1. Disulﬁde-bridged peptide macrobicycles from nature
Benjamin K. W. Chung, Andrei K. Yudin*. Org. Biomol. Chem.,2015, 13,8768–8779
Romidepsin is a DBPB marketed by Celgene Corporation and approved by the FDA for the treatment of cutaneous T-celllymphoma (CTCL). The compound was isolated in 1994 from Chromobacterium violaceum obtained in a soil sample, and demonstrated antitumor activity in mice. The total synthesis of romidepsin was first reported in 1996. Romidepsin acts as a prodrug, where reductive cleavage ofthe disulfide by glutathione yields the active monocyclic
dithiol. One of the released thiol groups (position 13) forms a reversible complex with the active site zinc atom in the binding pocket of Zn-dependent histone deacetylases (HDAC), with stronger inhibition of class 1 HDACs (HDAC1 and HDAC2) over class 2 HDACs (HDAC4 and HDAC6). HDAC inhibition prevents deacetylation from N-terminal Lys residues of histones, maintaining the transcriptionally active chromatinstate.
2. Small-molecular modulators of cancer-associated epigenetic mechanisms
Yukihiro Itoh, Takayoshi Suzuki*, Naoki Miyata*. Mol. BioSyst., 2013, 9, 873-896
Romidepsin is a cyclic tetrapeptide and shows strong inhibitory activity against HDAC1–3 and HDAC8. It has been shown that the disulfide bond-reduced form of 11 is the active form, and the reduced thiolate can chelate the zinc ion in the active site. Many reports on thiolate HDAC inhibitors support the idea that the reduced form of 11 inhibits HDACs. The response rate in treatment of CTCL with 11 was reported to be over 30%. However, only limited eﬃcacy was seen in a recent trial in patients with multiple myeloma and solid tumors.
3. Perspectives on natural product epigenetic modulators in chemical biology and medicine
Fanny L. Cherblanc, Robert W. M. Davidson, Paolo Di Fruscia, Nitipol Srimongkolpithak, Matthew J. Fuchter*. Nat. Prod. Rep., 2013, 30, 605–624
In 2009 the bicyclic depsipeptide romidepsin, isolated from Chromobacterium violaceum, was approved for intravenous infusion as an anticancer agent (Istodax) for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is a pro-drug, the disulfide bond being reduced in cells to yield the corresponding dithiol as the active molecule. It is a potent class I HDAC inhibitor agent, with a good selectivity over class IIHDACs. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of several cancer cell lines. In vivo studies have also demonstrated cytotoxic activity in xenogras of A549 andMCF-7 cancer cell lines. Romidepsin is currently undergoing a large number of clinical trials for the prevention and treatment of a variety of cancer types, either as a monotherapy or in combination with other agents. As highlighted earlier, the synergistic eﬀects of combinations of epigenetic modulators may prove particularly important to mediate a given epigenetic response. Indeed, a combination of romidepsin and azacitidine (DNMT inhibitor, see above), is being studied in order to determine their eﬃcacy in the treatment of advanced solid tumors.