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Role of the Acyl Groups in Carbohydrate Chains in Cytotoxic Properties of Olivomycin A

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Role of the Acyl Groups in Carbohydrate Chains in Cytotoxic Properties of Olivomycin A The Journal of Antibiotics (2013) 66, 523–530 & 2013 Japan Antibiotics Research Association All rights reserved 0021-8820/13 www.nature.com/ja ORIGINAL ARTICLE Role of the acyl groups in carbohydrate chains in cytotoxic properties of olivomycin A Anna N Tevyashova1, Nikita A Durandin2, Alexander M Vinogradov2, Victor B Zbarsky1, Marina I Reznikova1, Lyubov G Dezhenkova1, Eugeniy E Bykov1, Eugenia N Olsufyeva1, Vladimir A Kuzmin2, Alexander A Shtil3 and Maria N Preobrazhenskaya1 A series of olivomycin A derivatives containing different combinations of the acyl residues in the carbohydrate chains was obtained. The formation of complexes of Mg2 þ -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 2 þ the values of binding constants of complexes (antibiotic)2Mg –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 2 þ A-sugar residue is involved, to the most part, in the antibiotic–antibiotic interactions in the (olivomycin)2Mg dimers, whereas the 2 þ O-acyl group in E-olivomicose residue largely participates in the formation of the (olivomycin)2Mg –DNA complexes. The Journal of Antibiotics (2013) 66, 523–530; doi:10.1038/ja.2013.39; published online 22 May 2013 Keywords: aureolic acid antibiotics; cytotoxicity; olivomycin A; quantum chemical calculations; spectroscopy; structure–activity relationships; topoisomerase I inhibitors INTRODUCTION hydrolysis of carbohydrate chains in chromomycin A3 was Olivomycin A (1, Scheme 1) is a member of the aureolic acid family paralleled by a concomitant decrease of cytotoxicity.9 Moreover, it of antibiotics. This group of highly potent agents tentatively applic- has been demonstrated that the absence of the D-mycarose residue able in the clinic also includes mithramycin and chromomycins (E-sugar) of the trisaccharide branch of mithramycin decreased (Figure 1).1 antiproliferative activity of the mithramycin analog by one order of The aureolic acid derivatives contain a tricyclic chromophore magnitude.10 A combinatorial biosynthesis approach used to generate (aglycon) glycosylated at positions 6 and 2 with di- and trisaccharides, derivatives of the antitumor drug mithramycin with glycosylation respectively. The structures of olivomycins and chromomycins are profiles different from that of the parental compound revealed that very similar; the main difference is the presence of the 7-methyl group the presence of all five sugars is not absolutely essential for the in the chromomycin aglycon (Scheme 1, Figure 1). Total synthesis of antitumor activity of mithramycin.10 olivomycin A (1) has been described.2 Mithramycin carries the same Mithramycin lacks the O-acyl substituents in polysaccharide aglycon as chromomycin A3 but different sugar moieties (Figure 1). branches, and it has a lower DNA sequence preference than chromo- 11 The cytotoxicity of these compounds for mammalian cells has been mycin A3. The acetyl groups in the sugars of chromomycins are ascribed to their remarkably potent inhibitory effects on DNA- critical for the activity. Three tailoring modification steps occur dependent enzymatic processes including replication, transcription during chromomycin A3 biosynthesis, affecting the sugar moieties: and control of duplex topology due to the formation of non- two O-acetylations and one O-methylation.12 Acetylation of the 2 þ intercalative, Mg -containing complexes with GC-rich regions in E-sugar moiety is the ultimate step in chromomycin A3 the DNA minor groove.3–8 In these complexes, the compound acts as biosynthesis, being important for self-protection of the producing a bidentate ligand, coordinating the metal through a phenol (C9-OH) organism, as this step yields a more toxic antibiotic. The conversion of 5 group and the neighboring ketone oxygen (C1-O). a low-active molecule into a potent one is catalyzed by the enzyme The carbohydrate moieties are essential for biological properties of predicted to be located in the bacterial cell wall.12 Moreover, it has 1 these antibiotics. It has been demonstrated that the sequential been recently reported that deacetylchromomycin A3 obtained from 1Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia; 2Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia and 3Blokhin Cancer Center, Russian Academy of Medical Sciences, Moscow, Russia Correspondence: Professor MN Preobrazhenskaya, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 B. Pirogovskaya Street, Moscow 119021, Russia. E-mail: [email protected] Received 24 December 2012; revised 27 March 2013; accepted 5 April 2013; published online 22 May 2013 Acyl groups in cytotoxicity of olivomycin A AN Tevyashova et al 524 OCH3 CH3 OCH O 3 OCOCH3 CH3 HO 5' A4 OCH3 OH O OCOCH CH3 5 10 4 4' HO 3 B-olivomose 3 2' CH3 OCH OH O O O 3 1' 3' CH3 6 CH3 O OH O O O 7 A-oliose 8 9 1 2 O OH OH OH O O Alkali hydrolysis olivin OH OH O O H3C H3C HO O O O H3C HO O H3C HO O E-olivomicose C-olivose O O HO O O CH3 D-olivose H3C O O CH3 H3C O E4 HO HO HO H3C CH 3 Olivomycin A (1) De-E4-isobutyrylolivomycin A (4) OCH3 CH3 OCH3 O OH CH HO 3 OCH OH O OH CH 3 HO 3 CH OCH OH O O 3 3 O CH3 O CH3 O OH O O O OH OH OH O O OH OH O Alkali hydrolysis O H3C H3C HO O O O H3C HO H3C HO O O O O HO O CH3 O H3C O O CH3 H3C O HO HO HO H3C CH3 Olivomycin C (2) De-E4-isobutyrylolivomycin C (5) OCH3 CH3 O OCOCH HO 3 OH OCH CH3 3 O O O CH3 O OH OH OH O O CH3 CH3 HO O HO O O O CH3 H3C O O O OH CH 3 Olivomycin B (3) Scheme 1 Structures and synthesis of olivomycins 1–5. the marine-derived Streptomyces species SNB-005 strain demonstrated of selective hydrolysis of E4-isobutyryl group of olivomycins 13 a decreased cytotoxicity compared with chromomycin A3. (Scheme 1). It allowed investigating structure–activity relationships Whereas chromomycins and mithramycin have been intensively for a series of olivomycins 1–5, which have different combinations of studied, olivomycin A (1) was investigated mainly in the last century, the acyl resides in sugar moieties. and structure–activity relationships for 1 are much less established. It has been shown that the structure of the sugar moieties in the RESULTS saccharides is a major factor of 1–DNA complex formation, as the The natural antibiotics 1–3 were isolated from the olivomycin latter parameter has been directly attributed to the cytotoxicity of 1.14 complex obtained by fermentation of Streptoverticillum cinnamoneum In the present study, we elucidated the role of the acyl substituents strain and purified by column chromatography on silica gel in sugar moieties in anticancer properties of 1, namely, the drug– and semipreparative HPLC. The obtained compounds 1–3 were DNA complex formation, the interference with the catalytic function totally identical to natural olivomycins A, C and B, respectively, by of the DNA-dependent enzyme topoisomerase I (topo I) and the spectral characteristics.15 Two semisynthetic derivatives, de-E4- cytotoxicity for cultured human tumor cells. To this aim we isobutyrylolivomycin A (4) and de-E4-isobutyrylolivomycin C (5), considered three natural aureolic acid antibiotics: olivomycin A (1), were obtained by selective alkaline hydrolysis of E4-O-isobutyryl olivomycin C (2) and olivomycin B (3),15 and elaborated the methods group in 1 or 2, respectively (Scheme 1). Additional purification of 4 The Journal of Antibiotics Acyl groups in cytotoxicity of olivomycin A AN Tevyashova et al 525 H CO 3 CH3 OAcO HO OCH3 OH CH3 O CH3 B O O 7 O OH A H3C OH OH O O Chromomycin A3 H3C H3C HO O O O HO O C D CH3 H3C AcO O HO E OH H3C OCH3 H3C HO O HO O O CH3 O HO O OH A 7 B H3C OH OH O O Mithramycin OHCH H3C 3 HO O H3C O O O O HO C H3C D OH E Figure 1 Structures of chromomycin A3 and mithramycin. and 5 was performed by semipreparative HPLC. The structures of all The full overlap of the normalized absorption spectra of 1 2 þ the obtained compounds were confirmed by H NMR and mass (antibiotic)2Mg complexes of 1–5 (Figure2a)istheevidenceof spectral data obtained by MALDI MS (Table 1). The 1HNMRspectra a weak influence of acyl substituents in sugar residues on the aglycon. of compounds 1–5 contain all the corresponding signals of the On the other hand, noticeable differences in normalized uncorrected 2 þ aglycon moiety and carbohydrate residues, and corresponding acyl fluorescence spectra of (antibiotic)2Mg complexes of 1–5 substituents (if any) (Table 1). (Figure 2b) suggested that the acyl substituents in di- and trisacchar- As chemical acylation of the hydroxyl groups of carbohydrate ide moieties of 1–5 could alter the structure of Mg2 þ dimers. This moieties is accompanied by the simultaneous acylations of the hypothesis was supported by significantly different shape of CD 16 2 þ hydroxyl groups of the aglycon and the side chain, it is not spectra of (antibiotic)2Mg complexes (Figures 3a and b).
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