Esperamycin A1
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| Category | Antibiotics |
| Catalog number | BBF-00870 |
| CAS | |
| Molecular Weight | 1189.28 |
| Molecular Formula | C56H76N4O22S |
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Description
Esperamycin is an enediyne antibiotic produced by Actonomadura verrucaspora. It has strong anti-tumor activity.
Specification
| IUPAC Name | [3-hydroxy-6-[[(4R,5R,8Z,13S)-5-hydroxy-13-[4-hydroxy-5-[(4-hydroxy-6-methyl-5-methylsulfanyloxan-2-yl)oxyamino]-3-[4-methoxy-5-(propan-2-ylamino)oxan-2-yl]oxy-6-methyloxan-2-yl]oxy-2-(methoxycarbonylamino)-3-oxo-4-tricyclo[8.2.1.05,12]trideca-1,8,11-trien-6-ynyl]oxy]-2-methyloxan-4-yl] 4,5-dimethoxy-2-(2-methoxyprop-2-enoylamino)benzoate |
| Canonical SMILES | CC1C(C(C(C(O1)OC2C3C=CC#CC4(C(C(=O)C(=C2C4=C3)NC(=O)OC)OC5CC(C(C(O5)C)O)OC(=O)C6=CC(=C(C=C6NC(=O)C(=C)OC)OC)OC)O)OC7CC(C(CO7)NC(C)C)OC)O)NOC8CC(C(C(O8)C)SC)O |
| InChI | InChI=1S/C56H76N4O22S/c1-24(2)57-33-23-74-39(21-35(33)70-8)79-49-46(63)43(60-82-41-20-34(61)50(83-12)27(5)76-41)25(3)77-54(49)81-48-29-15-13-14-16-56(68)31(17-29)42(48)44(59-55(67)73-11)47(64)51(56)80-40-22-38(45(62)26(4)75-40)78-53(66)30-18-36(71-9)37(72-10)19-32(30)58-52(65)28(6)69-7/h13,15,17-19,24-27,29,33-35,38-41,43,45-46,48-51,54,57,60-63,68H,6,20-23H2,1-5,7-12H3,(H,58,65)(H,59,67)/b15-13-/t25?,26?,27?,29?,33?,34?,35?,38?,39?,40?,41?,43?,45?,46?,48-,49?,50?,51-,54?,56+/m0/s1 |
| InChI Key | PTUJLUSPXWWJSQ-KAOVMFEUSA-N |
Properties
| Appearance | Light Yellow Powder |
| Antibiotic Activity Spectrum | neoplastics (Tumor) |
| Melting Point | 156-158°C(dec.) |
Reference Reading
1. Cytosine methylation enhances DNA damage produced by groove binding and intercalating enediynes: studies with esperamicins A1 and C
P Mathur, J Xu, P C Dedon Biochemistry. 1997 Dec 2;36(48):14868-73. doi: 10.1021/bi971533w.
Methylation of the C5 position of cytosine in CG dinucleotides represents an important element in the control of gene expression in eukaryotic cells. This major groove modification of DNA causes changes in DNA conformation that are recognized by DNA-binding proteins and DNA-damaging chemicals. We have observed that CG methylation affects the DNA damage produced by the enediyne esperamicin A1 and its analog lacking the intercalating anthranilate, esperamicin C. Fragments of the human phosphoglycerate kinase gene (PGK1) and the plasmid pUC19 were methylated with SssI methylase and subjected to damage by esperamicins A1 and C. Damage produced by esperamicin A1 was enhanced 1.5-2-fold near a single CG sequence at position -101 in PGK1 and in a region containing several methylated CG dinucleotides between positions -120 and -131. Esperamicin C-induced damage was enhanced to a similar degree in PGK1 but only at the site that contained multiple CG dinucleotides. There was enhancement of damage for both drugs in the pUC19 fragment at several sites near CG sequences. Analysis of the chemistry of esperamicin-induced DNA damage suggests that cytosine methylation does not affect the identity of drug-abstracted hydrogen atoms. The damage chemistry was also used to identify the DNA binding orientation of the esperamicins. The anthranilate of esperamicin A1 is predicted to intercalate in a CT step four base pairs in a 3'-direction to the CG sequence at -101 in PGK1 and in a CG dinucleotide at the site containing multiple CGs (positions -120 to -131). These observations are consistent with other studies that indicate a long range effect of cytosine methylation on DNA conformation.
2. DNA damage produced by enediynes in the human phosphoglycerate kinase gene in vivo: esperamicin A1 as a nucleosome footprinting agent
J Xu, J Wu, P C Dedon Biochemistry. 1998 Feb 17;37(7):1890-7. doi: 10.1021/bi972508t.
We have used both conventional and a modified version of ligation-mediated polymerase chain reaction (LMPCR) to study the role of chromatin structure in the selection of DNA targets by three DNA-cleaving enediynes in whole cells. On the basis of previous studies of enediyne target selection in nucleosomes, we focused on nucleosomes present in the human X-linked phosphoglycerate kinase (PGK1) gene. Damage produced by esperamicin A1 in cells containing a transcriptionally inactive copy of the X-chromosome is reduced compared to that in naked DNA in two regions that encompass approximately 130 and approximately 150 base pairs upstream of the PGK1 gene. These sizes are consistent with nucleosome core DNA. Damage produced by esperamicin A1 in the transcriptionally active form of the gene, in which nucleosomes are not apparent, did not show such a pattern. Esperamicin C, an analogue of esperamicin A1 lacking an intercalating anthranilate moiety, and calicheamicin, both groove binders, were found to cleave DNA throughout the nucleosome core and linker. These results confirm hypotheses generated from studies in isolated chromatin and reconstituted nucleosomes and suggest that enediynes may prove useful as chromatin footprinting agents.
3. Solution structure of the esperamicin A1-DNA complex
R A Kumar, N Ikemoto, D J Patel J Mol Biol. 1997 Jan 17;265(2):173-86. doi: 10.1006/jmbi.1996.0719.
Esperamicin A1 is an enediyne antibiotic possessing antitumor activity associated with its ability to bind and, following activation, affect strand cleavage of DNA. We report on the solution structure of the esperamicin A1-d(C-G-G-A-T-C-C-G) duplex complex based on a combined analysis of NMR and molecular dynamics calculations including intensity refinement in a water box. The refined solution structures of the complex provide a molecular explanation of the sequence specificity for binding and cleavage by this member of the enediyne family of antitumor antibiotics. Esperamicin A1 binds to the DNA minor groove with its methoxyacrylyl-anthranilate moiety intercalating into the helix at the (G2-G3)-(C6'-C7') step. The methoxyacrylyl-anthranilate intercalator and the minor groove binding A-B-C+ risaccharide moieties rigidly anchor the enediyne in the minor groove such that the pro-radical centers of the enediyne are proximal to their anticipated proton abstraction sites. Specifically, the pro-radical C-3 and C-6 atoms are aligned opposite the abstractable H-5' (pro-S) proton of C6 and the H-1' proton of C6' on partner strands, respectively, in the complex. The thiomethyl sugar B residue is buried deep in an edgewise manner in the minor groove with its two faces sandwiched between the walls of the groove. Further, the polarizable sulfur atom of the thiomethyl group of sugar B residue is positioned opposite and can hydrogen-bond to the exposed amino proton of G3' in the complex. There is little perturbation away from a right-handed Watson-Crick base-paired duplex in the complex other than unwinding of the helix at the intercalation site and widening of the minor groove centered about the enediyne-binding and anthranilate intercalation sites. Sequence-specific binding of esperamicin A1 to the d(C-G-G-A-T-C-C-G) duplex is favored by the complementarity of the fit between the drug and the floor of the minor groove, good stacking between the intercalating anthranilate ring and flanking purine bases and intermolecular hydrogen-bonding interactions.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
