Olivomycin

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Category New Products
Catalog number BBF-05718
CAS 11006-70-5
Molecular Weight 941
Molecular Formula C45H64O21

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Description

Olivomycin is an antitumor antibiotic produced by Actinomyces (or Streptomyces) olivoreticuli. It is used for the treatment of testicular neoplasms, tonsillar tumors and reticulosarcoma with peripheral nodes.

Specification

Synonyms Toyomycin R; Olivomicina; Olivomycinum
IUPAC Name (2S,3S)-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-2-[(2R,4S,5S,6S)-4-[(4S,5R,6S)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-8,9-dihydroxy-6-[(2S,4R,5S,6R)-5-hydroxy-4-[(2S,4S,5S,6S)-4-hydroxy-5-methoxy-6-methyloxan-2-yl]oxy-6-methyloxan-2-yl]oxy-3,4-dihydro-2H-anthracen-1-one
Canonical SMILES CC1C(C(CC(O1)OC2CC(OC(C2O)C)OC3C(CC4=CC5=CC(=CC(=C5C(=C4C3=O)O)O)OC6CC(C(C(O6)C)O)OC7CC(C(C(O7)C)OC)O)C(C(=O)C(C(C)O)O)OC)O)O
InChI InChI=1S/C45H64O21/c1-16(46)36(50)42(56)44(58-7)24-10-22-8-21-9-23(63-32-14-28(38(52)18(3)60-32)65-31-13-27(49)43(57-6)20(5)62-31)11-25(47)34(21)40(54)35(22)41(55)45(24)66-33-15-29(39(53)19(4)61-33)64-30-12-26(48)37(51)17(2)59-30/h8-9,11,16-20,24,26-33,36-39,43-54H,10,12-15H2,1-7H3/t16-,17+,18-,19+,20+,24+,26+,27+,28-,29+,30?,31+,32+,33-,36+,37+,38+,39+,43-,44+,45+/m1/s1
InChI Key CZDBNBLGZNWKMC-MWQNXGTOSA-N

Properties

Antibiotic Activity Spectrum Neoplastics (Tumor)

Reference Reading

1. Discrimination between G/C Binding Sites by Olivomycin A Is Determined by Kinetics of the Drug-DNA Interaction
Artemy D Beniaminov, Galina V Chashchina, Mikhail A Livshits, Olga I Kechko, Vladimir A Mitkevich, Olga K Mamaeva, Anna N Tevyashova, Alexander A Shtil, Anna K Shchyolkina, Dmitry N Kaluzhny Int J Mol Sci. 2020 Jul 26;21(15):5299. doi: 10.3390/ijms21155299.
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-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-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.
2. Differential Impact of Random GC Tetrad Binding and Chromatin Events on Transcriptional Inhibition by Olivomycin A
Alexandra K Isagulieva, Dmitry N Kaluzhny, Artemy D Beniaminov, Nataliya V Soshnikova, Alexander A Shtil Int J Mol Sci. 2022 Aug 9;23(16):8871. doi: 10.3390/ijms23168871.
Olivomycin A (OA), an antibiotic of the aureolic acid family, interferes with gene transcription upon forming complexes with GC-rich regions in the DNA minor groove. We demonstrate that the mechanism of transcriptional deregulation is not limited to OA interaction with GC-containing binding sites for transcription factors. Using electrophoretic mobility shift assays and DNAse I footprinting of cytomegalovirus (CMV) promoter fragments carrying OA-preferred GC tetrads (CMVwt), we showed OA binding specifically to GC islands. Replacement of G for A in these tetrads (CMVmut) abrogated OA binding. Furthermore, OA decreased RNA polymerase II (RNAPII) binding to the CMVwt promoter and inhibited the reporter gene expression. In line with the absence of OA binding sites in CMVmut DNA, the expression driven from this promoter was weakly sensitive to OA. In the endogenous genes OA decreased RNAPII on promoters and coding regions. In certain cases this phenomenon was concomitant with the increased histone 3 abundance. However, the sensitivity to OA did not correlate with GC patterns around transcription start sites, suggesting that certain GC stretches play unequal roles in OA-induced transcriptional perturbations. Thus, OA affects transcription via complex mechanisms in which GC tetranucleotide binding causes RNAPII/chromatin alterations differentially manifested in individual gene contexts.
3. The Effect of Antitumor Antibiotic Olivomycin A and Its New Semi-synthetic Derivative Olivamide on the Activity of Murine DNA Methyltransferase Dnmt3a
A V Sergeev, A N Tevyashova, A P Vorobyov, E S Gromova Biochemistry (Mosc). 2019 Jan;84(1):62-70. doi: 10.1134/S0006297919010085.
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.

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