| Revision as of 18:36, 23 May 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (changes to watched fields - updated 'UNII_Ref', 'ChEMBL_Ref') per Chem/Drugbox validation (report errors or [[user talk:CheMoBot|bug← Previous edit |
Latest revision as of 07:53, 18 February 2024 edit undoInternetArchiveBot (talk | contribs)Bots, Pending changes reviewers5,382,322 edits Rescuing 0 sources and tagging 1 as dead.) #IABot (v2.0.9.5 |
| (50 intermediate revisions by 26 users not shown) |
| Line 1: |
Line 1: |
|
|
{{Short description|Anti-cancer drug}} |
|
{{chembox |
|
{{chembox |
|
|
|verifiedrevid = 430550712 |
|
| Watchedfields = changed |
|
|
|
|ImageFile = Dynemicin A.svg |
|
| verifiedrevid = 430383596 |
|
|
|
|IUPACName = (1''S'',4''R'',4a''R'',14''S'',14a''S'',18''Z'')-6,8,11-trihydroxy-3-methoxy-1-methyl-7,12-dioxo-1,4,7,12,13,14-hexahydro-4a,14a-epoxy-4,14-hexenediynonaphthophenanthridine-2-carboxylic acid |
|
| ImageFile = Dynemicin A.svg |
|
|
|
|OtherNames = (2R,4S,5S,8R,11Z,15S)-21,24,28-trihydroxy-7-methoxy-5-methyl-19,26-dioxo-3-oxa-16-azaheptacyclononacosa-1(29),6,11,17,20,22,24,27-octaen-9,13-diyne-6-carboxylic acid |
|
| ImageSize = 200px |
|
|
|
|Section1={{Chembox Identifiers |
|
| IUPACName = (1''S'',4''R'',4a''R'',14''S'',14a''S'',18''Z'')-6,8,11-trihydroxy-3-methoxy-1-methyl-7,12-dioxo-1,4,7,12,13,14-hexahydro-4a,14a-epoxy-4,14-hexenediynonaphthophenanthridine-2-carboxylic acid |
|
|
|
|CASNo = 124412-57-3 |
|
| OtherNames = |
|
|
|
|CASNo_Ref = {{cascite|correct|CAS}} |
|
| Section1 = {{Chembox Identifiers |
|
|
|
|UNII_Ref = {{fdacite|correct|FDA}} |
|
| Abbreviations = |
|
|
|
|UNII = D3G8N2863A |
|
| CASNo = 124412-57-3 |
|
|
|
|PubChem = 10030135 |
|
| CASNo_Ref = {{cascite|correct|CAS}} |
|
|
| EINECS = |
|
|ChEMBL = 2152479 |
|
|
|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
| PubChem = 10030135 |
|
|
|
|ChemSpiderID = 8205706 |
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
|
|
|SMILES = C1C(=C(2C#C/C=C\C#C3142(O4)c5cc(c6c(c5N3)C(=O)c7c(ccc(c7C6=O)O)O)O)OC)C(=O)O |
|
| ChemSpiderID = 8205706 |
|
|
|
|StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
| SMILES = C1C(=C(2C#C/C=C\C#C3142(O4)c5cc(c6c(c5N3)C(=O)c7c(ccc(c7C6=O)O)O)O)OC)C(=O)O |
|
|
|
|StdInChI=1S/C30H19NO9/c1-12-19(28(37)38)27(39-2)13-7-5-3-4-6-8-18-29(12)30(13,40-29)14-11-17(34)22-23(24(14)31-18)26(36)21-16(33)10-9-15(32)20(21)25(22)35/h3-4,9-13,18,31-34H,1-2H3,(H,37,38)/b4-3-/t12-,13+,18-,29-,30+/m0/s1 |
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
|
|
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChI=1S/C30H19NO9/c1-12-19(28(37)38)27(39-2)13-7-5-3-4-6-8-18-29(12)30(13,40-29)14-11-17(34)22-23(24(14)31-18)26(36)21-16(33)10-9-15(32)20(21)25(22)35/h3-4,9-13,18,31-34H,1-2H3,(H,37,38)/b4-3-/t12-,13+,18-,29-,30+/m0/s1 |
|
|
|
|StdInChIKey = AFMYMMXSQGUCBK-AKMKHHNQSA-N |
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
|
|
}} |
|
| StdInChIKey = AFMYMMXSQGUCBK-AKMKHHNQSA-N |
|
|
|
|Section2={{Chembox Properties |
|
| RTECS = |
|
|
|
|Formula = C<sub>30</sub>H<sub>19</sub>NO<sub>9</sub> |
|
| MeSHName = |
|
|
|
|MolarMass = 537.473 |
|
| ChEBI = |
|
|
|
}} |
|
| KEGG_Ref = {{keggcite|correct|kegg}} |
|
|
| KEGG = |
|
|
| ATCCode_prefix = |
|
|
| ATCCode_suffix = |
|
|
| ATC_Supplemental = |
|
|
}} |
|
|
|
|
|
| Section2 = {{Chembox Properties |
|
|
| Formula = C<sub>30</sub>H<sub>19</sub>NO<sub>9</sub> |
|
|
| MolarMass = 537.473 |
|
|
| Appearance = |
|
|
| Density = |
|
|
| MeltingPt = |
|
|
| Melting_notes = |
|
|
| BoilingPt = |
|
|
| Boiling_notes = |
|
|
| Solubility = |
|
|
| SolubleOther = |
|
|
| Solvent = |
|
|
| pKa = |
|
|
| pKb = |
|
|
}} |
|
|
|
|
|
| Section7 = {{Chembox Hazards |
|
|
| ExternalMSDS = |
|
|
| EUClass = |
|
|
| EUIndex = |
|
|
| MainHazards = |
|
|
| NFPA-H = |
|
|
| NFPA-F = |
|
|
| NFPA-R = |
|
|
| NFPA-O = |
|
|
| RPhrases = |
|
|
| SPhrases = |
|
|
| RSPhrases = |
|
|
| FlashPt = |
|
|
| Autoignition = |
|
|
| ExploLimits = |
|
|
| PEL = |
|
|
}} |
|
|
}} |
|
}} |
|
|
|
|
|
'''Dynemicin A''' is an anti-cancer ] drug. It displays properties which illustrate promise for innovative ] treatments, but still requires further research. |
|
'''Dynemicin A''' is an anti-cancer ] drug. It displays properties which illustrate promise for ] treatments, but still requires further research. |
|
|
|
|
|
==History and background== |
|
== History and background == |
|
Dynemicin A was first isolated from the soil in the ] of ]. It was discovered to be the natural product of the indigenous bacteria, ''Micromonospora chernisa''. The natural product displays a bright purple color due to the ] ] structure within Dynemicin A. Initially this compound was isolated for its aesthetic properties as a dye, until further research demonstrated its anti-cancer properties. Shortly after the compound’s discovery, the Bristol-Myers Pharmaceutical Company first elucidated the structure in ]. The structure of dynemicin A was determined from ] studies of triacetyldynemicin A; a closely related compound. |
|
Dynemicin A was first isolated from the soil in the ] of ]. It was discovered to be the natural product of the indigenous bacteria '']''. The natural product displays a bright purple color due to the ] ] structure within it. Initially, this compound was isolated for its aesthetic properties as a dye until further research demonstrated its anti-cancer properties. Shortly after the compound's discovery, the Bristol-Myers Pharmaceutical Company elucidated the structure in ] using ] studies of triacetyldynemicin A; a closely related compound. |
|
|
|
|
|
==Synthesis == |
|
== Synthesis == |
|
|
The first reported chemical synthesis of dynemicin was accomplished by Myers and coworkers.<ref>{{cite journal|last1=Myers|first1=AG|last2=Fraley|first2=ME|last3=Tom|first3=NJ|last4=Cohen|first4=SB|last5=Madar|first5=DJ|title=Synthesis of (+)-dynemicin A and analogs of wide structural variability: establishment of the absolute configuration of natural dynemicin A.|journal=Chemistry & Biology|date=January 1995|volume=2|issue=1|pages=33–43|pmid=9383401|doi=10.1016/1074-5521(95)90078-0|doi-access=free}}</ref> |
|
The early steps of the synthesis process of dynemicin A are catalyzed by a ] ] (Dyn E8) and a ] (DynE7), however the exact mechanism for the complete synthesis of the natural compound is not fully understood. Currently, there are several proposed mechanisms demonstrating the synthesis of Dynemicin A; however they have only been proven in a laboratory setting. These proposed mechanisms have incorporated retrosynthesis to help illustrate the mechanism utilized by the bacterium. |
|
|
|
|
|
|
|
== Biosynthesis == |
|
Although several pathways exist for the synthesis of dynemicin A, below is the mechanism suggested by the ] Company. This pathway for the synthesis of dynemicin A is currently the most widely accepted model. |
|
|
|
Dynemicin A is an antitumor natural product isolated from ''Micromonospora chersina'' which causes DNA strand cleavage. Iwasaki et al. first studied the biosynthetic pathway of Dynemicin A by <sup>13</sup>C NMR labeling experiments.<ref>{{cite journal | last1 = Tokiwa | first1 = Y. | last2 = Miyoshi-Saitoh | first2 = M. | last3 = Kobayashi | first3 = H. | last4 = Sunaga | first4 = R. | last5 = Konishi | first5 = M. | last6 = Oki | first6 = T. | last7 = Iwasaki | first7 = S | year = 1992 | title = Biosynthesis of dynemicin A, a 3-ene-1,5-diyne antitumor antibiotic| journal = J. Am. Chem. Soc. | volume = 114 | issue = 11| pages = 4107–4110 | doi=10.1021/ja00037a011}}</ref> Dynemicin A is thought to be biosynthesized separately from two different heptaketide chains originated from seven head-to-tail coupled acetate units, which is then connected to form Dynemicin A. Initially, precursors such as 3 and 4 were proposed to derive from the oleate/crepenynate pathway, as initially put forth for NSC Chrom A biosynthesis.<ref>{{cite journal | last1 = Hensens | first1 = O. D. | last2 = Giner | first2 = J. | last3 = Goldberk | first3 = I. H | year = 1989 | title = Biosynthesis of NCS Chrom A, the chromophore of the antitumor antibiotic neocarzinostatin| journal = J. Am. Chem. Soc. | volume = 111 | issue = 9| pages = 3295–3299 | doi=10.1021/ja00191a028}}</ref> However, recent work by Thorson and coworkers revealed the biosynthesis of the dynemicin enediyne core to be catalyzed by an enediyne polyketide synthase (PKSE) similar to that employed in ] biosynthesis.<ref>{{cite journal|last1=Liu|first1=W|last2=Ahlert|first2=J|last3=Gao|first3=Q|last4=Wendt-Pienkowski|first4=E|last5=Shen|first5=B|last6=Thorson|first6=JS|title=Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=14 October 2003|volume=100|issue=21|pages=11959–63|pmid=14528002|doi=10.1073/pnas.2034291100|pmc=218695|bibcode=2003PNAS..10011959L|doi-access=free}}</ref><ref>{{cite journal|last1=Gao|first1=Q|last2=Thorson|first2=JS|title=The biosynthetic genes encoding for the production of the dynemicin enediyne core in Micromonospora chersina ATCC53710.|journal=FEMS Microbiology Letters|date=May 2008|volume=282|issue=1|pages=105–14|pmid=18328078|doi=10.1111/j.1574-6968.2008.01112.x|pmc=5591436}}</ref> |
|
|
|
|
|
|
] |
|
==Mechanism of action== |
|
|
Dynemicin A is specific for ], and functions by intercalating into the minor groove of the ]. For intercalation to occur the separation between strands which is usually 3-4 ] needs to be widened to 7-8 ] to allow enough space for the ligand to bind. Given this the DNA must be strained to accommodate the Dynemicin A resulting in an induced fit-like process. Once intercalated within the DNA the epoxide is activated in one of two ways. First, if ] or a thiol reduces the molecule the Bergman re-cyclization of the ] proceeds. Second if a ] mechanism is utilized then the retro-Bergman re-cyclization of the ] is used. The final products of these two mechanisms are outlined below. When the re-cyclization occurs, the conformational changes and chemical reactions taking place result in a non-reversible double stranded cleavage of the ], leading to in cell death. This mechanism is extremely cytotoxic because ] and ] cells alike do not possess a mechanism to repair a double stranded cleavage of their DNA. During in vitro studies the molecule showed an increased affinity for a specific 10 base pair sequence (CTACTACTTG). In vivo studies have yet to confirm this phenomenon. Professor Martin Semmelhack from ] was the first person to propose the ] reduction pathway. |
|
|
|
|
|
|
|
== Mechanism of action == |
|
==Pharmacological properties== |
|
|
|
Dynemicin A is specific for ], and functions by ] into the minor groove of the ]. For intercalation to occur, the separation between strands, which is usually 3-4 ], needs to be widened to 7-8 ] to allow enough space for the ] to bind. Given this, the DNA must be strained to accommodate the Dynemicin A, resulting in an induced fit-like process. Once intercalated within the DNA, the epoxide is activated in one of two ways. First, if ] or a ] reduces the molecule the Bergman re-cyclization of the ] proceeds. Second, if a ] mechanism is utilized then the retro-Bergman re-cyclization of the ] is used. The final products of these two mechanisms are outlined below. When the re-cyclization occurs, the conformational changes and chemical reactions taking place result in an irreversible double stranded cleavage of the ], leading to cell death. During ] studies, the molecule showed an increased affinity for the specific 10 base pair sequence CTACTACTTG. However, ] studies have yet to confirm this phenomenon. Professor Martin Semmelhack of ] was the first person to propose the ] reduction pathway. |
|
The pharmacological properties of this drug have not yet been fully explored but currently suggest that it may be a more potent anti-cancer agent than other chemotherapeutic drugs. The bacterium is believed to use dynemicin A as an antibacterial agent to help it survive in its niche in the environment. Dynemicin A, as a drug, specifically targets ] and is most effective in rapidly dividing cells. The broad spectrum of the drug prevents current use because it creates unwanted damage in normal healthy tissues. ] studies in mice and rats suggest that the treatment is most effective in ], breast and lung cancers. Synthetic alternatives which are more specific to ] cells and leave healthy tissues unharmed are being researched. Other animal models are available but have proven ineffective and therefore there are currently no human trials underway. The ] property of this drug relates to another antibiotic known as ] which is approved for clinical use. As with dynemicin A, ] also interacts with DNA. |
|
|
|
|
|
|
== Pharmacological properties == |
|
|
The pharmacological properties of this drug have not yet been fully explored but currently suggest that it may be a more potent anti-cancer agent than other chemotherapeutic drugs. The bacterium is believed to use dynemicin A as an antibacterial agent to help it survive in its niche in the environment. Dynemicin A, as a drug, specifically targets ] and is most effective in rapidly dividing cells. The broad spectrum of the drug prevents current use because it creates unwanted damage in normal healthy tissues. In vivo studies in mice and rats suggest that the treatment is most effective in ], breast, and lung cancers. Synthetic alternatives which are more specific to ] cells and leave healthy tissues unharmed are being researched. Other animal models are available, but have proven ineffective and therefore have no human trials currently underway. The ] property of this drug relates to another antibiotic known as ] which is approved for clinical use. As with dynemicin A, ] also interacts with DNA. |
|
|
|
|
|
== References == |
|
== References == |
| Line 84: |
Line 49: |
|
{{refstyle|date=May 2011}} |
|
{{refstyle|date=May 2011}} |
|
{{Reflist}} |
|
{{Reflist}} |
|
|
|
|
*ElSohly, Adel. "Dynemicin A: Molecule in Review." Columbia University. 12 June 2009. |
|
|
|
== Notes == |
|
*Liew, C. W., A. Scharff, M. Kotaka, R. Kong, H. Sun, I. Qureshi, G. Bricogne, Z. Liang, and J. Lescar. "Induced-fit upon Ligand Binding Revealed by Crystal Structures of the Hot-dog Fold Thioesterase in Dynemicin Biosynthesis." J Mol Bio 404 (2010): 291-306. |
|
|
|
* ElSohly, Adel. "Dynemicin A: Molecule in Review." Columbia University. 12 June 2009. |
|
*Nicolaou, K. C., S. A. Snyder, A. G. Meyers, and S. J. Danishefsky. "Dynemicin A." Classics in Total Synthesis II: More Targets, Strategies, Methods. Weinheim: Wiley-VCH, 2003. 75-107. |
|
|
|
* {{cite journal | last1 = Liew | first1 = C. W. | last2 = Scharff | first2 = A. | last3 = Kotaka | first3 = M. | last4 = Kong | first4 = R. | last5 = Sun | first5 = H. | last6 = Qureshi | first6 = I. | last7 = Bricogne | first7 = G. | last8 = Liang | first8 = Z. | last9 = Lescar | first9 = J. | year = 2010 | title = Induced-fit upon Ligand Binding Revealed by Crystal Structures of the Hot-dog Fold Thioesterase in Dynemicin Biosynthesis | journal = J. Mol. Biol. | volume = 404 | issue = 2| pages = 291–306 | doi=10.1016/j.jmb.2010.09.041 | pmid=20888341}} |
|
*Schulz-Aellen, Marie-Françoise. "Cancer Drugs." Aging and Human Longevity. Boston: Birkhäuser, 1997. 203-04 |
|
|
|
* Nicolaou, K. C., S. A. Snyder, A. G. Meyers, and S. J. Danishefsky. "Dynemicin A." Classics in Total Synthesis II: More Targets, Strategies, Methods. Weinheim: Wiley-VCH, 2003. 75–107. |
|
*Silverman, Richard B. "Dynemicin A." The Organic Chemistry of Drug Design and Drug Action. Amsterdam: Elsevier Academic, 2004. 381-85 |
|
|
|
* Schulz-Aellen, Marie-Françoise. "Cancer Drugs." Aging and Human Longevity. Boston: Birkhäuser, 1997. 203-04 |
|
*Tuttle, Tell, Elfi Kraka, and Dieter Cremer. "Docking, Triggering, and Biological Activity of Dynemicin A in DNA: A Computational Study." Journal of the American Chemical Society 127.26 (2005): 9469-484 |
|
|
|
* Silverman, Richard B. "Dynemicin A." The Organic Chemistry of Drug Design and Drug Action. Amsterdam: Elsevier Academic, 2004. 381-85 |
|
*Tuttle, Tell, Elfi Kraka, Walter Theil, and Dieter Cremer. "A QM/MM Study of the Bergman Reaction of Dynemicin A in the Minor Groove of DNA." J Phys Chem 111 (2007): 8321-328. |
|
|
|
* {{cite journal | last1 = Tuttle | first1 = Tell | last2 = Kraka | first2 = Elfi | last3 = Cremer | first3 = Dieter | year = 2005 | title = Docking, Triggering, and Biological Activity of Dynemicin A in DNA: A Computational Study | journal = Journal of the American Chemical Society | volume = 127 | issue = 26| pages = 9469–484 | doi=10.1021/ja046251f | pmid=15984874}} |
|
|
* {{cite journal | last1 = Tuttle | first1 = Tell | last2 = Kraka | first2 = Elfi | last3 = Theil | first3 = Walter | last4 = Cremer | first4 = Dieter | year = 2007 | title = A QM/MM Study of the Bergman Reaction of Dynemicin A in the Minor Groove of DNA | journal = J Phys Chem | volume = 111 | issue = 28| pages = 8321–328 | doi=10.1021/jp072373t| pmid = 17585802 }} |
|
|
|
|
|
== External links == |
|
== External links == |
|
*http://www.columbia.edu/cu/chemistry/groups/synth-lit/MIR2009/2009_06_12-AElsohly-Dynemycin.pdf |
|
* https://web.archive.org/web/20100626231055/http://www.columbia.edu/cu/chemistry/groups/synth-lit/MIR2009/2009_06_12-AElsohly-Dynemycin.pdf |
|
*http://www.pdb.org/pdb/explore/pubmedArticle.do?structureId=2XFL# |
|
* http://www.pdb.org/pdb/explore/pubmedArticle.do?structureId=2XFL#{{Dead link|date=February 2024 |bot=InternetArchiveBot |fix-attempted=yes }} |
|
*http://books.google.com/books?id=PE587tLs3w0C&pg=PA76&lpg=PA76&dq=Bristol-Myers+structure+dynemicin+a&source=bl&ots=X-l9kgIwfu&sig=H6RCeET9W75_KSupYJhxx3gYRsc&hl=en&ei=_CG6TdWJL8rz0gHYusRt&sa=X&oi=book_result&ct=result&resnum=5&ved=0CDgQ6AEwBA#v=onepage&q=Bristol-Myers%20structure%20dynemicin%20a&f=false |
|
* https://books.google.com/books?id=PE587tLs3w0C&dq=Bristol-Myers+structure+dynemicin+a&pg=PA76 |
|
*http://books.google.com/books?id=7l6IOF2t3vIC&pg=PA203&lpg=PA203&dq=where+does+dynemicin+a+come+from&source=bl&ots=fcczlI2BvW&sig=mUWUqTwG283RgGvAxUARhqMJNcw&hl=en&ei=GKe0TabeNouO0QGSwPSfCQ&sa=X&oi=book_result&ct=result&resnum=1&ved=0CBYQ6AEwAA#v=onepage&q=dynemycin&f=false |
|
* https://books.google.com/books?id=7l6IOF2t3vIC&q=dynemycin&pg=PA203 |
|
*http://smu.edu/catco/pdf/jacs_127_9469.pdf |
|
* https://web.archive.org/web/20120405090957/http://smu.edu/catco/pdf/jacs_127_9469.pdf |
|
*http://smu.edu/catco/pdf/JPC-B_111_8321.pdf |
|
* https://web.archive.org/web/20121001181112/http://smu.edu/catco/pdf/JPC-B_111_8321.pdf |
|
*http://www.britannica.com/EBchecked/media/81/Examples-of-anthraquinone-pigments |
|
* http://www.britannica.com/EBchecked/media/81/Examples-of-anthraquinone-pigments |
|
*http://www.chem.strath.ac.uk/people/academic/tell_tuttle/research/qmmm |
|
* http://www.chem.strath.ac.uk/people/academic/tell_tuttle/research/qmmm |
|
|
|
|
|
{{Enediynes}} |
|
|
|
|
|
] |
|
|
] |
|
] |
|
] |
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |