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Drug Analysis of Protein Microspheres: From Pharmaceutical Preparation to In Vivo Fate
Published in Neville Willmott, John Daly, Microspheres and Regional Cancer Therapy, 2020
Jeffrey Cummings, David Watson, John F. Smyth
The anthracyclines consist of a large group of naturally occurring and semisynthetic antibiotic compounds based on a highly colored benzanthraquinone nucleus and carbohydrate side chain and are structurally and functionally divided into three classes. The class I compounds (Figure 1A), including doxorubicin and daunorubicin, the prototypes of the whole group, are all monosaccharides in which the sugar is the unusual daunosamine moiety, which contains a positively charged basic amino group on position 3′ that is critical for anticancer activity. The class II compounds (Figure 1B), including aclacinomycin and marcellomycin, are polysaccharides. They inhibit RNA synthesis at concentrations several hundredfold lower than required to inhibit DNA synthesis, which distinguishes them from class I. Included in this class is the nonsugar containing semisynthetic antibiotic menogaril. The third class has more recently emerged and is characterized by high activity (1000-fold greater cytotoxicity in vitro than doxorubicin). These compounds are based on class I but with substitution of morpholino and cyanomorpholino (MRA-CN) ring systems on the amino group of daunosamine but are distinguished from class I and II by a mechanism of action that probably involves covalent binding to DNA.
Biological Response Modifiers and Chemotherapeutic Agents that Alter Interleukin 2 Activities
Published in Ronald H. Goldfarb, Theresa L. Whiteside, Tumor Immunology and Cancer Therapy, 2020
William L. West, Allen R. Rhoads, Clement O. Akogyeram
Doxorubicin, daunorubicin and aclacinomycin are examples of naturally occurring anthracycline glycoside antibiotics. These molecules consist of an aromatic tetracyclic aglycone and an amino sugar. The sugars and amino sugars found in the three glycosides include daunosamine, rhodosamine, 2-deoxy-L-fucose, and rhodonose. Doxorubicin and daunorubicin contain amino sugar daunosamine, whereas aclacinomycin contains rhodosamine and a trisaccharide. The aglycone region of each molecule is hydrophobic whereas the amino sugar is hydrophilic. These compounds are amphipathic, containing both basic and hydrophobic regions. Doxorubicin (pKa 7.2–7.4) is partially ionized at pH 7.4 by protonation of the amino group. The pKa of aclacinomycin is lower resulting in even less of this compound being ionized at physiological pH.
Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Malignancies
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
G.E. Bates, P. Kim, C.M. DeRosa, L. Petrukhin, Y. Bressler, R.N. Taub
Doxorubicin, also hydroxyldaunorubicin, is a DNA-interacting drug widely used in chemotherapy. It is an anthracycline antibiotic which is structurally similar to daunomycin, both of which intercalate DNA. Doxorubicin is used in the treatment of a wide range of cancers and is administered by injection. The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is understood to interact with DNA by intercalation, thereby inhibiting macromolecular biosynthesis. The planar aromatic chromophore portion of the doxorubicin molecule intercalates between two base pairs of DNA, while six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by crystallography.
Synthesis and cellular characterization of various nano-assemblies of cell penetrating peptide-epirubicin-polyglutamate conjugates for the enhancement of antitumor activity
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Samaneh Mohammadi, Parvin Zakeri-Milani, Nasim Golkar, Samad Mussa Farkhani, Ali Shirani, Javid Shahbazi Mojarrad, Ali Nokhodchi, Hadi Valizadeh
Epirubicin (EPR) is an anthracycline drug that has been used alone or in combination with other drugs for treatment of various cancers such as breast, ovarian, gastric and lung [5,6]. EPR is a stereoisomer of doxorubicin and is flavored over it. It has been shown that EPR is generally more successful than doxorubicin due to the higher tumor therapeutic efficiency and less side effects [7,8]. In fact, as a consequence of the reorientation of the hydroxyl group in the 4'-position of the daunosamine ring, epirubicin possess different pharmacologic properties than doxorubicin [9]. First, it has a lower pKa. Accordingly, it is more lipophilic and better able to penetrate cells. Second, the glucuronidation of epirubicin and epirubicinol to inactive metabolites leads to a shorter terminal half-life for epirubicin (30 h) when compared with doxorubicin (45 h) [8,9]. Third, higher doses of epirubicin are required to produce the same degree of toxicity as doxorubicin. The doxorubicin-epirubicin dose ratios for similar toxicities are 1:1.2 for hematologic, 1:1.5 for nonhematologic and 1:1.8 for cardiac [8,10].
Pixantrone: novel mode of action and clinical readouts
Published in Expert Review of Hematology, 2018
Giorgio Minotti, Haiyong Han, Valérie Cattan, Anton Egorov, Francesco Bertoni
The chemical structure of pixantrone is unique compared with other quinone-hydroquinone anthracycline-like drugs. It is different from the prototypic anthracenedione mitoxantrone and the anthracycline doxorubicin [9]. Anthracenediones are a class of synthetic anticancer compounds that differ from doxorubicin and other anthracyclines in that they do not have an amino sugar moiety (daunosamine) and have only three molecular rings compared with four in doxorubicin and other anthracyclines [9]. Pixantrone in turn differs from mitoxantrone by having no hydroquinone, a nitrogen heteroatom inserted in the ring lacking the hydroquinone, and a substitution of (ethylamino)diethylamino for (hydroxyethylamino)-ethylamino side chains [9]. Figure 1 shows the chemical structure of pixantrone compared with doxorubicin and mitoxantrone.
Doxorubicin conjugated with a trastuzumab epitope and an MMP-2 sensitive peptide linker for the treatment of HER2-positive breast cancer
Published in Drug Delivery, 2018
Yiwen You, Zhiyuan Xu, Yun Chen
As mentioned earlier, the peptide component of the peptide-DOX conjugate MAHNP-DOX is composed of the cleavable linker GPLGLAGDD and the anti-HER2 peptide AHNP, followed by conjugation with DOX (Figure 1). To avoid an undesired coupling reaction between the amino group on the daunosamine moiety of DOX and the peptide, we first prepared N-Fmoc-DOX by protecting the amino group with Fmoc-Cl (Nagy et al., 1996). Afterwards, N-Fmoc-DOX was reacted with glutaric anhydride in the presence of DIPEA to produce the intermediate N-Fmoc-DOX-14-O-hemiglutarate. Finally, the peptide was conjugated to N-Fmoc-DOX-14-O-hemiglutarate, and the Fmoc groups were removed with piperidine treatment to obtain MAHNP-DOX with 43.5% yield and 95.1% purity (Figure 2(A)). The peaks occurred at 5.5 min for DOX, at 18.2 min for N-Fmoc-DOX, at 19.2 min for N-Fmoc-DOX-14-O-hemiglutarate and at 14.1 min for MAHNP-DOX.