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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A number of PBD monomers were evaluated in the clinic in the 1960s and 1970s. Anthramycin itself was demonstrated to have antitumor activity but could not be further developed due to a serious dose-limiting cardiotoxicity. This was attributed to the phenolic hydroxyl group at C9 which could be converted to a quinone species capable of producing free radicals potentially damaging to the heart muscle. Other side effects included bone marrow suppression and tissue necrosis at the injection site.
Ultraviolet and Light Absorption Spectrometry
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Zoltan M. Dinya, Ferenc J. Sztaricskai
Several another nitrogen-containing heterocyclic antibiotics are to be mentioned as practically important agents, for example, mitomycin (108) and the anthramycin antibiotics. These latter contain usually a substituted benzodiazepine skeleton, such as neothramycin A and B (109) and tomaymycin (110).
Chemical Causes of Cancer
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Gary M. Williams, Alan M. Jeffrey
Major challenges still exist in the structural elucidation of many adducts of DNA-reactive carcinogens formed in vivo. Their presence is often known, but, since the levels of modification of DNA are typically less than one adduct in 106 normal nucleotides and often three or four orders of magnitude less, the quantities of these adducts that can be isolated are, consequently, extremely small. In general, clues as to possible structures of an adduct have been inferred from the structure of the chemical producing the adduct, its metabolism, and the possible structure of the ultimate carcinogenic metabolite. The latter can then be prepared synthetically or biosynthetically, at least in a transient state, and reacted directly with DNA or homopolymers in vitro. Digestion of the DNA to the modified nucleotides will often provide sufficient material for comparison with adducts formed in vivo and subsequent structural elucidation. Only a few adducts have been prepared by direct chemical synthesis. Structure identification is normally by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. However, if isolated at the deoxyribo-nucleotide level, adducts with chiral centers will frequently separate as dia-stereomeric pairs with often approximately mirror image circular dichroism spectra. Such pairing of spectra simplifies the identification of multiple adducts, and can provide information on their absolute steriochemistry. Formation of some DNA adducts results in unstable products; for example aflatoxin forms several DNA adducts including those at N-7 position of guanine residues (256). This charged product is released from DNA either by depurination to yield 2,3-dihydro-2-(N-7-guanyl)-3-hydroxyafla-toxin B1 which can be found in the urine of exposed animals or, by opening of the imidazole ring of the guanine, forms chemically stable adducts. Anthramycin reacts with DNA to produce adducts which are unstable during DNA digestion but whose structure can be determined in oligonucleotides (293).
Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy
Published in Expert Opinion on Biological Therapy, 2021
Anthramycin was the first of the pyrrolobenzodiazepine (PBD) family of antitumour antibiotics to be discovered in the 1960s. This class of naturally occurring, and later synthetic, compounds are tricyclic systems consisting of an aromatic A-ring, a 1-4-diazepin-5-one B-ring and a pyrrolidine C-ring (Figure 1(a)). Their mechanism of action involves sequence selective binding in the minor groove of DNA and covalent binding to the exocyclic C2-amino group of guanine bases. Wholly synthetic PBD dimers, in which two PBD monomer units are joined through their C8-positions via a flexible tether, are significantly more cytotoxic due to their ability to form two covalent bonds and thereby cross-link DNA. The development of PBDs and PBD dimers as stand-alone agents has been reviewed previously [1,2].
Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer
Published in mAbs, 2019
Jason B. White, Ryan Fleming, Luke Masterson, Ben T. Ruddle, Haihong Zhong, Christine Fazenbaker, Patrick Strout, Kim Rosenthal, Molly Reed, Vanessa Muniz-Medina, Philip Howard, Rakesh Dixit, Herren Wu, Mary Jane Hinrichs, Changshou Gao, Nazzareno Dimasi
Although pyrrolobenzodiazepines (PBDs) such as anthramycin and sibiromycin were shown to be potent antitumor agents over 50 years ago, they have only recently emerged as cytotoxic warheads for antibody-drug conjugates (ADCs),1-3 which are a class of targeted therapeutics for the treatment of cancers.4-6 In their monomeric form, PBDs derive their cytotoxic activity by selectively binding to the minor groove of DNA and forming covalent bonds with the C2-NH2 group of guanine bases.7-10 Efforts to enhance this cytotoxic activity led to the synthesis of dimeric PBDs,11,12 which have two alkylating imine functions that allow the formation of minor groove DNA adducts, resulting in greater interference with DNA replication than monomeric PBDs.13-15
Management of relapsed or refractory large B-cell lymphoma in patients ineligible for CAR-T cell therapy
Published in Expert Review of Hematology, 2022
Salvatore Perrone, Paolo Lopedote, Mario Levis, Alice Di Rocco, Stephen Douglas Smith
The CD19 molecule is a 95 kd transmembrane glycoprotein belonging to the immunoglobulin superfamily that is highly expressed in malignant B cells [75]. Therefore, CD19 has become one of the most exploited targets in LBCL: CAR-T, blinatumomab, and several ADCs like Coltuximab ravtansine [76] conjugated to a cytotoxic maytansinoid DM4, and denintuzumab mafodotin (SGN-CD19A) [77] conjugated to monomethyl auristatin F. In April 2021, the results of the LOTIS-2 trial prompted the accelerated approval by the FDA of loncastuximab tesirine-ipyl (lonca) for treatment of patients with r/r DLBCL or HGBCL who failed ≥2 lines of therapy [78]. Lonca is constituted by the humanized anti-CD19 RB4v1.2 antibody and SG3249, which in turn includes the synthetic pyrrolobenzodiazepine (PBD) dimer SG-3199 (the warhead), and a valine-alanine cleavable maleimide linker. CD19 is a type I trans-membrane B cell coreceptor which plays a key role in regulating lymphopoiesis of pre-B cells as well as, in mature B cells, transducing and modulating both the tonic and the activating BCR signaling upon antigen recognition through phosphorylation of its cytoplasmic tail [79]. In the pathological setting, an interaction between upregulated CD19 expression and c-Myc signaling to promote lymphomagenesis has been proposed [80,81]. After binding, the CD19-antibody complex is rapidly internalized and progressively accumulate in an endosomal compartment [82]. Subsequent in vitro studies of lonca (ADCT-402) were able indeed to confirm the effective release of SG-3199 and its selective antitumor activity [83]. This warhead belongs to the class of the synthetic PBD dimers, which are derived from the natural occurring antibiotic anthramycin, produced by the Streptomyces spp. More specifically, SG-3199 was obtained from few key structural alterations of talirine (or SGD-1910) aimed at optimizing its kinetic (increased drug solubility) and pharmacodynamic (high potency and short half-life) [84,85]. Once inside, it rapidly intercalates in the DNA minor groove and leads to the formation of the cytotoxic interstrand cross-links. Notably, this mechanism does not require the target cell to be in metaphase and does not cause any bulky helix-distortion, which would trigger the nucleotide excision repair machinery [86].