, we observed tetramers and octamers when the N-Ac-d-Ala-d-Ala dipeptide was added. To the contrary, the N-Ac-d-Ala or (N-Ac)2-l-Lys-d-Ala-d-Ala tripeptide did not induce higher-order oligomers. These observations are interesting examples of tailored supramolecular self-organization. New antimicrobial tests have also been carried out with these self-assemblies against MRSA and VRE (resistant) strains.

Mycobacterium tuberculosis is one of the most dangerous pathogens. Bacterial resistance to antituberculosis drugs grows each year, but searching for new drugs is a long process. Testing for available drugs to find active against mycobacteria may be a good alternative. In this work, antibiotics of the aureolic acid group were tested on a model organism Mycobacterium smegmatis. We presumed that antibiotics of this group may be potential G4 ligands. However, this was not confirmed in our analyses. We determined the antimicrobial activity of these drugs and revealed morphological changes in the cell structure upon treatment. Transcriptomic analysis documented increased expression of MSMEG_3743/soj and MSMEG_4228/ftsW, involved in cell division. Therefore, drugs may affect cell division, possibly disrupting the function of the Z-ring and the formation of a septum. Additionally, a decrease in the transcription level of several indispensable genes, such as nitrate reductase subunits (MSMEG_5137/narI and MSMEG_5139/narX) and MSMEG_3205/hisD was shown. We concluded that the mechanism of action of aureolic acid and its related compounds may be similar to that bedaquiline and disturb the NAD+/NADH balance in the cell. All of this allowed us to conclude that aureolic acid derivatives can be considered as potential antituberculosis drugs.

Amphotericin B (AmB, 1) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. With the objective of obtaining AmB derivatives with lower self-aggregation and improved solubility, we synthesized a series of amides of AmB bearing an additional basic group in the introduced residue. The screening of antifungal activity in vitro revealed that N-(2-aminoethyl)amide of AmB (amphamide, 6) had superior antifungal activity compared to that of the paternal AmB. Preclinical studies in mice confirmed that compound 6 had a much lower acute toxicity and higher antifungal efficacy in the model of mice candidosis sepsis compared with that of AmB (1). Thus, the discovered amphamide is a promising drug candidate for the second generation of polyene antibiotics and is also prospective for in-depth preclinical and clinical evaluation.

The review summarizes recent advances in the synthesis of new derivatives of polyene macrolide antibiotics by chemical modification and genetic engineering methods, results of structure – activity relationship studies and progress in the development of effective and safe drug formulations of this class of antibiotics. Attention is focused on structural changes of polyenes, resulting in a significant decrease in toxicity with retention or even enhancement of antifungal activity. Current concepts on the mechanisms of biological action of these antiobiotics in terms of their therapeutic activity and toxicity are considered. The bibliography includes 77 references.

Olivomycin A is a highly active antitumor drug that belongs to the family of aureolic acid antibiotics. The antitumor effect of olivomycin A is related to its ability to bind to the DNA minor groove in GC-rich regions as Mg2+-coordinated complexes. Characterization of cellular targets of olivomycin A and its mechanism of action is crucial for the successful application of this antibiotic in clinical practice and development of semi-synthetic derivatives with improved pharmacological properties. Previously, we have shown that minor groove ligands are able to disrupt the key epigenetic process of DNA methylation. In this paper, we have studied the impact of olivomycin A and its improved semi-synthetic analogue N,N-dimethylaminoethylamide of 1'-des-(2,3-dihydroxy-n-butyroyl)-1'-carboxy-olivomycin A (olivamide) on the functioning of de novo DNA methyltransferase Dnmt3a (enzyme that carries out methylation of cytosine residues in the DNA CG-sites in eukaryotic cells) using an in vitro system consisting of the murine Dnmt3a catalytic domain and a 30-mer DNA duplex containing four consecutive GC pairs. We have shown that olivomycin A and olivamide inhibit Dnmt3a with IC50 of 6 ± 1 and 7.1 ± 0.7 μM, respectively. Neither olivomycin A nor olivamide interfered with the formation of the specific enzyme-substrate complex; however, olivomycin A prevented formation of the covalent DNA-Dnmt3a intermediate that is necessary for the methylation reaction to proceed. The inhibitory effects of olivomycin A and olivamide can be explained by the disruption of the enzyme catalytic loop movement through the DNA minor groove (the reaction stage that precedes the covalent bond formation between DNA and the enzyme). The results of this work indicate the epigenetic contribution to the antitumor effect of aureolic acid group antibiotics.

One of the promising directions of the combined approach is the design of dual-acting antibiotics - heterodimeric structures on the basis of antimicrobial agents of different classes. In this study a novel series of azithromycin-glycopeptide conjugates were designed and synthesized. The structures of the obtained compounds were confirmed using NMR spectroscopy and mass spectrometry data including MS/MS analysis. All novel hybrid antibiotics were found to be either as active as azithromycin and vancomycin against Gram-positive bacterial strains or have superior activity in comparison with their parent antibiotics. One compound, eremomycin-azithromycin conjugate 16, demonstrated moderate activity against Enterococcus faecium and Enterococcus faecalis strains resistant to vancomycin, and equal to vancomycin's activity for the treatment of mice with Staphylococcus aureus sepsis.

Triarylmethane derivatives are extensively investigated as antitumor and antibacterial drug candidates alone and as photoactivatable compounds. In the series of tris(1-alkylindol-3-yl)methylium salts (TIMs) these two activities differed depending on the length of N-alkyl chain, with C4-5 derivatives being the most potent compared to the shorter or longer chain analogs and to the natural compound turbomycin A (no N-substituent). Given that the human serum albumin (HSA) is a major transporter protein with which TIMs can form stable complexes, and that the formation of these complexes might be advantageous for phototoxicity of TIMs we determined the quantitative parameters of TIMs-HSA binding using spectroscopic methods and molecular docking. TIMs bound to HSA (1:1 stoichiometry) altered the protein's secondary structure by changing the α-helix/β-turn ratio. The IIa subdomain (Sudlow site I) is the preferred TIM binding site in HSA as determined in competition experiments with reference drugs ibuprofen and warfarin. The values of binding constants increased with the number of CH2 groups from 0 to 6 and then dropped down for C10 compound, a dependence similar to the one observed for cytocidal potency of TIMs. We tend to attribute this non-linear dependence to an interplay between hydrophobicity and steric hindrance, the two key characteristics of TIMs-HSA complexes calculated in the molecular docking procedure. These structure-activity relationships provide evidence for rational design of TIMs-based antitumor and antimicrobial drugs.

Olivomycin A (OA) exerts its cytotoxic potency due to binding to the minor groove of the G/C-rich DNA and interfering with replication and transcription. Screening of the complete set of tetranucleotide G/C sites by electrophoretic mobility gel shift assay (EMSA) revealed that the sites containing central GC or GG dinucleotides were able to bind OA, whereas the sites with the central CG dinucleotide were not. However, studies of equilibrium OA binding in solution by fluorescence, circular dichroism and isothermal titration calorimetry failed to confirm the sequence preference of OA, indicating instead a similar type of complex and comparable affinity of OA to all G/C binding sites. This discrepancy was resolved by kinetics analysis of the drug&ndash, DNA interaction: the dissociation rate significantly differed between SGCS, SGGS and SCGS sites (S stands for G or C), thereby explaining the disintegration of the complexes during EMSA. The functional relevance of the revealed differential kinetics of OA&ndash, DNA interaction was demonstrated in an in vitro transcription assay. These findings emphasize the crucial role of kinetics in the mechanism of OA action and provide an important approach to the screening of new drug candidates.

Novel benzoxaborole derivatives of azithromycin in which benzoxaborole residue is attached to the 4″-hydroxy-group of azithromycin have been synthesized. Antibacterial activity of synthesized derivatives in comparison with azithromycin was tested on a panel of Gram-positive and Gram-negative bacterial strains. All the investigated compounds demonstrated broad spectrum of antibacterial activity being in general more active against Gram-positive strains. New benzoxaborole derivatives of azithromycin demonstrated high activity against Streptococcus pyogenes ATCC 19615 and Propionibacterium acnes ATCC 6919 strains. Some of the new compounds were more active than azithromycin against Streptococcus pneumoniae ATCC 49619 strain or Enterococcus faecium strains. Using a reporter construct created on the basis of the transcription attenuator region of the Escherichia coli tryptophan operon pRFPCER-TrpL2A it has been demonstrated that the mechanism of action of azithromycin analogs is blocking nascent peptide in ribosome tunnel.

The current model of binding of the antitumor antibiotic olivomycin A (1) to GC-rich DNA regions presumes that coordination of the magnesium divalent cation with drug dimers is necessary for binding of 1 into the minor groove of the DNA duplex. Previously we have synthesized the derivatives of 1 termed 'short acid' (2) and its N,N-dimethylaminoethylamide (3). The latter compound demonstrated an improved tolerance in vivo compared to 1 and good therapeutic potency in animal models. We herein report that compound 3 is able to form stable complexes with DNA in the absence of Mg2+, in striking contrast to 1 whose binding to the DNA absolutely requires Mg2+. The mode of binding of 3 to DNA is similar in the presence or absence of Mg2+ as determined by circular dichroism. The affinity to DNA of 3 in Mg2+-free solution was similar to that of 1 or 3 in the presence of Mg2+ at low ionic strength. Non-electrostatic contributions to total free energy of binding of 1 and 3 to DNA were comparable for Mg2+-free complexes. Our data strongly suggest that electrostatic interaction of the positively charged 3 can compensate for the absence of divalent ions in complexes with DNA. This new property of the olivomycin A derivative expands the mechanistic knowledge of the modes of interaction with DNA of small molecular weight drug candidates.

This review presents progress made in recent years in the creation of conjugates based on anthracycline antibiotics and macromolecules. Conjugates are classified depending on the size of the macromolecule and the presence or absence within it of a structural element responsible for selective binding (interaction) with particular cell membrane or cytoplasm structures.

The review is devoted to the latest achievements in the design of dual action antibiotics ? heterodimeric (chimeric) structures based on antibacterial agents of different classes (fluoroquinolones, anthracyclines, oxazolidines, macrolides and so on). Covalent binding can make the pharmacokinetic characteristics of these molecules more predictable and improve the penetration of each component into the cell. Consequently, not only does the drug efficacy increase owing to inhibition of two targets but also the resistance to one or both antibiotics can be overcome. The theoretical grounds of elaboration, design principles and methods for the synthesis of dual action antibiotics are considered. The structures are classified according to the type of covalent spacer (cleavable or not) connecting the moieties of two agents. Dual action antibiotics with a spacer that can be cleaved in a living cell are considered as dual action prodrugs. Data on the biological action of heterodimeric compounds are presented and structure?activity relationships are analyzed. The bibliography includes 225 references.

Introduction The increased resistance of glycopeptide based antibiotics has become a serious problem for the chemotherapy of infections triggered by resistant Gram-positive bacteria. This has motivated the urgent sincere efforts to develop potent glycopeptide-based antibiotics in both academy and industry research laboratories. Understanding of the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve the fundamental results. Several hydrophobic glycopeptide analogues active against resistant strains were developed during the last two decades. Three drugs, namely, oritavancin, telavancin and dalbavancin were approved by FDA in 2013-2014. It was found that hydrophobic derivatives act through different mechanisms without binding with the modified target of resistant bacteria. Types: Different types of chemical modifications led to several glycopeptide analogues active against Gram-negative bacteria as advocated by in vitro studies or demonstrating potent antiviral activity in the cell models. Conclusion A new class of glycopeptide antibiotics with potent activity against sensitive and resistant bacterial strains has been recently reported with the aim to overcome the resistance, however, there are a lot of obscure problems in the complete understanding of their mechanisms of actions. In this review, we summarized the achievements of synthetic methods devoted to the construction of new polycyclic glycopeptide antibiotics and described the studies related to their mechanism of actions.

A series of amides of the antifungal antibiotic amphotericin B (AmB) and its conjugates with benzoxaboroles was tested to determine whether they form pores in lipid bilayers and to compare their channel characteristics. The tested derivatives produced pores of larger amplitude and shorter lifetime than those of the parent antibiotic. The pore conductance was related to changes in the partial charge of the hydrogens of the hydroxyl groups in the lactone ring that determined the anion coordination in the channel. Neutralization of one of the polar group charges in the AmB head during chemical modification produced a pronounced effect by diminishing the dwell time of the polyene channel compared to modification of both groups. In this study, compounds that had a modification of one carboxyl or amino group were less effective in initializing phase separation in POPC-membranes compared to derivatives that had modifications of both polar groups as well as the parent antibiotic. The effects were attributed to the restriction of the aggregation process by electrical repulsion between charged derivatives in contrast to neutral compounds. The significant correlation between the ability of derivatives to increase the permeability of model membranes-causing the appearance of single channels in lipid bilayers or inducing calcein leakage from unilamellar vesicles-and the minimal inhibitory concentration indicated that the antifungal effect of the conjugates was due to pore formation in the membranes of target cells.

A series of olivomycin A derivatives containing different combinations of the acyl residues in the carbohydrate chains was obtained. The formation of complexes of Mg(2+)-coordinated dimers of these compounds with double-stranded DNA was studied using spectral methods such as absorption, fluorescence and circular dichroism (CD) spectral analyses. There was a good correlation of the values of binding constants of complexes (antibiotic)2Mg(2+)-DNA, the quantum yields of fluorescence and changes of the induced CD spectra with topoisomerase I inhibition and cytotoxicity. We demonstrate that the presence of the acyl groups in the saccharide residues of olivomycin A derivatives is absolutely necessary for a high cytotoxic potency of these antibiotics. On the basis of the experimental results and quantum chemical calculations, we presume that the acyl residue in the 4-O-position in the A-sugar residue is involved, to the most part, in the antibiotic-antibiotic interactions in the (olivomycin)2Mg(2+) dimers, whereas the O-acyl group in E-olivomicose residue largely participates in the formation of the (olivomycin)2Mg(2+)-DNA complexes.

A novel way of chemical modification of the antibiotic olivomycin A (1) at the side chain of the aglycon moiety was developed. Interaction of olivomycin A with the sodium periodate produced the key acid derivative olivomycin SA (2) in 86% yield. This acid was used in the reactions with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidino-phosphonium hexafluorophosphate (PyBOP) or diphenylphosphoryl azide (DPPA) to give corresponding amides. Whereas olivomycin SA was two orders of magnitude less cytotoxic than the parent antibiotic, the amides of 2 demonstrated a higher cytotoxicity. In particular, N,N-dimethylaminoethylamide of olivomycin SA showed a pronounced antitumor effect against transplanted experimental lymphoma and melanoma and a remarkably high binding constant to double stranded DNA. The therapeutic effects of this derivative were achievable at tolerable concentrations, suggesting that modifications of the aglycon’s side chain, namely, its shortening to methoxyacetic residue and blocking of free carboxyl group, are straightforward for the design of therapeutically applicable derivatives of olivomycin A.

The azo coupling of the antibiotic olivomycin I (1) with aryl diazonium tetrafluoroborates produced 5-aryldiazenyl-6-O-deglycosyl derivatives of 1. The structures of new compounds were confirmed by (1)H NMR and mass spectrometry analysis. A quantum-chemical study was performed to analyze the possible directions of electrophilic substitution of 1 and the easiness of 6-O-disaccharide hydrolysis in the course of azo coupling. The antiproliferative and anti-retroviral activities of novel derivatives were studied.

A novel way of chemical modification of the antibiotic olivomycin I at the 2'-keto group of the side chain of the aglycone moiety was developed. Reaction of olivomycin I with the carboxymethoxylamine hemihydrochloride gave the key intermediate, 2'-carboxymethoxime-olivomycin I, which was further reacted with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate to give the corresponding amides. The antiproliferative and topoisomerase I (Topo-I)-poisoning activities of the novel derivatives were examined. One of the novel derivatives showed a marked inhibitory activity against Topo-I, a pronounced antitumor activity in in vivo experiments on mice bearing leukemia P-388 and lower toxic side effects compared with the parent olivomycin I.

A novel series of conjugates of the antifungal antibiotic amphotericin B (AmB) with benzoxaboroles was synthesized. Antifungal activity of new compounds was tested on yeastβ Candida albicans and Cryptococcus humicolus and filamentous fungi Aspergillus niger and Fusarium oxysporum using the broth microdilution method. The potency of di-modified derivatives against the tested strains was similar to that of the parent AmB. New derivatives demonstrated differential toxicity against human cells (colon epithelium or red blood cells). The di-modified conjugate 2-(N,N-dimethylamino)ethylamide of 3'-N-[3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-yl)propanoyl] AmB (9) showed the best combination of a high antifungal activity with a low cytotoxic and hemolytic potency.

The reaction of the anthracycline glycoside antibiotics 1 – 3 with the squaric acid ester 4 gave the squaric acid amide esters 5 – 7 under neutral conditions, whereas over pH 7 the products are the symmetric diamides ( 8 , 9 , 11 , and 12 ). Of the prepared compounds 11 was the most active on MCF-7 human mammary adenocarcinoma cells.

The new hydrophilic derivatives of 14-hydroxycarminomycin were obtained using 13-dimethyl ketal of 14-bromocarminomycin (6) as the starting compound. The reductive alkylation of 6 with melibiose or D-galactose followed by hydrolysis of the corresponding intermediate bromoketals 9 and 11 produced 3'-N-[-alpha-D-(galactopyranosyl-(1 --6)-O-D-1-desoxyglucit-1-yl]-14-hydroxycarminomycin (10) and 3'-N-(1-desoxy-D-galactit-1-yl)-14-hydroxycarminomycin (12), respectively. These novel derivatives 10 and 12 were less toxic than carminomycin or 14-hydroxycarminomycin for leukemia (K562) and breast carcinoma (MCF-7) cells. Importantly, carminomycin, 14-hydroxycarminomycin and compounds 10 and 12 were similarly active for wild type cells and their multidrug resistant (MDR) sublines, K562i/S9 and MCF-7Dox.

A general scheme of synthesis of antibiotic doxorubicin derivatives is based on the 13-dimethyl ketal of 14-bromodaunorubicin ( 4 ). The interaction of 4 with melibiose ( 5 ), lactose ( 6 ), 3-methoxy-4- O -(2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-4-oxybenzaldehyde ( 12 ) or 4- O -(2,3,4,6-tetra- O -acetyl-β- d -galactopyranosyl)-4-oxybenzaldehyde ( 13 ) by reductive alkylation followed by hydrolysis of the corresponding intermediate bromoketals produced 3′- N -[α- d -galactopyranosyl-(1→6)- O -1-deoxy- d -glucit-1-yl]doxorubicin ( 7 ), 3′- N -[β- d -galactopyranosyl-(1→4)- O -1-deoxy- d -glucit-1-yl]doxorubicin ( 8 ), 3′- N -[3″-methoxy-4″- O -(β- d -galactopyranosyl)-4″-oxybenzyl]doxorubicin ( 16 ), and 3′- N -[4″- O -(β- d -galactopyranosyl)-4″-oxybenzyl]doxorubicin ( 17 ). Cytotoxic and antitumor activity of the synthesized drug candidates compared to the parent doxorubicin was studied using various experimental models, in particular, on mice bearing lymphocyte leukemia P-388 at single and multiple i.v. injection regimens.

A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10. Antibiotics with OH groups at both C-7 and C-9 had the lowest activity. The replacement of the C-16 carboxyl with methyl group did not significantly affect the in vitro antifungal activity of antibiotics without modifications at the amino group of mycosamine. In contrast, the activity of the N-modified derivatives was modulated both by the presence of CH 3 or COOH group in the position C-16 and by the structure of the modifying substituent. The most active compounds were tested in vivo to determine the maximum tolerated doses and antifungal activity on the model of candidosis sepsis in leukopenic mice (cyclophosphamide-induced). Study of our library of semisynthetic polyene antibiotics led to the discovery of compounds, namely, N -( l -lysyl)-BSG005 (compound 3n) and, especially, l -glutamate of 2-( N , N -dimethylamino)ethyl amide of S44HP (compound 2j), with high antifungal activity that were comparable in in vitro and in vivo tests to AMB and that have better toxicological properties.

Mono- and disubstituted novel derivatives of the heptaene nystatin analog 28,29-didehydronystatin A(1) (S44HP, 1) were obtained by chemical modification of the exocyclic C-16 carboxyl and/or an amino group of mycosamine moiety. The strategy of preparation of mono- and double-modified polyene macrolides was based on the use of intermediate hydrophobic N-Fmoc (9-fluorenylmethoxycarbonyl) derivatives that facilitated the procedures of isolation and purification of new compounds. The antifungal activity of the new derivatives was first tested in vitro against yeasts and filamentous fungi, allowing the selection of the most active compounds that were subsequently tested for acute toxicity in mice. 2-(N,N-dimethylamino)ethylamide of 1 (2) and 2-(N,N-dimethylamino)ethylamide of N-fructopyranosyl-28,29-didehydronystatin A(1) (2a) were then selected for further evaluation in a mouse model of disseminated candidosis, and showed high efficacy while being considerably less toxic than amphotericin B (AmB). The compound with improved water solubility (2G, L-glutamic acid salt of 2) showed better chemotherapeutic activity than AmB in the mouse model of candidosis sepsis on a leucopenic background. Very low antifungal effect was seen after treatment with AmB, even if it was used in maximum tolerated dose (2 mg kg(-1)). Unlike AmB, compound 2G exhibited high activity in doses from 0.4 up to 4.0 mg kg(-1), despite leucopenic conditions.

Twenty-three new derivatives of the heptaene nystatin analogue 28,29-didehydronystatin A(1) (1) (S44HP) were obtained by chemical modification of C16 carboxyl and amino groups of mycosamine. These derivatives comprised 15 carboxamides, 4 N-alkyl derivatives, 3 N-derivatives containing additional N-linked monosaccharide or disaccharide moiety (products of Amadori rearrangement), and 1 N-aminoacyl derivative. The derivatives have been tested in vitro against yeasts Candida albicans, Cryptococcus humicolus, and filamentous fungi (molds) Aspergillus niger and Fusarum oxysporum, as well as for hemolytic activity against human erythrocytes. Structure-activity relationships for the compounds obtained are discussed. The most active and least hemolytic derivative 3-(N,N-dimethylamino)propylamide of S44HP (6) was tested for acute toxicity and antifungal activity in animal model. Whereas amphotericin B and S44HP were active in vivo at doses close to the maximal tolerated dose, 6 was considerably less toxic and more active compared to these two antibiotics.

Olivomycin (DNA-binding antibiotic) in nanomolar concentrations induces apoptosis of human tumor cells and inhibits p53-dependent transcription of the reporter gene (basal and induced by antitumor drugs). Olivomycin aglycon induces no cytotoxicity and does not block transcription.