128517-07-7 Usage
Uses
1. Used in Pharmaceutical Applications:
(1S,4Z,7S,10S,11E,20R)-4-ethylidene-7,20-dipropan-2-yl-9-oxa-15,16-dit hia-3,6,18,21-tetrazabicyclo[8.7.6]tricos-11-ene-2,5,8,19,22-pentone is used as a histone deacetylase inhibitor for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one systemic therapy. It alters chromatin structure and gene transcription, leading to multiple changes in cellular protein production, which may result in cell cycle arrest and tumor growth inhibition.
2. Used in Combination Therapy:
(1S,4Z,7S,10S,11E,20R)-4-ethylidene-7,20-dipropan-2-yl-9-oxa-15,16-dit hia-3,6,18,21-tetrazabicyclo[8.7.6]tricos-11-ene-2,5,8,19,22-pentone can be administered with a second agent, such as a cytotoxic agent, a steroidal agent, a proteasome inhibitor, or a kinase inhibitor, to enhance its anti-tumor effects and overcome drug resistance.
3. Used in Drug Delivery Systems:
To improve the bioavailability and therapeutic outcomes of (1S,4Z,7S,10S,11E,20R)-4-ethylidene-7,20-dipropan-2-yl-9-oxa-15,16-dit hia-3,6,18,21-tetrazabicyclo[8.7.6]tricos-11-ene-2,5,8,19,22-pentone, various drug delivery systems, including organic and metallic nanoparticles, have been developed to act as carriers for its delivery to target cancer cells.
Application Industries:
Pharmaceutical Industry: For the development and production of histone deacetylase inhibitors and other cancer therapeutics.
Biotechnology Industry: For research and development of drug delivery systems and combination therapies involving this compound.
Oncology: For the treatment of cutaneous T-cell lymphoma and potentially other cancer types.
Originator
Fujisawa (Astellas Pharma) (Japan)
Biochem/physiol Actions
Romidepsin is a very potent natural prodrug inhibitor of HDAC1 and HDAC2 that is converted to active form by glutathione. Romidepsin has IC50 values of 36 nM and 47 nM for HDAC1 and HDAC2, respectively. Romidepsin kills lymphoma cell lines overexpressing Bcl-2 and Bcl-XL, and has been approved for the treatment for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma, and a variety of other cancers.
Clinical Use
Romidepsin, a histone deacetylase inhibitor, originally developed by Fujisawa (now Astellas
Pharma), causes cell cycle arrest, differentiation, and apoptosis in various cancer cells. In 2004,
the FDA granted fast-track designation for romidepsin as monotherapy for the treatment of cutaneous Tcell
lymphoma (CTCL) in patients who have relapsed following, or become refractory to, other systemic
therapies. The FDA designated romidepsin as an orphan drug and it was approved in 2009 for this
indication and it was commercialized in 2010. In 2007, another fast-track designation was granted for
the product as monotherapy of previously treated peripheral T-cell lymphoma. Romidepsin (FR901228)
was originally discovered and isolated from the fermentation broth of Chromobacterium violaceum No.
968. It was identified through efforts in the search for novel agents which selectively reverse the
morphological phenotype of Ras oncogene-transformed cells since the Ras signaling pathway plays a
critical role in cancer development. Therefore, the drug could also have multiple molecular targets for
its anticancer activity besides HDAC. FR901228 is a bicyclic depsipeptide which is structurally
unrelated to any known class of cyclic peptides with an unusual disulfide bond connecting a thiol and Dcysteine.
Synthesis
Romidepsin is commercially produced by fermentation; however its interesting and novel
structure warrants examination of its synthesis within the context of this review. The
synthesis of romidepsin described is based on the total synthesis reported by the Williams and
Simon groups. L-Valine methyl ester (134) was coupled to N-Fmoc-L-threonine in
the presence of the BOP reagent in 95% yield. The N-Fmoc protecting group was removed with Et2NH
and the corresponding free amine was coupled to N-alloc-(S-triphenylmethyl)-D-cysteine with 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide (EDCI) and HOBT in DMF and CH2Cl2 to yield the tripeptide
135 in good yield. The threonine residue of tripeptide 135 was then subjected to dehydrating conditions
to give alkene 136 in 95% yield. The N-alloc protecting group of the dehydrated tripeptide 136 was
removed with palladium and tin reagents and the corresponding free amine was subsequently coupled with N-Fmoc-D-valine to give tetrapeptide 137 in 83% yield. After removal of the N-Fmoc protecting
group of compound 137 with Et2NH amine 138 was obtained in quantitative yield. The acid coupling
partner 145 for amine 138 was prepared as follows: methyl 3,3-dimethoxypropionate (139) was
converted to its corresponding Weinreb amide by standard conditions and reacted with lithium acetylide
140 to give propargylic ketone 141 in 75% yield. Noyori’s asymmetric reduction of ketone 141 using
ruthenium catalyst 142 gave the (R)-propargylic alcohol in 98% ee. This was followed by Red-Al
reduction of the alkyne to selectively yield (E)-alkene 143 in 58% yield for the two steps. Liberation of
the primary alcohol with tetrabutylammonium fluoride (TBAF) followed by selective tosylation gave
144 in 70% yield in two steps. Hydrolysis of the dimethyl acetal of 144 with LiBF4 was followed by a
Pinnick oxidation to give the corresponding carboxylic acid. The tosylate was displaced with trityl
mercaptan in the presence of tert-butyl alcohol to give allylic alcohol 145 in 65% yield for the three
steps. Aminoamide 138 was then coupled to acid 145 using BOP to give peptide 146 in quantitative
yield. The methyl ester of compound 146 was hydrolyzed with lithium hydroxide to provide the free
carboxylic acid which underwent macrolactonization under Mitsunobu conditions in the presence of
diisopropyl azodicarboxylate (DIAD) and triphenylphosine to give macrocycle 147 in 24% yield.
Finally, the disulfide linkage was formed by treating bis-tritylsulfane 147 with iodine in methanol at
room temperature to give romidepsin (XIII) in 81% yield.
References
1) Furumai et al. (2002), FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases; Cancer Res., 62 4916
2) Panicker et al. (2010), Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells; Cell Cycle, 9 1830
3) Ueda et al. (1994), FR901228, a novel anti-tumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice; J. Antibiot. (Tokyo), 47 315
4) VanderMolin et al. (2011), Romodepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma; J. Antibiotic. (Tokyo), 64 525
Check Digit Verification of cas no
The CAS Registry Mumber 128517-07-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,8,5,1 and 7 respectively; the second part has 2 digits, 0 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 128517-07:
(8*1)+(7*2)+(6*8)+(5*5)+(4*1)+(3*7)+(2*0)+(1*7)=127
127 % 10 = 7
So 128517-07-7 is a valid CAS Registry Number.
InChI:InChI=1/C24H36N4O6S2/c1-6-16-21(30)28-20(14(4)5)24(33)34-15-9-7-8-10-35-36-12-17(22(31)25-16)26-23(32)19(13(2)3)27-18(29)11-15/h6-7,9,13-15,17,19-20H,8,10-12H2,1-5H3,(H,25,31)(H,26,32)(H,27,29)(H,28,30)/b9-7+,16-6-/t15-,17+,19+,20-/m0/s1
128517-07-7Relevant articles and documents
AN IMPROVED PROCESS FOR THE PREPARATION OF (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
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Page/Page column 32; 35, (2017/05/19)
The present invention is relates to an improved process for the preparation (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabi-cyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone of formula I.
Total synthesis of the bicyclic depsipeptide hdac inhibitors spiruchostatins a and b, 5″-epi-spiruchostatin b, fk228 (fr901228) and preliminary evaluation of their biological activity
Narita, Koichi,Kikuchi, Takuya,Watanabe, Kazuhiro,Takizawa, Toshiya,Oguchi, Takamasa,Kudo, Kyosuke,Matsuhara, Keisuke,Abe, Hideki,Yamori, Takao,Yoshida, Minoru,Katoh, Tadashi
experimental part, p. 11174 - 11186 (2010/04/29)
The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins A and B, 5″-ep(-spiruchostatin B and FK228 were efficiently synthesized in a convergent and unified manner. The synthetic method involved the following crucial steps : i) a JuliaKocienski olefination of a 1,3-propanediol-derived sulfone and a L- or Dmalic acid-derived aldehyde to access the most synthetically challenging unit, (35 or 3R,4E)-3-hydroxy-7- mercaptohept-4-enoic acid, present in a D-alanine- or D-valine-containing segment; ii) a condensation of a D-valine-D-cysteine- or D-allo-isoleucine-D- cysteinecontaining segment with a D-alanineor D-valine-containing segment to directly assemble the corresponding secoacids; and iii) a macrocyclization of a seco-acid using the Shiina method or the Mitsunobu method to construct the requisite 15- or 16-membered macrolactone. The present synthesis has established the C5″ stereochemistry of spiruchostatin B. In addition, HDAC inhibitory assay and the cell-growth inhibition analysis of the synthesized depsipeptides determined the order of their potency and revealed some novel aspects of structure-activity relationships. It was also found that unnatural 5″-epi-spiruchostatin B shows extremely high selectivity (ca. 1600-fold) for class I HDAC1 (IC50 = 2.4 nM) over class II HDAC6 (IC 50 = 3900nM) with potent cell-growth-inhibitory activity at nanomolar levels of IC50 values.
Improved total synthesis of the potent HDAC inhibitor FK228 (FR-901228)
Greshock, Thomas J.,Johns, Deidre M.,Noguchi, Yasuo,Williams, Robert M.
, p. 613 - 616 (2008/09/16)
A scaleable synthesis of the potent histone deacetylase (HDAC) inhibitor FK228 is described. A reliable strategy for preparing the key β-hydroxy mercapto heptenoic acid partner was accomplished in nine steps and 13% overall yield. A Noyori asymmetric hydrogen-transfer reaction established the hydroxyl stereochemistry in >99:1 er via the reduction of a propargylic ketone.
Macrolactamization versus macrolactonization: Total synthesis of FK228, the depsipeptide histone deacetylase inhibitor
Wen, Shijun,Packham, Graham,Ganesan
experimental part, p. 9353 - 9361 (2009/04/05)
(Chemical Equation Presented) The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.
