Pyrrolobenzodiazepines

Pyrrolobenzodiazepines

Catalog Product Name CAS Number Molecular Formula Molecular Weight
BADC-00015 MC-Val-Ala-PBD 1342820-51-2 C60H64N8O12 1089.20
BADC-00340 PBD dimer 1222490-34-7 C42H39N5O7 725.79
BADC-00670 Mal-PEG4-VA-PBD 2259318-50-6 C70H83N9O17 1322.46
BADC-00738 MA-PEG4-VA-PBD 1342820-68-1 C68H79N9O17 1294.43
BADC-00826 Aniline-MPB-amino-C3-PBD 2412923-79-4 C42H46N8O6 758.86 g/mol
BADC-00827 Py-MPB-amino-C3-PBD 2412924-07-1 C41H44N8O6 744.84 g/mol
BADC-00851 Tesirine 1595275-62-9 C75H101N9O23 1496.65 g/mol

Pyrrolobenzodiazepines (PBDs) are well known naturally occurring DNA interactive antitumour antibiotics like anthramycin, chicamycin and DC-81, which are produced from various Streptomyces bacteria. This natural product was shown to be significantly cytotoxic toward tumour cells in vitro. Meanwhile, PBDs-dimers are DNA alkylators that exhibit extremely potent cytotoxic activities against multiple cancer cell lines. These molecules function by covalently binding to the 2-amino groups of guanine in the minor grooves of cellular DNA, thereby forming DNA adducts that disrupt normal cell functions.

Chemical structure

Pyrrolobenzodiazepines (PBDs) are all tricyclic systems consisting of an aromatic A-ring, a 1-4-diazepin-5-one B-ring and a pyrrolidine C-ring, which differ from one another principally by the position and type of substituents in the A- and C-rings, and the degree and position of points of unsaturation in the C-ring. All the naturally occurring compounds possess the S-configuration at C11a which results in a right-handed helical conformation allowing them to fit perfectly in the minor groove of DNA.

Mechanism of action

Pyrrolobenzodiazepine’s biological activity through covalent binding via their N10–C11 imine/carbinolamine moiety to the C2-amino position of a guanine residue within the minor groove of duplex DNA. PBDs monomers span three DNA base pairs with a preference for 50-Pu-G-Pu, particularly 50-AG or 50-GA sequences. The cytotoxicity of these agents is thought to be due to their ability to inhibit cellular processes such as replication and transcription. PBDs-dimers can form interstrand and intrastrand DNA cross-links as well as mono-alkylated DNA adducts, and are significantly more cytotoxic than PBD monomers such as anthramycin, a characteristic attributed to their ability to cross-link DNA.

Application

Since the discovery of the pyrrolobenzodiazepines in 1965, examples of both PBD monomers (anthramycin, tomaymycin, neothramycin and sibiromycin) and a PBD dimer (SJG-136) have been evaluated in the clinic as single-agent anticancer agents. Due to their exquisite cytotoxicity in tumour cell lines, PBD dimers were first evaluated as ADC payloads in the late 2000s. The first conjugates to reach the clinic were rovalpituzumab tesirine (Rova-T), targeted to DLL3 (Cancer Stem Cell-Associated Target Delta-Like Protein 3) for lung cancer, and vadastuximab talirine (SGN-CD33A), targeted to CD33 (SIGLEC-3, a transmembrane receptor expressed on cells of myeloid lineage) for acute myeloid leukaemia (AML). Since then, a number of other ADCs containing a PBD dimer payload have entered the clinic. The linker-payload Tesirine (SG3249) incorporating the payload SG3199 is the construct of choice for several ADCs including rovalpituzumab tesirine, ADCT-301, ADCT-402, ADCT-601, ADCT-602, MEDI7247 and MEDI3726 which are all currently at different stages of clinical development.

References

  1. Kamal, A.; et al. Synthesis and potential cytotoxic activity of new phenanthrylphenol-pyrrolobenzodiazepines. European Journal of Medicinal Chemistry, 2010, 45: 2173-2181.
  2. Hartley; J.A. The development of pyrrolobenzodiazepines as antitumour agents. Expert Opin. Investig. Drugs, 2011, 20(6): 733-744.
* Only for research. Not suitable for any diagnostic or therapeutic use.

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