Cortistatin A
Names
IUPAC name
(1R,2R,3S,5R,8β,17β)-3-(Dimethylamino)-17-(isoquinolin-7-yl)-5,8-epoxy-9,19-cyclo-9,10-secoandrosta-9(11),10-diene-1,2-diol
Other names
Cortistatine A
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • InChI=1S/C30H36N2O3/c1-28-10-8-21-15-23-26(33)27(34)24(32(2)3)16-29(23)11-12-30(21,35-29)25(28)7-6-22(28)19-5-4-18-9-13-31-17-20(18)14-19/h4-5,8-9,13-15,17,22,24-27,33-34H,6-7,10-12,16H2,1-3H3/t22-,24+,25-,26-,27-,28-,29-,30-/m1/s1
    Key: KSGZCKSNTAJOJS-DZBMUNJRSA-N
  • InChI=1/C30H36N2O3/c1-28-10-8-21-15-23-26(33)27(34)24(32(2)3)16-29(23)11-12-30(21,35-29)25(28)7-6-22(28)19-5-4-18-9-13-31-17-20(18)14-19/h4-5,8-9,13-15,17,22,24-27,33-34H,6-7,10-12,16H2,1-3H3/t22-,24+,25-,26-,27-,28-,29-,30-/m1/s1
    Key: KSGZCKSNTAJOJS-DZBMUNJRBJ
  • C[C@]12CC=C3C=C4[C@H]([C@@H]([C@H](C[C@]45CC[C@@]3([C@@H]1CC[C@@H]2c6ccc7ccncc7c6)O5)N(C)C)O)O
Properties
C30H36N2O3
Molar mass 472.629 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

The cortistatins are a group of steroidal alkaloids first isolated in 2006 from the marine sponge Corticium simplex.[1] The cortistatins were first discovered in a search for naturally occurring compounds that inhibit proliferation of human umbilical vein endothelial cells (HUVECs), with cortistatin A being the most potent compound in the class.[2]

The Shair group at Harvard along with collaborators have shown that cortistatin A is a highly potent and selective inhibitor of CDK8 and CDK19, the kinases that associate with Mediator complex.[3] Out of 386 kinases evaluated, cortistatin A only inhibited CDK8 and CDK19, revealing that it is among the most selective kinase inhibitors. It was also shown that cortistatin A potently inhibits growth of acute myeloid leukemia cells and AML in two in vivo mouse models. Identification of dominant drug-resistant alleles of CDK8 and CDK19 demonstrate that these kinases mediate the activity of cortistatin A in AML cells. Thus, inhibition of CDK8 and CDK19 is a new therapeutic approach to AML. Cortistatin A caused selective and disproportionate up-regulation of super-enhancer-associated genes in AML cells which contributed to its anti-leukemic activity. This work indicated that CDK8 and CDK19 are negative regulators of super-enhancer-associated genes in AML.

Di-dehydrocortistatin A suppresses viral replication in cells infected with HIV via binding to the Tat protein.[4]

Cortistatin A was synthesized first by Baran,[5] thereafter by Shair,[6] Myers, and Nicolaou labs.[7]

Chemical structures

References

  1. ↑ Aoki, S; Watanabe, Y; Sanagawa, M; Setiawan, A; Kotoku, N; Kobayashi, M (2006). "Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex". Journal of the American Chemical Society. 128 (10): 3148–9. doi:10.1021/ja057404h. PMID 16522087.
  2. ↑ Aoki, S; Watanabe, Y; Tanabe, D; Arai, M; Suna, H; Miyamoto, K; Tsujibo, H; Tsujikawa, K; Yamamoto, H (2007). "Structure-activity relationship and biological property of cortistatins, anti-angiogenic spongean steroidal alkaloids". Bioorganic & Medicinal Chemistry. 15 (21): 6758–62. doi:10.1016/j.bmc.2007.08.017. PMID 17765550.
  3. ↑ Pelish, Henry E.; Liau, Brian B.; Nitulescu, Ioana I.; Tangpeerachaikul, Anupong; Poss, Zachary C.; Silva, Diogo H. Da; Caruso, Brittany T.; Arefolov, Alexander; Fadeyi, Olugbeminiyi (2015). "Mediator kinase inhibition further activates super-enhancer-associated genes in AML". Nature. 526 (7572): 273–276. Bibcode:2015Natur.526..273P. doi:10.1038/nature14904. PMC 4641525. PMID 26416749.
  4. ↑ Mousseau, G.; Clementz, M. A.; Bakeman, W. N.; Nagarsheth, N.; Cameron, M.; Shi, J.; Baran, P.; Fromentin, R. M.; Chomont, N.; Valente, S. T. (2012). "An Analog of the Natural Steroidal Alkaloid Cortistatin a Potently Suppresses Tat-Dependent HIV Transcription". Cell Host & Microbe. 12 (1): 97–108. doi:10.1016/j.chom.2012.05.016. PMC 3403716. PMID 22817991.
  5. ↑ Shenvi, Ryan A.; Guerrero, Carlos A.; Shi, Jun; Li, Chuang-Chuang; Baran, Phil S. (2008). "Synthesis of (+)-Cortistatin A". Journal of the American Chemical Society. 130 (23): 7241–7243. doi:10.1021/ja8023466. PMC 2652360. PMID 18479104.
  6. ↑ Lee, Hong Myung; Nieto-Oberhuber, Cristina; Shair, Matthew D. (2008-12-17). "Enantioselective Synthesis of (+)-Cortistatin A, a Potent and Selective Inhibitor of Endothelial Cell Proliferation". Journal of the American Chemical Society. 130 (50): 16864–16866. doi:10.1021/ja8071918. ISSN 0002-7863. PMID 19053422. S2CID 207132632.
  7. ↑ Nicolaou, K. C.; Sun, Ya-Ping; Peng, Xiao-Shui; Polet, Damien; Chen, David Y.-K. (2008). "Total Synthesis of (+)-Cortistatin A". Angewandte Chemie International Edition. 47 (38): 7310–7313. doi:10.1002/anie.200803550. PMID 18704899.
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