Alvocidib

Alvocidib

Names
IUPAC name 2′-Chloro-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]flavone
Systematic IUPAC name 2-(2-Chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4H-1-benzopyran-4-one
Other names Flavopiridol, HMR 1275, L-868275
Identifiers
CAS Number	146426-40-6  N
3D model (JSmol)	Interactive image
ChEBI	CHEBI:47344  N
ChEMBL	ChEMBL428690  N
ChemSpider	4450222  Y
DrugBank	DB03496  Y
IUPHAR/BPS	5680
KEGG	D09868
MeSH	Flavopiridol
PubChem CID	5287969
UNII	45AD6X575G  Y
CompTox Dashboard (EPA)	DTXSID20904970
InChI InChI=1S/C21H20ClNO5/c1-23-7-6-12(17(27)10-23)19-14(24)8-15(25)20-16(26)9-18(28-21(19)20)11-4-2-3-5-13(11)22/h2-5,8-9,12,17,24-25,27H,6-7,10H2,1H3/t12-,17+/m0/s1 Y Key: BIIVYFLTOXDAOV-YVEFUNNKSA-N Y
SMILES Clc4ccccc4C=2Oc1c(c(O)cc(O)c1C(=O)C=2)[C@H]3CCN(C)C[C@H]3O
Properties
Chemical formula	C21H20ClNO5
Molar mass	401.8402
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N  verify  (what is  YN ?) Infobox references

Alvocidib (INN; also known as flavopiridol) is a flavonoid alkaloid CDK9 kinase inhibitor under clinical development by Tolero Pharmaceuticals for the treatment of acute myeloid leukemia. It has been studied also for the treatment of arthritis ^[1] and atherosclerotic plaque formation. ^[2] The target of alvocidib is the positive transcription elongation factor P-TEFb. ^{[3] [4]} Treatment of cells with alvocidib leads to inhibition of P-TEFb and the loss of mRNA production. ^{[5] [6]}

The compound is a synthetic analog of natural product rohitukine which was initially extracted from Aphanamixis polystachya (formerly Amoora rohituka, hence the name) and later from Dysoxylum binectariferum . ^{[7] [8]}

Orphan drug

The FDA has granted orphan drug designation to alvocidib for the treatment of patients with acute myeloid leukemia. ^[9]

References

1. Sekine C, Sugihara T, Miyake S, Hirai H, Yoshida M, Miyasaka N, Kohsaka H (2008). "Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclin-dependent kinase inhibitors". J. Immunol. 180 (3): 1954–61. doi: 10.4049/jimmunol.180.3.1954 . PMID   18209094.
2. Ruef J, Meshel AS, Hu Z, Horaist C, Ballinger CA, Thompson LJ, Subbarao VD, Dumont JA, Patterson C (1999). "Flavopiridol inhibits smooth muscle cell proliferation in vitro and neointimal formation In vivo after carotid injury in the rat". Circulation. 100 (6): 659–65. doi: 10.1161/01.cir.100.6.659 . PMID   10441105.
3. Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM, Peterlin BM, Price DH (2000). "Flavopiridol inhibits P-TEFb and blocks HIV-1 replication". J. Biol. Chem. 275 (37): 28345–8. doi: 10.1074/jbc.C000446200 . PMID   10906320.
4. Chao SH, Price DH (2001). "Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo". J. Biol. Chem. 276 (34): 31793–9. doi: 10.1074/jbc.M102306200 . PMID   11431468.
5. Cheng B, Li T, Rahl PB, Adamson TE, Loudas NB, Guo J, Varzavand K, Cooper JJ, Hu X, Gnatt A, Young RA, Price DH (2012). "Functional association of Gdown1 with RNA polymerase II poised on human genes". Mol. Cell. 45 (1): 38–50. doi:10.1016/j.molcel.2011.10.022. PMC   3259526 . PMID   22244331.
6. Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, Sharp PA, Young RA (2010). "c-Myc regulates transcriptional pause release". Cell. 141 (3): 432–45. doi:10.1016/j.cell.2010.03.030. PMC   2864022 . PMID   20434984.
7. Harmon, AD; Weiss, U; Silverton, JV (1979). "The structure of rohitukine, the main alkaloid of Amoora rohituka (syn.Aphanamixis polystachya) (Meliaceae)". Tetrahedron Lett. 20 (1): 721–724. doi:10.1016/S0040-4039(01)93556-7.
8. Lakdawala, AD; Shirole, MV; Mandrekar, SS; Dohadwalla, AN (1988). "Immunopharmacological potential of rohitukine: a novel compound isolated from the plant Dysoxylum binectariferum". Asia Pac J Pharmcol. 3 (1): 91–98.
9. "FDA grants orphan drug status to Alvocidib for AML".