alsterpaullone (CHEBI:138488)

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CHEBI:138488 - alsterpaullone

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ChEBI Name	alsterpaullone

ChEBI ID	CHEBI:138488

Definition	An organic heterotetracyclic compound that is 1,3-dihydro-2H-1-benzazepin-2-one which shares its 4-5 bond with the 3-2 bond of 5-nitro-1H-indole.

Stars	This entity has been manually annotated by the ChEBI Team.

Submitter	Charles Tapley Hoyt

Secondary ChEBI IDs	CHEBI:40939

Supplier Information	ChemicalBook:CB0778141, eMolecules:534252, ZINC000000023894

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Molfile

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The Resolver thinks Mol

Marvin 09130717273D

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Marvin 09130717273D

33 36 0 0 0 0 999 V2000

2.7150 1.6610 0.6360 N 0 0 0 0 0 0 0 0 0 0 0 0

1.5920 2.2560 0.2380 C 0 0 0 0 0 0 0 0 0 0 0 0

0.7060 1.6540 -0.8240 C 0 0 0 0 0 0 0 0 0 0 0 0

1.2730 3.3110 0.7440 O 0 0 0 0 0 0 0 0 0 0 0 0

2.5270 -0.6830 -0.0470 C 0 0 0 0 0 0 0 0 0 0 0 0

3.2690 0.4730 0.1950 C 0 0 0 0 0 0 0 0 0 0 0 0

4.6520 0.4390 0.0030 C 0 0 0 0 0 0 0 0 0 0 0 0

5.2810 -0.7250 -0.3820 C 0 0 0 0 0 0 0 0 0 0 0 0

4.5470 -1.8810 -0.5870 C 0 0 0 0 0 0 0 0 0 0 0 0

3.1790 -1.8620 -0.4280 C 0 0 0 0 0 0 0 0 0 0 0 0

0.2890 -1.7710 0.4880 N 0 0 0 0 0 0 0 0 0 0 0 0

0.2350 0.3130 -0.3190 C 0 0 0 0 0 0 0 0 0 0 0 0

1.0510 -0.7070 0.0450 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.1260 -0.1350 -0.1220 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.0370 -1.4560 0.3910 C 0 0 0 0 0 0 0 0 0 0 0 0

-2.1890 -2.1770 0.6950 C 0 0 0 0 0 0 0 0 0 0 0 0

-3.4010 -1.5460 0.4710 C 0 0 0 0 0 0 0 0 0 0 0 0

-3.4830 -0.2570 -0.0290 C 0 0 0 0 0 0 0 0 0 0 0 0

-2.3650 0.4770 -0.3420 C 0 0 0 0 0 0 0 0 0 0 0 0

-4.8180 0.3460 -0.2400 N 0 3 0 0 0 0 0 0 0 0 0 0

-4.9130 1.4800 -0.6750 O 0 0 0 0 0 0 0 0 0 0 0 0

-5.8230 -0.2900 0.0260 O 0 5 0 0 0 0 0 0 0 0 0 0

-2.4390 1.4790 -0.7360 H 0 0 0 0 0 0 0 0 0 0 0 0

-4.3150 -2.0770 0.6960 H 0 0 0 0 0 0 0 0 0 0 0 0

-2.1390 -3.1830 1.0860 H 0 0 0 0 0 0 0 0 0 0 0 0

0.6410 -2.6120 0.8170 H 0 0 0 0 0 0 0 0 0 0 0 0

1.2720 1.5240 -1.7470 H 0 0 0 0 0 0 0 0 0 0 0 0

-0.1500 2.3040 -1.0030 H 0 0 0 0 0 0 0 0 0 0 0 0

3.2110 2.1230 1.3300 H 0 0 0 0 0 0 0 0 0 0 0 0

5.2350 1.3350 0.1590 H 0 0 0 0 0 0 0 0 0 0 0 0

6.3510 -0.7360 -0.5250 H 0 0 0 0 0 0 0 0 0 0 0 0

5.0460 -2.7960 -0.8710 H 0 0 0 0 0 0 0 0 0 0 0 0

2.6060 -2.7610 -0.5980 H 0 0 0 0 0 0 0 0 0 0 0 0

1 2 1 0 0 0 0

1 6 1 0 0 0 0

1 29 1 0 0 0 0

2 3 1 0 0 0 0

2 4 2 0 0 0 0

3 12 1 0 0 0 0

3 27 1 0 0 0 0

3 28 1 0 0 0 0

5 6 4 0 0 0 0

5 10 4 0 0 0 0

5 13 1 0 0 0 0

6 7 4 0 0 0 0

7 8 4 0 0 0 0

7 30 1 0 0 0 0

8 9 4 0 0 0 0

8 31 1 0 0 0 0

9 10 4 0 0 0 0

9 32 1 0 0 0 0

10 33 1 0 0 0 0

11 13 4 0 0 0 0

11 15 4 0 0 0 0

11 26 1 0 0 0 0

12 13 4 0 0 0 0

12 14 4 0 0 0 0

14 15 4 0 0 0 0

14 19 4 0 0 0 0

15 16 4 0 0 0 0

16 17 4 0 0 0 0

16 25 1 0 0 0 0

17 18 4 0 0 0 0

17 24 1 0 0 0 0

18 19 4 0 0 0 0

18 20 1 0 0 0 0

19 23 1 0 0 0 0

20 21 2 0 0 0 0

20 22 1 0 0 0 0

M CHG 2 20 1 22 -1

M END): 15 ms

reading 33 atoms

ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false

1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them.

Default Van der Waals type for model set to Babel

33 atoms created

ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation

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Molfile

Formula

C16H11N3O3

Net Charge

Average Mass

293.277

Monoisotopic Mass

293.08004

InChI

InChI=1S/C16H11N3O3/c20-15-8-12-11-7-9(19(21)22)5-6-14(11)18-16(12)10-3-1-2-4-13(10)17-15/h1-7,18H,8H2,(H,17,20)

InChIKey

OLUKILHGKRVDCT-UHFFFAOYSA-N

SMILES

C12=CC=C(C=C2C=3CC(NC4=CC=CC=C4C3N1)=O)[N+](=O)[O-]

Roles Classification
Biological Role(s):	apoptosis inducer Any substance that induces the process of apoptosis (programmed cell death) in multi-celled organisms. anti-HIV-1 agent An anti-HIV agent that destroys or inhibits the replication of HIV-1, the more infective and more virulent of the two types of HIV virus. EC 2.7.11.22 (cyclin-dependent kinase) inhibitor An EC 2.7.11.* (protein-serine/threonine kinase) inhibitor that interferes with the action of cyclin-dependent kinase (EC 2.7.11.22). EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor An EC 2.7.11.* (protein-serine/threonine kinase) inhibitor that interferes with the action of non-specific serine/threonine protein kinase (EC 2.7.11.1), a kinase enzyme involved in phosphorylation of hydroxy group of serine or threonine. EC 2.7.11.26 (tau-protein kinase) inhibitor An EC 2.7.11.* (protein-serine/threonine kinase) inhibitor that interferes with the action of tau-protein kinase inhibitor (EC 2.7.11.26).

Application(s):	antineoplastic agent A substance that inhibits or prevents the proliferation of neoplasms.

View more via ChEBI Ontology

ChEBI Ontology
Outgoing	alsterpaullone (CHEBI:138488) has functional parent paullone (CHEBI:138487) alsterpaullone (CHEBI:138488) has role anti-HIV-1 agent (CHEBI:64947) alsterpaullone (CHEBI:138488) has role antineoplastic agent (CHEBI:35610) alsterpaullone (CHEBI:138488) has role apoptosis inducer (CHEBI:68495) alsterpaullone (CHEBI:138488) has role EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor (CHEBI:50925) alsterpaullone (CHEBI:138488) has role EC 2.7.11.22 (cyclin-dependent kinase) inhibitor (CHEBI:82665) alsterpaullone (CHEBI:138488) has role EC 2.7.11.26 (tau-protein kinase) inhibitor (CHEBI:91092) alsterpaullone (CHEBI:138488) is a C-nitro compound (CHEBI:35716) alsterpaullone (CHEBI:138488) is a caprolactams (CHEBI:23000) alsterpaullone (CHEBI:138488) is a organic heterotetracyclic compound (CHEBI:38163)

IUPAC Name

9-nitro-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one

Synonyms	Sources
14-nitro-8,18-diazatetracyclo[9.7.0.0^{2,7}.0^{12,17}]octadeca-1(11),2,4,6,12(17),13,15-heptaen-9-one	SUBMITTER
9-NITRO-5,12-DIHYDRO-7H-BENZO[2,3]AZEPINO[4,5-B]INDOL-6-ONE	PDBeChem
9-nitro-7,12-dihydro-5H-indolo[3,2-d][1]benzazepin-6-one	SUBMITTER
9-nitro-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one	PDBeChem
9-nitropaullone	SUBMITTER

Manual Xrefs	Databases
1Q3W	PDB
24890918	PubChem
4185120	ChemSpider
ATU	PDBeChem
DB04014	DrugBank
LSM-6558	LINCS
View more database links

Registry Numbers	Types	Sources
237430-03-4	CAS Registry Number	ChemIDplus
8340480	Reaxys Registry Number	Reaxys

Citations

Bae T, Weon KY, Lee JW, Eum KH, Kim S, Choi JW (2015)
Restoration of paclitaxel resistance by CDK1 intervention in drug-resistant ovarian cancer.
Carcinogenesis 36, 1561-1571 [PubMed:26442525]
[show Abstract]

Faria CC, Agnihotri S, Mack SC, Golbourn BJ, Diaz RJ, Olsen S, Bryant M, Bebenek M, Wang X, Bertrand KC, Kushida M, Head R, Clark I, Dirks P, Smith CA, Taylor MD, Rutka JT (2015)
Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma.
Oncotarget 6, 21718-21729 [PubMed:26061748]
[show Abstract]

Cui C, Wang Y, Wang Y, Zhao M, Peng S (2013)
Alsterpaullone, a Cyclin-Dependent Kinase Inhibitor, Mediated Toxicity in HeLa Cells through Apoptosis-Inducing Effect.
Journal of analytical methods in chemistry 2013, 602091 [PubMed:23577282]
[show Abstract]

Trevino M, Stefanik DJ, Rodriguez R, Harmon S, Burton PM (2011)
Induction of canonical Wnt signaling by alsterpaullone is sufficient for oral tissue fate during regeneration and embryogenesis in Nematostella vectensis.
Developmental dynamics : an official publication of the American Association of Anatomists 240, 2673-2679 [PubMed:22052821]
[show Abstract]

Guendel I, Agbottah ET, Kehn-Hall K, Kashanchi F (2010)
Inhibition of human immunodeficiency virus type-1 by cdk inhibitors.
AIDS research and therapy 7, 7 [PubMed:20334651]
[show Abstract]

Lahusen T, De Siervi A, Kunick C, Senderowicz AM (2003)
Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential.
Molecular carcinogenesis 36, 183-194 (Source: SUBMITTER) [PubMed:12669310]
[show Abstract]
The majority of human neoplasms have aberrations in the retinoblastoma pathway due to hyperactivation of cyclin-dependent kinases (CDK). Based on this observation, novel small molecules, such as flavopiridol and UCN-01, are being developed and are currently being tested in the clinic. Efforts to develop CDK modulators led us to the discovery of a novel class of CDK inhibitors, the paullones [Cancer Res 1999;59:2566]. Initial studies demonstrated that paullones inhibit CDKs in vitro, thereby blocking cell-cycle progression. However, the exact mechanism for the antiproliferative effects of paullones was never explored. In this report, we demonstrate for the first time that the most potent paullone, alsterpaullone (Alp), induced apoptosis and promoted loss in clonogenicity in the Jurkat cell line. Alp caused early activation of both caspase-8 and -9, leading to cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, apoptosis by Alp was not associated with loss in anti-apoptotic proteins such as XIAP or BCL-XL. Pre-incubation with cell-permeable inhibitors z-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (ZVAD) blocked Alp-induced apoptosis. Moreover, the general caspase inhibitor ZVAD blocked the cleavage and activation of most caspases tested except caspase-9. Studies of mitochondrial membrane potential also demonstrated that Alp is able to disrupt mitochondrial potential in the presence of ZVAD, suggesting that the activation of caspase-9 by Alp follows mitochondrial perturbation. Pre-incubation of Jurkat cells with ZVAD did not prevent the depletion of cyclin D3, loss of CDK, or cell-cycle arrest by Alp. In summary, these experiments suggest that Alp activates caspase-9 via mitochondrial perturbation. Active caspase-9 cleaves and activates caspase-8 and caspase-3, leading to apoptosis. In the presence of the general caspase inhibitor ZVAD, the cell-cycle effects of Alp are unaltered while apoptosis is blocked, suggesting that the CDK effects of Alp are not sufficient for Alp-induced apoptosis. Additional studies with paullones are warranted to further characterize their preclinical effects and to explore their potential use in the clinical setting.

Schultz C, Link A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L, Kunick C (1999)
Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity.
Journal of medicinal chemistry 42, 2909-2919 [PubMed:10425100]
[show Abstract]
The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of kenpaullone. Replacement of the 9-bromo substituent of kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 microM) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC(50) = 0.035 microM) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M).

Last Modified

25 September 2017

CHEBI:138488 - alsterpaullone

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