Abstract:The pyrrolobenzodiazepines (PBD) are naturally occurring antitumor antibiotics, and a PBD dimer (SJG-136, SG2000) is in phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble prodrug of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites are eliminated, the imine moieties can bind covalently in the DNA minor groove, forming an i… Show more
“…This observation is expected, as the bisulphate forms are considered as the pro-drug of the corresponding imine form of PBD dimers and are expected to hydrolyse to generate the imine form under experimental conditions. 36
Figure 3.DNase I footprints showing the interaction of the PBD dimers with HexA and HexB fragments. The sequences of these fragments are shown in Figure S1.…”
ObjectivesPyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.MethodsDNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.ResultsIncreasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.ConclusionsPBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates.
“…This observation is expected, as the bisulphate forms are considered as the pro-drug of the corresponding imine form of PBD dimers and are expected to hydrolyse to generate the imine form under experimental conditions. 36
Figure 3.DNase I footprints showing the interaction of the PBD dimers with HexA and HexB fragments. The sequences of these fragments are shown in Figure S1.…”
ObjectivesPyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.MethodsDNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.ResultsIncreasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.ConclusionsPBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates.
“…The MTD of cytokines in patients may vary substantially [e.g., 9.4-132 mg/kg/d for IL2 (52), 1 mg/kg/d for IL12 (53,54), 4 mg/kg/d for TNF (55)(56)(57), 0.5 mg/kg/d for granulocyte macrophage colony-stimulating factor (GM-CSF) (58), 0.46-0.95 mg/kg/d for IFNa (58,59), 1-20 mg/kg/d for IL10 (60), 178 mg/kg/d for IFNb (61)]. Similarly, the cytotoxic agents which have been used for ADC development range from doxorubicin and methotrexate, with in vitro cell killing potency in the 0.1 to 1 mmol/L range (62) to pyrrolobenzodiazepines which are able to kill tumor cells in vitro at subpicomolar concentrations (63). Should the cytokine payload be more active compared with the cytotoxic agent, it would be conceivable to fine-tune the corresponding biologic activity by amino acid mutations.…”
The combination of immunostimulatory agents with cytotoxic drugs is emerging as a promising approach for potentially curative tumor therapy, but advances in this field are hindered by the requirement of testing individual combination partners as single agents in dedicated clinical studies, often with suboptimal efficacy. Here, we describe for the first time a novel multipayload class of targeted drugs, the immunocytokine-drug conjugates (IDC), which combine a tumor-homing antibody, a cytotoxic drug, and a proinflammatory cytokine in the same molecular entity. In particular, the IL2 cytokine and the disulfide-linked maytansinoid DM1 microtubular inhibitor could be coupled to the F8 antibody, directed against the alternatively spliced EDA domain of fibronectin, in a site-specific manner, yielding a chemically defined product with selective tumorhoming performance and potent anticancer activity in vivo, as tested in two different immunocompetent mouse models.
“…Dieser Ansatz wurde auch von Spirogen Ltd. für die Synthese des PBD-Dimer-Vorläufers SG2285 verwendet (Abbildung 22 B). [128] Abbildung 22. A) PBD-Dimerkomponente, die von Hangzhou DAC Biotech Ltd. [127] patentiert wurde, und B) das von Spirogen Ltd. synthetisierte PBD-Dimer SG2285.…”
Section: Pbd-basierte Adcs In Der Klinischen Entwicklungunclassified
Die Pyrrolo[2,1‐c][1,4]benzodiazepine (PBDs) sind eine Familie sequenzselektiver Wirkstoffe, die an die kleine Furche der DNA binden und eine kovalente Aminalbindung zwischen der C11‐Position und den C2‐NH2‐Gruppen der Guaninbasen bilden. Anthramycin ist das erste Beispiel eines PBD‐Monomers und wurde in den 1960er Jahren entdeckt. In den 1990er Jahren wurde das bekannteste PBD‐Dimer SJG‐136 entwickelt und hat jetzt bereits die klinischen Studien der Phase II in Patienten mit Leukämie und Eierstockkrebs durchlaufen. Seit kurzem werden aus PBD‐Dimeranaloga und spezifisch an Tumorzellen bindenden Antikörpern Antikörper‐Wirkstoff‐Konjugate (ADCs) hergestellt. Von diesen befinden sich derzeit mehrere in klinischen Studien und viele andere in der präklinischen Entwicklung. Dieser Aufsatz zeigt die Entwicklung der PBDs ausgehend von Anthramycin über die ersten PBD‐Dimere bis hin zu PBD‐haltigen ADCs und behandelt sowohl die Struktur‐Wirkungs‐Beziehungen und die Biologie der PBDs als auch die Strategien für ihre Verwendung als Wirkstoffkomponente in ADCs.
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