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

Abstract

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–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.

C2‐linked alkynyl poly‐ethylene glycol(PEG) adenosine conjugates as water‐soluble adenosine receptor agonists

“… c SI is the ratio between GIC 50 and the MIC 90 BCG . d Data in agreement with previously published results (Ferguson et al, 2020 ). …”

“…d Data in agreement with previously published results (Ferguson et al, 2020). (Thomson & Lamont, 2019;Vitali et al, 2012).…”

“…Subsequently, the alkynyl‐PEG 3‐6 ‐mesylated units 8a‐d were installed at the C2 position of 2‐iodoadenosine 9 , which was synthesized as previously described (Ferguson et al, 2020 ) using established Sonogashira cross‐coupling reaction protocols to give derivatives 10a‐d . The synthetic strategy proceeded with the protection of the C‐2′, C‐3′ and C‐5′ hydroxyl groups of the ribose ring in order to reduce the number of H‐Bond Donor (HBD) groups present in the compounds' frameworks.…”

“…Nucleoside derivatives are extensively used in the clinic as antiviral and anticancer drugs, and several analogues containing modified nucleobase and sugar components were reported to exhibit promising antibacterial activity (Thomson & Lamont, 2019 ; Vitali et al, 2012 ). It was previously found that 2‐methyl adenosine inhibited the growth of Mycobacterium tuberculosis in a persistent state (Barrow et al, 2003 ), whilst 2‐iodo‐adenosine ( 9 ) exhibited bactericidal activity against M. bovis but not M. aurum (Ferguson et al, 2020 ). To this end, we sought to evaluate the anti‐mycobacterial activity of the novel ADN‐PEG conjugates against M. aurum and M. bovis strains using the HT‐SPOTi technique and isoniazid (INH) as a positive control (Gupta, 2012 ; Rizi et al, 2015 ; Danquah et al, 2016 ) (Table 3 ).…”

Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective

“…Many actinomycetes species naturally produce or contain pyrrolo-benzodiazepines (PBD) derivatives. PBD binds covalently to DNA, inhibiting transcription factors and DNA replication, thus slowing cellular growth [ 263 ]. Bose et al (2012) synthesized pyrrole-benzodiazepine derivatives and evaluated the cytotoxic activities of the synthesized compounds against HL-60 (human promyelocytic leukemia), THP-1 (human acute monocytic leukemia), U-937 (human histiocytic lymphoma), A-549 (lung carcinoma), and Jurkat (Human T-cell leukemia) cell lines.…”