Synthesis and Biological Evaluation of a Novel C8-Pyrrolobenzodiazepine (PBD) Adenosine Conjugate. A Study on the Role of the PBD Ring in the Biological Activity of PBD-Conjugates
| Autor: | Geoff Wells, Sanjib Bhakta, Lindsay Ferguson, Federico Brucoli, Keith R. Fox |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adenosine
dnase i footprinting Pharmaceutical Science Ligands 01 natural sciences Analytical Chemistry Mice chemistry.chemical_compound Drug Discovery Moiety c8-linked pyrrolobenzodiazepine (pbd) conjugates 0303 health sciences Chemistry dna minor groove binding agents Chemistry (miscellaneous) heterodimeric hybrids Molecular Medicine medicine.drug Guanine Stereochemistry Pyrrolobenzodiazepine Molecular Dynamics Simulation Dioxins behavioral disciplines and activities High-throughput spot-culture growth inhibition assay Article Cell Line lcsh:QD241-441 03 medical and health sciences lcsh:Organic chemistry adenosine nucleoside medicine Animals Physical and Theoretical Chemistry 030304 developmental biology DNase I footprinting Base Sequence 010405 organic chemistry Organic Chemistry C8-linked pyrrolobenzodiazepine (PBD) conjugates DNA 0104 chemical sciences high-throughput spot-culture growth inhibition assay anti-mycobacterial compounds DNA minor groove binding agents Linker Nucleoside Conjugate |
| Zdroj: | Molecules, Vol 25, Iss 5, p 1243 (2020) Molecules Volume 25 Issue 5 |
| Popis: | Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid. The PBD and adenosine (ADN) moieties were synthesized separately and then linked through a pentynyl linker. To our knowledge, this is the first report of a PBD connected to a nucleoside. Surprisingly, the compound showed no cytotoxicity against murine cells and was inactive against Mycobacterium aurum and M. bovis strains and did not bind to guanine-containing DNA sequences, as shown by DNase I footprinting experiments. Molecular dynamics simulations revealed that the PBD&ndash ADN conjugate was poorly accommodated in the DNA minor groove of two DNA sequences containing the AGA-PBD binding motif, with the adenosine moiety of the ligand preventing the covalent binding of the PBD unit to the guanine amino group of the DNA duplex. These interesting findings shed further light on the ability of the substituents attached at the C8 position of PBDs to affect and modulate the biological and biophysical properties of PBD hybrids. |
| Databáze: | OpenAIRE |
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