198632-67-6Relevant academic research and scientific papers
A Mutasynthesis Approach with a Penicillium chrysogenum ΔroqA Strain Yields New Roquefortine D Analogues
Ouchaou, Kahina,Maire, Florian,Salo, Oleksandr,Ali, Hazrat,Hankemeier, Thomas,Van Der Marel, Gijsbert A.,Filippov, Dmitri V.,Bovenberg, Roel A. L.,Vreeken, Rob J.,Driessen, Arnold J. M.,Overkleeft, Herman S.
, p. 915 - 923 (2015)
Penicillium chrysogenum, which lacks the roqA gene, processes synthetic, exogenously added histidyltryptophanyldiketopiperazine (HTD) to yield a set of roquefortine-based secondary metabolites also produced by the wild-type strain. Feeding a number of synthetic HTD analogues to the ΔroqA strain gives rise to the biosynthesis of a number of new roquefortine D derivatives, depending on the nature of the synthetic HTD added. Besides delivering semisynthetic roquefortine analogues, the mutasynthesis studies presented here also shed light on the substrate preferences and molecular mechanisms employed by the roquefortine C/D biosynthesis gene cluster, knowledge that may be tapped for the future development of more complex semisynthetic roquefortine-based secondary metabolites.
Mithramycin 2′-Oximes with Improved Selectivity, Pharmacokinetics, and Ewing Sarcoma Antitumor Efficacy
Liu, Yang,Eckenrode, Joseph M.,Zhang, Yinan,Zhang, Jianjun,Hayden, Reiya C.,Kyomuhangi, Annet,Ponomareva, Larissa V.,Cui, Zheng,Rohr, Jürgen,Tsodikov, Oleg V.,Van Lanen, Steven G.,Shaaban, Khaled A.,Leggas, Markos,Thorson, Jon S.
, p. 14067 - 14086 (2020/11/30)
Mithramycin A (MTM) inhibits the oncogenic transcription factor EWS-FLI1 in Ewing sarcoma, but poor pharmacokinetics (PK) and toxicity limit its clinical use. To address this limitation, we report an efficient MTM 2′-oxime (MTMox) conjugation strategy for rapid MTM diversification. Comparative cytotoxicity assays of 41 MTMox analogues using E-twenty-six (ETS) fusion-dependent and ETS fusion-independent cancer cell lines revealed improved ETS fusion-independent/dependent selectivity indices for select 2′-conjugated analogues as compared to MTM. Luciferase-based reporter assays demonstrated target engagement at low nM concentrations, and molecular assays revealed that analogues inhibit the transcriptional activity of EWS-FLI1. These in vitro screens identified MTMox32E (a Phe-Trp dipeptide-based 2′-conjugate) for in vivo testing. Relative to MTM, MTMox32E displayed an 11-fold increase in plasma exposure and improved efficacy in an Ewing sarcoma xenograft. Importantly, these studies are the first to point to simple C3 aliphatic side-chain modification of MTM as an effective strategy to improve PK.
MITHRAMYCIN DERIVATIVES HAVING INCREASED SELECTIVITY AND ANTI-CANCER ACTIVITY
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Paragraph 0097, (2019/04/05)
Mithramycin side chain carboxylic acid (MTM-SA) derivative are provided, which include a substituted amino acid derivative, a substituted amino acid dipeptide derivative, or an unsubstituted dipeptide derivative. The MTM-SA derivatives are useful for treatment of cancer or neuro-diseases associated with an aberrant erythroblast transformation-specific transcription factor. Unique MTM-SA derivatives have increased selectively toward ETS transcription factor.
Development of Mithramycin Analogues with Increased Selectivity toward ETS Transcription Factor Expressing Cancers
Mitra, Prithiba,Eckenrode, Joseph M.,Mandal, Abhisek,Jha, Amit K.,Salem, Shaimaa M.,Leggas, Markos,Rohr, Jürgen
, p. 8001 - 8016 (2018/09/06)
Mithramycin A (1) was identified as the top potential inhibitor of the aberrant ETS transcription factor EWS-FLI1, which causes Ewing sarcoma. Unfortunately, 1 has a narrow therapeutic window, compelling us to seek less toxic and more selective analogues. Here, we used MTMSA (2) to generate analogues via peptide coupling and fragment-based drug development strategies. Cytotoxicity assays in ETS and non-ETS dependent cell lines identified two dipeptide analogues, 60 and 61, with 19.1- and 15.6-fold selectivity, respectively, compared to 1.5-fold for 1. Importantly, the cytotoxicity of 60 and 61 is 100 nM in ETS cells. Molecular assays demonstrated the inhibitory capacity of these analogues against EWS-FLI1 mediated transcription in Ewing sarcoma. Structural analysis shows that positioning the tryptophan residue in a distal position improves selectivity, presumably via interaction with the ETS transcription factor. Thus, these analogues may present new ways to target transcription factors for clinical use.
Diketo acids and their amino acid/dipeptidic analogues as promising scaffolds for the development of bacterial methionine aminopeptidase inhibitors
Masood, Mir Mohammad,Pillalamarri, Vijay K.,Irfan, Mohammad,Aneja, Babita,Jairajpuri, Mohamad Aman,Zafaryab,Rizvi, M. Moshahid A.,Yadava, Umesh,Addlagatta, Anthony,Abid, Mohammad
, p. 34173 - 34183 (2015/04/27)
Using diketoesters as the template, various derivatives were designed and the selected compounds were synthesized as bacterial methionine aminopeptidase (MetAP) inhibitors. The results of in vitro antibacterial screening revealed fifteen compounds (1a-c,
Novel antibiotics: C-2 symmetrical macrocycles inhibiting Holliday junction DNA binding by E. coli RuvC
Pan, Po-Shen,Curtis, Fiona A.,Carroll, Chris L.,Medina, Irene,Liotta, Lisa A.,Sharples, Gary J.,McAlpine, Shelli R.
, p. 4731 - 4739 (2007/10/03)
Holliday junctions (HJs) are formed as transient DNA intermediates during site-specific and homologous recombination. Both of these genetic exchange pathways are critical for normal DNA metabolism and repair. Trapping HJs leads to bacterial cell death by
Selective inhibitors of the serine protease plasmin: Probing the S3 and S3′ subsites using a combinatorial library
Xue, Fengtian,Seto, Christopher T.
, p. 6908 - 6917 (2007/10/03)
A combinatorial library of 400 serine protease inhibitors with the general structure Cbz-Xaa-Trp-cyclohexanone-Trp-Yaa-OH has been constructed. The library was synthesized on the solid phase using mix-and-split synthesis, where 20 di
Simple synthesis of 1,3,4,5a,6,10b,11,11a-octahydro-2H-pyrazino[1′,2′:1,5]pyrrolo[2, 3-b]indole derivatives based on 1-hydroxyindole chemistry
Fukui, Yoshikazu,Somei, Masanori
, p. 2055 - 2057 (2007/10/03)
3-Substituted (3S,6S)-6-(1-hydroxyindol-3-ylmethyl)-2,5-piperazinediones are prepared for the first time. They are shown to be suitable intermediates for the synthesis of 3,10b-disubstituted (3S,5aR,10bS,11as)-1,3,4,5a,6,10b,11, 11a-octahydro-2H-pyrazino[
