Abstract Title

Isolation and Characterization of a Group of TS-FK228 Analogues

RAD Assignment Number

214

Presenter Name

Xiangyang Liu

Abstract

FK228 (Istodax/Romidepsin) is an FDA approved anticancer drug for the treatment of human cutaneous T-cell lymphoma and peripheral T-cell lymphoma via the inhibition of class I histone deacetylases (HDACs). Fermentation of Chromobacterium violaceum No. 968 is still the main preparation method for the large-scale production of FK228 for its research and clinical applications. Interestingly, we previously discovered the production of authentic FK228 by Burkholderia thailandensis MSMB43. During a pilot scale production of FK228 through the fermentation of B. thailandensis MSMB43, we unexpectedly isolated and purified one labile compound (thiosulfinate-FK228, TS-FK228, existed as isomers) which is structurally similar to FK228 but distinctive from their cytotoxic effects against tumor cells. Through LC-MS analysis and subsequent chemical synthesis of five TS-compounds from the prepared FK228 and FK228 analogues (thailandepsins, TDPs), we were able to prove that the oxidation of the disulfide bond in FK228 is derived from silica gel during the course of silica gel chromatography rather than through de novo biosynthesis by perspective bacterial strain. We showed that one of the TS-FK228 isomers has similar HDAC inhibitory activities with FK228, but has higher antiproliferative activities than FK228 against representative human cancer cell lines.

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Isolation and Characterization of a Group of TS-FK228 Analogues

FK228 (Istodax/Romidepsin) is an FDA approved anticancer drug for the treatment of human cutaneous T-cell lymphoma and peripheral T-cell lymphoma via the inhibition of class I histone deacetylases (HDACs). Fermentation of Chromobacterium violaceum No. 968 is still the main preparation method for the large-scale production of FK228 for its research and clinical applications. Interestingly, we previously discovered the production of authentic FK228 by Burkholderia thailandensis MSMB43. During a pilot scale production of FK228 through the fermentation of B. thailandensis MSMB43, we unexpectedly isolated and purified one labile compound (thiosulfinate-FK228, TS-FK228, existed as isomers) which is structurally similar to FK228 but distinctive from their cytotoxic effects against tumor cells. Through LC-MS analysis and subsequent chemical synthesis of five TS-compounds from the prepared FK228 and FK228 analogues (thailandepsins, TDPs), we were able to prove that the oxidation of the disulfide bond in FK228 is derived from silica gel during the course of silica gel chromatography rather than through de novo biosynthesis by perspective bacterial strain. We showed that one of the TS-FK228 isomers has similar HDAC inhibitory activities with FK228, but has higher antiproliferative activities than FK228 against representative human cancer cell lines.