10223. Romidepsin

Nomenclature

CAS number: 128517-07-7
Cyclo[(2Z)-2-amino-2-butenoyl-l-valyl-(3S,4E)-3-hydroxy-7-mercapto-4-heptenoyl-d-valyl-d-cysteinyl] cyclic (3→5)-disulfide; [S-(E)]-N-(3-hydroxy-7-mercapto-1-oxo-4-heptenyl)-d-valyl-d-cysteinyl-(Z)-2,3-didehydro-2-aminobutanoyl-l-valine (4→1)-lactone cyclic (1→2)-disulfide; (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone; FK-228; FR-901228; NSC-630176; Chromadax (Gloucester).
C24H36N4O6S2; mol wt 540.70.
C 53.31%, H 6.71%, N 10.36%, O 17.75%, S 11.86%.

Description and references

Bicyclic depsipeptide antibiotic produced by Chromobacterium violaceum WB968. Natural prodrug converted by glutathione-mediated reduction of the disulfide bond to the active histone deacetylase (HDAC) inhibitor. Isoln: M. Okuhara et al., EP 352646; eidem, US 4977138 (both 1990 to Fujisawa). Series of articles on isoln, structure, and activity: J. Antibiot. 47, 301-323 (1994) PubMed. Total synthesis: K. W. Li et al., J. Am. Chem. Soc. 118, 7237 (1996) DOI. HPLC determn in plasma: C. Chassaing et al., J. Chromatogr. B 719, 169 (1998) DOI PubMed. Mechanism of action studies: H. Nakajima et al., Exp. Cell Res. 241, 126 (1998) DOI PubMed; R. Furumai et al., Cancer Res. 62, 4916 (2002) PubMed. Clinical pharmacokinetics and toxicological evaluation: V. Sandor et al., Clin. Cancer Res. 8, 718 (2002) PubMed. Clinical evaluation in leukemias: J. C. Byrd et al., Blood 105, 959 (2005) DOI PubMed. Review of pharmacology and clinical experience: D. M. Vigushin, Curr. Opin. Investig. Drugs 3, 1396-1402 (2002) PubMed; P. A. Konstantinopoulos et al., Cancer Chemother. Pharmacol. 58, 711-715 (2006) DOI PubMed.

Chemical structure

Properties

Colorless prisms, mp 235-245° (dec). [α]D23 +39° (c = 1.0 in CHCl3). Sol in chloroform, ethyl acetate; sparingly sol in methanol, ethanol. Insol in water, hexane.

Therapeutic Category

Antineoplastic.

Keywords

Antineoplastic; Histone Deacetylase Inhibitors