7
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Design, synthesis, and antitumor evaluation of histone deacetylase inhibitors with l-phenylglycine scaffold

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          In our previous research, a novel series of histone deacetylase (HDAC) inhibitors with l-phenylglycine scaffold were designed and synthesized, among which amides D3 and D7 and ureido D18 were far superior to the positive control (suberoylanilide hydroxamic acid [SAHA]) in HDAC inhibition, but were only comparable to SAHA in antiproliferation on tumor cell lines. Herein, further structural derivation of lead compounds D3, D7, and D18 was carried out to improve their cellular activities. Most of our newly synthesized compounds exhibited more potent HDAC inhibitory activities than the positive control SAHA, and several derivatives were even better than their parent compounds. However, compared with SAHA and our lead compounds, only secondary amine series compounds exhibited improved antiproliferative activities, likely due to their appropriate topological polar surface area values and cell permeabilities. In a human histiocytic lymphoma (U937) xenograft model, the most potent secondary amine 9d exhibited similar in vivo antitumor activity to that of SAHA.

          Related collections

          Most cited references 9

          • Record: found
          • Abstract: found
          • Article: not found

          Histone deacetylase inhibitors in the treatment of cancer: overview and perspectives.

          Histone deacetylase inhibitors (HDACis) are one of the last frontiers in pharmaceutical research. Several classes of HDACi have been identified. Although more than 20 HDACi are under preclinical and clinical investigation as single agents and in combination therapies against different cancers, just two of them were approved by the US FDA: Zolinza(®) and Istodax(®), both licensed for the treatment of cutaneous T-cell lymphoma, the latter also of peripheral T-cell lymphoma. Since HDAC enzymes act by forming multiprotein complexes (clusters), containing cofactors, the main problem in designing new HDACi is that the inhibition activity evaluated on isolated enzyme isoforms does not match the in vivo outcomes. In the coming years, the research will be oriented toward a better understanding of the functioning of these protein complexes as well as the development of new screening assays, with the final goal to obtain new drug candidates for the treatment of cancer.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            New insights into the treatment of multiple myeloma with histone deacetylase inhibitors.

            Multiple Myeloma (MM) is a common hematologic malignancy of plasma cells representing an excellent model of epigenomics dysregulation in human disease. Importantly, these findings, in addition to providing a better understanding of the underlying molecular changes leading to this malignance, furnish the basis for an innovative therapeutic approach. Histone deacetylase inhibitors (HDACIs), including Vorinostat and Panobinostat, represent a novel class of drugs targeting enzymes involved in epigenetic regulation of gene expression, which have been evaluated also for the treatment of multiple myeloma. Although the clinical role in this setting is evolving and their precise utility remains to be determined, to date that single-agent anti-MM activity is modest. More importantly, HDACIs appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, mainly proteasome inhibitors including bortezomib. The molecular basis underlying this synergism seems to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment. Here we review molecular events underling antitumor effects of HDACIs and the most recent results of clinical trials in relapsed and refractory MM.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Discovery of the First N-Hydroxycinnamamide-Based Histone Deacetylase 1/3 Dual Inhibitors with Potent Oral Antitumor Activity

              In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which the representative compound 14a exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using 14a as lead, among which, compound 11r gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Compounds 11e, 11r, 11w, and 11y showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compound 11r as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity.
                Bookmark

                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                8 October 2015
                : 9
                : 5553-5567
                Affiliations
                [1 ]Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji’nan, People’s Republic of China
                [2 ]Weifang Bochuang International Biological Medicinal Institute, Weifang, Shandong, People’s Republic of China
                Author notes
                Correspondence: Yingjie Zhang; Wenfang Xu, Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji’nan, Shandong 250012, People’s Republic of China, Tel/fax +86 531 8838 2009; +86 531 8838 2264, Email zhangyingjie@ 123456sdu.edu.cn ; wenfxu@ 123456163.com
                Article
                dddt-9-5553
                10.2147/DDDT.S94037
                4603714
                © 2015 Zhang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                phenylglycine, histone deacetylases, inhibitor, antitumor

                Comments

                Comment on this article