663918-95-4

Upstream product

• 121929-87-1 (R)-1-(4-isopropyl-2-thioxothiazolidin-3-yl)ethanone 
• 180973-22-2 (2E)-5-[(triphenylmethyl)thio]-2-pentenal 
• 180973-37-9 (E)-5-(tritylthio)-2-penten-1-ol 
• 100360-56-3 3-(tritylthio)propan-1-ol 
• 27144-18-9 3-(tritylthio) propanoic acid 
• 76-83-5 trityl chloride 
• 150350-28-0 S-trityl 3-mercaptopropionaldehyde 
• 3695-77-0 triphenylmethanethiol 

Downstream Products

• 180973-24-4 (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid 
• 1092363-37-5 (R)-methyl 2-(2-(((3S,4E)-3-hydroxy-7-(tritylthio)hept-4-enamido)methyl)thiazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carboxylate 
• 1009815-87-5 largazole 
• 1043577-37-2 (5R,8S,11S)-8-isopropyl-5-methyl-11-((E)-4-(tritylthio)but-1-en-1-yl)-10-oxa-3,17-dithia-7,14,19,20-tetraazatricyclo[14.2.1.12,5]icosa-1⁽¹⁸⁾,2⁽²⁰⁾,16⁽¹⁹⁾-triene-6,9,13-trione 
• 1092363-38-6 C₅₅H₅₄N₄O₇S₃ 
• 1191242-43-9 C₄₀H₄₄N₄O₅S₃ 
• 1338230-01-5 C₂₈H₃₄N₄O₅S₃ 
• 1092363-40-0 (4R)-methyl 2-(2-((8S)-1-(9H-fluoren-9-yl)-5-isopropyl-3,6,10-trioxo-8-((E)-4-(tritylthio)-but-1-enyl)-2,7-dioxa-4,11-diazadodecan-12-yl)thiazol-4-yl)-4-methyl-4,5-dihydrothiazole-4-carboxylate 

Relevant academic research and scientific papers

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

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.

Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2 at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-a-methylcysteine makes the molecule more amenable to chemical synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

HDAC Inhibitors as Anti-Cancer Agents

Largazole analogues, methods of making the same, and methods of using the same, are described.

Largazole and analogues with modified metal-binding motifs targeting histone deacetylases: Synthesis and biological evaluation

The histone deacetylase inhibitor largazole 1 was synthesized by a convergent approach that involved several efficient and high yielding single pot multistep protocols. Initial attempts using tert-butyl as thiol protecting group proved problematic, and synthesis was accomplished by switching to the trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized, and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6, as indicated by the lack of increased acetylation of α-tubulin.

Macrolactamization versus macrolactonization: Total synthesis of FK228, the depsipeptide histone deacetylase inhibitor

(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.

FK 228 DERIVATES AS HDAC INHIBITORS

Compounds which are FK228 analogues of the general formula (I) or (I/), isosteres thereof and pharmaceutically acceptable salts thereof are found to inhibit HDAC wherein R1, R2, R3 and R4 are the same

Total Synthesis of Spiruchostatin A, a Potent Histone Deacetylase Inhibitor

The total synthesis of spiruchostatin A was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction and as an activated acylating agent for amide formation, and macrolactonization by the Yamaguchi protocol. Spiruchostatin A is shown to have biological activity similar to that of FK228, a potent histone deacetylase (HDAC) inhibitor in clinical trials. The spiruchostatin A analogue, epimeric at the β-hydroxy acid, is inactive, highlighting the importance of stereochemistry at this position for interactions with HDACs. Copyright