Papers by Clemens Zwergel
Journal of Medicinal Chemistry, 2014
DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expre... more DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent nonnucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.
Journal of Medicinal Chemistry, 2015
Musculoskeletal sarcomas are aggressive malignancies of bone and soft tissues often affecting chi... more Musculoskeletal sarcomas are aggressive malignancies of bone and soft tissues often affecting children and adolescents. Histone deacetylase inhibitors (HDACi) have been proposed to counteract cancer stem cells (CSCs) in solid neoplasms. When tested in human osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma stem cells, the new HDACi MC1742 (1) and MC2625 (2) increased acetyl-H3 and acetyl-tubulin levels and inhibited CSC growth by apoptosis induction. At nontoxic doses, 1 promoted osteogenic differentiation. Further investigation with 1 will be done in preclinical sarcoma models. Figure 1. Design of the novel HDACi 1 and 2 and structure of the SIRTi 3 tested in this study.
Expert opinion on drug discovery, Jan 20, 2015
Histone deacetylases (HDACs) are key players in the mediation of gene expression for both cancero... more Histone deacetylases (HDACs) are key players in the mediation of gene expression for both cancerous and noncancerous malignancies. Overexpression of these enzymes has been demonstrated in numerous types of cancer with some enzyme isoforms also involved in neurological, inflammatory and viral pathologies. Hence, the development of HDAC inhibitors (HDACis) represents a promising approach for their treatment. Numerous chemical entities have been studied in the recent years and some of them have reached clinical trials. Areas covered: This review summarizes the recent efforts in the drug development of HDACis and their potential application as therapeutic agents in cancerous, neurological, inflammatory and viral diseases. Expert opinion: The development of novel potent and selective HDACis is ongoing. However, increased scientific effort is needed to aid the fight of specific types of cancerous or noncancerous disease with more selective agents required to avoid side effects during ther...
Natural product communications, 2012
Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging... more Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only for their physiological properties and effects on Nature, but also for their therapeutic potential. Aurones are recently attracting the interest of an increasing number of research groups, and, since the last review, some interesting advances have been made in understanding the aurones. In this review, we report the recent advances made on the synthetic routes towards aurones. We also highlight their activity in different biological areas, as well as applied genetic plant modifications to produce these colored compounds. Their synthesis, structure-activity relationships and the importance of the substitution pattern will also be mentioned. Finally, some aspects regarding the...
Bioorganic & Medicinal Chemistry Letters, 2014
ChemInform, 2012
Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging... more Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only for their physiological properties and effects on Nature, but also for their therapeutic potential. Aurones are recently attracting the interest of an increasing number of research groups, and, since the last review, some interesting advances have been made in understanding the aurones.
European Journal of Organic Chemistry, 2013
The reactivity of 4-(1-butoxyvinyl)-2H-chromen-2-one and (E)-4-(2-butoxyvinyl)-2H-chromen-2-one (... more The reactivity of 4-(1-butoxyvinyl)-2H-chromen-2-one and (E)-4-(2-butoxyvinyl)-2H-chromen-2-one (2) as diene in thermal Diels-Alder cycloaddition reactions with several electron-poor dienophiles is reported. Among several dienophiles used in this study 1,4-benzoquinone afforded cyclo-
DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expre... more DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent nonnucleoside DNMTi that is also selective toward other AdoMet-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.
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Papers by Clemens Zwergel