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Angewandte Chemie (International Ed. in... Jan 2017The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective DNA minor-groove binding agents that form a covalent aminal bond between their... (Review)
Review
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective DNA minor-groove binding agents that form a covalent aminal bond between their C11-position and the C2-NH groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG-136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor-targeting antibodies to create antibody-drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre-clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD-containing ADCs, and explores both structure-activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.
Topics: Anthramycin; Antibiotics, Antineoplastic; Antibodies; Benzodiazepines; Cell Proliferation; Female; Humans; Leukemia; Molecular Structure; Ovarian Neoplasms; Pyrroles
PubMed: 27862776
DOI: 10.1002/anie.201510610 -
Molecules (Basel, Switzerland) Jan 2016Pyrrolo[1,4]benzodiazepines are tricyclic compounds that are considered "privileged structures" since they possess a wide range of biological activities. The first... (Review)
Review
Pyrrolo[1,4]benzodiazepines are tricyclic compounds that are considered "privileged structures" since they possess a wide range of biological activities. The first encounter with these molecules was the isolation of anthramycin from cultures of Streptomyces, followed by determination of the X-ray crystal structure of the molecule and a study of its interaction with DNA. This opened up an intensive synthetic and biological study of the pyrrolo[2,1-c][1,4]benzodiazepines that has culminated in the development of the dimer SJG-136, at present in Phase II clinical trials. The synthetic efforts have brought to light some new synthetic methodology, while the contemporary work is focused on building trimeric pyrrolo[2,1-c][1,4]benzodiazepines linked together by various heterocyclic and aliphatic chains. It is the broad spectrum of biological activities of pyrrolo[1,2-a][1,4]benzodiazepines that has maintained the interest of researchers to date whereas several derivatives of the even less studied pyrrolo[1,2-d][1,4]benzodiazepines were found to be potent non-nucleoside HIV-1 reverse transcriptase inhibitors. The present review is an update on the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines since the last major review of 2011, while the overview of the synthesis of the other two tricyclic isomers is comprehensive.
Topics: Anti-HIV Agents; Antineoplastic Agents; Benzodiazepines; Clinical Trials as Topic; Cyclization; DNA; HIV Infections; Humans; Molecular Structure; Neoplasms; Pyrroles; Structure-Activity Relationship
PubMed: 26828475
DOI: 10.3390/molecules21020154 -
The Journal of Antibiotics Sep 1981Streptomyces refuineus, the microorganism which produces the DNA reactive antibiotic anthramycin, has shown to possess a quite specific mechanism to survive and grow in...
Streptomyces refuineus, the microorganism which produces the DNA reactive antibiotic anthramycin, has shown to possess a quite specific mechanism to survive and grow in the presence of this antibiotic. Stationary phase cells are insensitive to anthramycin since the antibiotic is prevented form entering these cells. However, cells in early log phase are inhibited by concentrations of anthramycin that are later produced by these same cells. Significantly, sibiromycin, a closely related antibiotic, is taken up by cells of S. refuineus independent of the age of the culture. Anthramycin reacts in vitro equally as well as DNA isolated from S. refuineus and other procaryotic and eucaryotic cells. When S. refuineus has reached the production phase the anthramycin is probably biosynthesized outside the cell membrane which also becomes specifically impermeable to anthramycin.
Topics: Aminoglycosides; Anthramycin; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Benzodiazepinones; Cell Membrane Permeability; Streptomyces
PubMed: 6895748
DOI: 10.7164/antibiotics.34.1171 -
Medicinal Research Reviews Mar 2012Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes... (Review)
Review
Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The remarkable broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA-binding sequence specificity and in the potency of this class of compounds. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. Only recently, the biosynthetic gene clusters for PBDs have been identified opening the doors to the production of glycosylated PBDs by mutasynthesis and biosynthetic engineering. This review describes the recent studies on the biosynthesis of naturally produced pyrrolobenzodiazepines. In addition, it provides an overview on the isolation and characterization of naturally produced PBDs, chemical synthesis of PBDs, mechanism of DNA alkylation, and DNA-binding affinity and cytotoxic properties of both naturally produced and synthetic pyrrolobenzodiazepines.
Topics: Actinobacteria; Aminoglycosides; Anthramycin; Antineoplastic Agents, Alkylating; Benzodiazepines; DNA; Models, Molecular; Multigene Family; Pyrroles; Structure-Activity Relationship
PubMed: 20544978
DOI: 10.1002/med.20212 -
The Journal of Biological Chemistry Dec 1992The repair of anthramycin-DNA adducts by the UVR proteins in Escherichia coli follows two pathways: the adducts may be incised by the combined actions of UVRA, UVRB, and... (Comparative Study)
Comparative Study
The repair of anthramycin-DNA adducts by the UVR proteins in Escherichia coli follows two pathways: the adducts may be incised by the combined actions of UVRA, UVRB, and UVRC, or alternatively, the anthramycin may be removed by UVRA and UVRB in the absence of UVRC and with no DNA strand incision. To assess the competition between these two competing pathways, the rate of UVRABC-mediated excision repair of anthramycin-N2-guanine DNA adducts and the rate of UVRAB-mediated removal of the adduct were measured with single end-labeled DNAs under identical reaction conditions. UVR protein concentrations of 15 nM UVRA, 100 nM UVRB, and 10 nM UVRC protein were chosen to mimic in vivo concentrations. With these UVR protein concentrations and anthramycin-DNA concentrations of 1-2 nM the incision reaction and the release reactions are described by first-order kinetics. The rate of the UVRABC reaction, measured as the increase in incised fragments, was six to seven times faster than the rate of the UVRAB reaction, measured as the decrease in incised fragments. The UVRABC incision rate on anthramycin-modified linear DNA was four to five times the incision rate measured on the same DNA irradiated with ultraviolet light. We also investigated the role of the ATPase function of UVRB in UVRAB-mediated anthramycin removal. We found that a UVRB analogue with alanine at arginine 51, which retains near wild type ATPase activity, supported removal of anthramycin in the presence of UVRA, whereas a UVRB analogue with alanine at lysine 45, which abolishes the ATPase activity, did not. UVRB*, a specific proteolytic cleavage product of UVRB which retains the ATPase activity, did support removal of anthramycin in the presence of UVRA.
Topics: Anthramycin; DNA; DNA Adducts; DNA Repair; DNA, Bacterial; Drug Combinations; Endodeoxyribonucleases; Escherichia coli; Escherichia coli Proteins; Genes, Bacterial; Guanine; Kinetics; Plasmids; Time Factors
PubMed: 1447212
DOI: No ID Found -
The Journal of Antibiotics May 1977
Comparative Study Review
Topics: Animals; Anthramycin; Antibiotics, Antineoplastic; Benzodiazepinones; Chemical Phenomena; Chemistry; DNA; Dihydroxyphenylalanine; Humans; Kinetics; Microbial Sensitivity Tests; Streptomyces; Structure-Activity Relationship; Tyrosine
PubMed: 328469
DOI: 10.7164/antibiotics.30.349 -
Nature Communications Aug 2018
Topics: Anthramycin; Bacterial Proteins; Carbon; Catalytic Domain; Lincomycin; Methylation; Molecular Structure; Mutation; Phenylpyruvic Acids; Proline; Protein Binding; Streptomyces
PubMed: 30093642
DOI: 10.1038/s41467-018-05455-3 -
Bioorganic & Medicinal Chemistry Feb 2015A description of pyrrolo[1,4]benzodiazepine (PBD) biosynthesis is a prerequisite for engineering production of analogs with enhanced antitumor activity. Predicted...
A description of pyrrolo[1,4]benzodiazepine (PBD) biosynthesis is a prerequisite for engineering production of analogs with enhanced antitumor activity. Predicted dioxygenases Orf12 and SibV associated with dihydropyrrole biosynthesis in PBDs anthramycin and sibiromycin, respectively, were expressed and purified for activity studies. UV-visible spectroscopy revealed that these enzymes catalyze the regiospecific 2,3-extradiol dioxygenation of l-3,4-dihydroxyphenylalanine (l-DOPA) to form l-2,3-secodopa (λmax=368 nm). (1)H NMR spectroscopy indicates that l-2,3-secodopa cyclizes into the α-keto acid tautomer of l-4-(2-oxo-3-butenoic-acid)-4,5-dihydropyrrole-2-carboxylic acid (λmax=414 nm). Thus, the dioxygenases are key for establishing the scaffold of the dihydropyrrole moiety. Kinetic studies suggest the dioxygenase product is relatively labile and is likely consumed rapidly by subsequent biosynthetic steps. The enzymatic product and dimeric state of these dioxygenases are conserved in dioxygenases involved in dihydropyrrole and pyrrolidine biosynthesis within both PBD and non-PBD pathways.
Topics: Aminoglycosides; Anthramycin; Dioxygenases; Magnetic Resonance Spectroscopy; Molecular Structure; Pyrroles
PubMed: 25564379
DOI: 10.1016/j.bmc.2014.12.024 -
The Journal of Biological Chemistry Jul 1984Nuclear magnetic resonance techniques are used to confirm the points of attachment of anthramycin to DNA. Using 13C NMR spectroscopy, the C-11 resonance of anthramycin...
Nuclear magnetic resonance techniques are used to confirm the points of attachment of anthramycin to DNA. Using 13C NMR spectroscopy, the C-11 resonance of anthramycin is shown to undergo a 16-ppm upfield shift upon formation of a covalent bond with DNA, indicative of an aminal linkage at that position. The site of attachment on the DNA is determined using the self-complementary oligodeoxyribonucleotide d-(ApTpGpCpApT) as a DNA model. Proton NMR, both in H2O and D2O solutions, provides a direct characterization of the anthramycin-oligonucleotide adduct. Upon covalent attachment to the duplex, a loss in the helical symmetry is observed, resulting in a doubling of several of the oligonucleotide resonances. Examination of the data confirms that the point of attachment of the anthramycin to the d-(ApTpGpCpApT) is at the guanine-NH2-position, consistent with the model proposed by Hurley and Petrusek (Hurley, L. H., and Petrusek, R. L. (1979) Nature (Lond.) 282, 529-531) and Petrusek et al. (Petrusek, R. L., Anderson, G. L., Garner, T. F., Fannin, Q. L., Kaplan, D. J., Zimmer, S. G., and Hurley, L. H. (1981) Biochemistry 20, 1111-1119).
Topics: Animals; Anthramycin; Benzodiazepinones; Cattle; Chemical Phenomena; Chemistry; DNA; Magnetic Resonance Spectroscopy; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Oligonucleotides; Spectrophotometry, Ultraviolet; Thermodynamics; Thymus Gland
PubMed: 6736032
DOI: No ID Found -
Nature Communications Aug 2018
Topics: Anthramycin; Lincomycin; Methylation; Proline; Streptomyces
PubMed: 30093620
DOI: 10.1038/s41467-018-05500-1