(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

Base Information

• Chemical Name: (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
• CAS No.: 128517-07-7
• Molecular Formula: C24H36 N4 O6 S2
• Molecular Weight: 540.705
• Hs Code.: 29349990
• European Community (EC) Number: 686-179-1
• Wikipedia: Romidepsin
• Wikidata: Q104193374
• ChEMBL ID: CHEMBL2130995
• Mol file: 128517-07-7.mol

Synonyms:L-Valine,N-(3-hydroxy-7-mercapto-1-oxo-4-heptenyl)-D-valyl-D-cysteinyl-(Z)-2,3-didehydro-2-aminobutanoyl-,(4?;1)-lactone, cyclic (1?;2)-disulfide, [S-(E)]-;2-Oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricosane, cyclic peptidederiv.;Antibiotic FR 901228;Chromadax;FK 228;FR 901228;NSC 630176;Romidepsin;

Chemical Property 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

Chemical Property:

• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 219-224°C
• Refractive Index: 1.529
• Boiling Point: 942.8oC at 760 mmHg
• PKA: 11.33±0.60(Predicted)
• Flash Point: 524oC
• PSA: 193.30000
• Density: 1.174g/cm3
• LogP: 2.74480
• Storage Temp.: Amber Vial, -20°C Freezer, Under Inert Atmosphere
• Solubility.: Soluble in DMSO (up to 10 mg/ml).
• XLogP3: 2.2
• Hydrogen Bond Donor Count: 4
• Hydrogen Bond Acceptor Count: 8
• Rotatable Bond Count: 2
• Exact Mass: 540.20762723
• Heavy Atom Count: 36
• Complexity: 905

Purity/Quality:

FK 228 ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC=C1C(=O)NC(C(=O)OC2CC(=O)NC(C(=O)NC(CSSCCC=C2)C(=O)N1)C(C)C)C(C)C
• Recent EU Clinical Trials: A MULTICENTER, PHASE I/II STUDY OF SEQUENTIAL EPIGENETIC AND IMMUNE TARGETING IN COMBINATION WITH NAB-PACLITAXEL/GEMCITABINE IN PATIENTS WITH ADVANCED PANCREATIC DUCTAL ADENOCARCINOMA
• Description: The U.S. FDA approved romidepsin (also referredto as FK228) in 2009 for the treatment of cutaneous T-cell lymphoma (CTCL) for patients who received at least one systemic therapy. Romidepsin is a natural product that was first isolated from the fermentation broth of C. violaceum. Romidepsin is the second histone deacetylase (HDAC) inhibitor approved for CTCL, the other being vorinostat,whichwas approved by the FDA in 2006. Unlike vorinostat which is a pan-HDAC inhibitor, romidepsin shows modest selectivity for class I HDACs in in vitro assays. It has been shown that after romidepsin enters the cytoplasm, the disulfide bond is cleaved by glutathione to release the sulfhydryl groupwhich chelateswith the activesite zinc of class IHDACs and inhibits the enzymatic activity at nanomolar concentrations. Although romidepsin inhibits class I HDACs, it is 17–23 times less potent as the parent than the corresponding reduced form at each isozyme. For example, the IC50 of romidepsin at HDAC1 is 36±16nM while that of the reduced form is IC50=1.6± 0.9nM.Romidepsinhasalsobeenshownto induce cell cycle arrest, differentiation, and apoptosis in tumor cells by mechanisms that cannot be completely explained by HDAC inhibition alone.
• Uses: Labelled Romidepsin (R425060). Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xeno graft models. Romidepsin can be administered with a second agent, such as a cytotoxic agent, a steroidal agent, a proteasome inhibitor, or a kinase inhibitor. Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models. Romidepsin can be administered with a second agent, such as a cytotoxic agent, a steroidal agent, a proteasome inhibitor, or a kinase inhibitor.
• 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.

Technology Process 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

There total 24 articles about (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 which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 84.0%

(3S,9S,12R,16S)-6-eth-(Z)-ylidene-3,12-diisopropyl-16-((E)-4-tritylsulfanyl-but-1-enyl)-9-tritylsulfanylmethyl-1-oxa-4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14-pentaone (180973-35-7) → romidepsin (128517-07-7)

Guidance literature:

With iodine; In methanol; water;

DOI:10.1021/ja9613724

Reference yield:

(3S,9S,12R,16S,Z)-6-ethylidene-3,12-diisopropyl-16-((E)-4-(tritylthio)but-1-en-1-yl)-9-((tritylthio)methyl)-1-oxa-4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14-pentaone → romidepsin (128517-07-7)

Guidance literature:

With iodine; In methanol; dichloromethane; at 0 - 30 ℃; for 1h; Temperature;

Reference yield:

(2E)-5-[(triphenylmethyl)thio]-2-pentenal (180973-22-2) → romidepsin (128517-07-7)

Guidance literature:

Multi-step reaction with 6 steps

1: 95 percent / Ti(IV) complex with (R)-(-)-binaphthyl amino alcohol

2: 100 percent / LiOH / methanol; H₂O

3: 98 percent / (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, DIEA

4: 93 percent / LiOH

5: 62 percent / DIAD, PPh₃, TsOH*H₂O / tetrahydrofuran / 2 h / 0 °C

6: 84 percent / I₂ / methanol; H₂O

With lithium hydroxide; di-isopropyl azodicarboxylate; iodine; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; toluene-4-sulfonic acid; N-ethyl-N,N-diisopropylamine; triphenylphosphine; Ti(IV) complex with (R)-(-)-binaphthyl amino alcohol; In tetrahydrofuran; methanol; water;

DOI:10.1021/ja9613724

upstream raw materials:

(3S,9S,12R,16S)-6-eth-(Z)-ylidene-3,12-diisopropyl-16-((E)-4-tritylsulfanyl-but-1-enyl)-9-tritylsulfanylmethyl-1-oxa-4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14-pentaone

L-Valine methyl ester

(2E)-5-[(triphenylmethyl)thio]-2-pentenal

(E)-5-(tritylthio)-2-penten-1-ol

Refernces

• 1、 Narita, Koichi,Kikuchi, Takuya,Watanabe, Kazuhiro,Takizawa, Toshiya,Oguchi, Takamasa,Kudo, Kyosuke,Matsuhara, Keisuke,Abe, Hideki,Yamori, Takao,Yoshida, Minoru,Katoh, Tadashi. "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". experimental part. p. 11174 - 11186. Retrieved 2010/04/29.
• 2、 Wen, Shijun,Packham, Graham,Ganesan. "Macrolactamization versus macrolactonization: Total synthesis of FK228, the depsipeptide histone deacetylase inhibitor". experimental part. p. 9353 - 9361. Retrieved 2009/04/05.