Effect of hairpin loop structure on reactivity, sequence preference and adduct orientation of a DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumour agent

Abstract

The pyrrolobenzodiazepines (PBDs) are a family of covalent-binding DNA-interactive minor-groove binding agents with a thermodynamic preference for binding to 5'-Pu-G-Pu-3' sequences (Pu = Purine) but a kinetic preference for 5'-Py-G-Py-3' (Py = Pyrimidine). Using HPLC/MS methodology and a range of designed hairpin-forming oligonucleotides, the kinetics of reaction of a C8-bis-pyrrole pyrrolobenzodiazepine (PBD) conjugate (GWL-78, 2) with sixteen isomeric oligonucleotides has been evaluated, each containing a single PBD binding site in one of two locations. The PBD-binding base-pair triplets were designed to include every possible combination of A and T bases adjacent to the covalently-reacting guanine, with the set of hairpins consisting of isomeric pairs containing the same sequence in the hairpin stem but with either hexaethylene glycol (HEG) or TTT loops. The PBD 2 reacted most rapidly with TGT and TGA sequences, with the possibility that adducts might form in both the 3'- and 5'-directions with some sequences according to modelling studies. A faster reaction rate was observed for all hairpins containing the HEG loop except one (Seq 10) when the PBD binding triplets were located either near the loop or adjacent to the 5'-end. Modelling studies have suggested that this difference in reactivity could be due to the structural flexibility of the HEG loop allowing both A-ring-3' and A-ring-5' adducts to form, while a TTT loop should favour only A-ring-5' adducts due to steric considerations. These findings contrast with the results reported by Nguyen and Wilson for the interaction of non-covalent DNA-binding molecules with DNA hairpins, where the loop structure was found to have little effect on interaction in the main stem of the hairpin.

Green synthesis of 1,4-benzodiazepines over La2O3 and La(OH)3 catalysts: possibility of Langmuir–Hinshelwood adsorption

“…[17][18][19][20] Benzodiazepines are heterocyclic compounds with pharmacological applications 21,22 involving anti-tumor and anti-parasitic activities. [23][24][25] Synthesis of these biologically relevant benzodiazepine derivatives was achieved through ionic liquid catalysis, 26 solid phase synthesis, 5,27 organometallic reagents [28][29][30] and by other methods. 31 Previous examples of heterogeneous catalysts utilized for the synthesis of substituted benzodiazepines include ZnS nanoparticles, chitosan supported Fe 3 O 4 nanoparticulate materials, 32 silver salts of silico-tungstic acid, Sn(HPO 4 ) 2 $H 2 O, MoO 3 -SiO 2 bifunctional catalysts, mixed-metal oxides [33][34][35][36][37][38][39] etc.…”

Isolation, chemistry, and biology of pyrrolo[1,4]benzodiazepine natural products

“…9 The biological mechanism responsible for the anticancer potential of PBD has been broadly studied and is well understood. [131][132][133] The majority of PBD natural products possess a tricyclic core consisting of an aromatic A-ring, a diazepine B-ring and a pyrrolidine C-ring as well as an S-configured stereocenter at the C11a position (Figure 1).…”

“…In 1997, a DC‐81 ( 2 ) synthesis involving late‐stage amine oxidation was reported by Kamal et al 162 (Scheme 4). Exposure of nitroaldehyde 81 132 to classic hydrogenation conditions led to overreduction. The amine intermediate 82 could be converted to a natural product by oxidation using a combination of TPAP and NMO in acetonitrile.…”

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

“…[ 26 – 34 ]. In addition, these azaheterocycles also exhibit anti-inflammatory, antitumor, antiparasitic and anxiolytic activities [ 35 – 42 ]. In particular, 1,4-benzodiazepine derivatives are proposed to serve as a structural mimic of peptide β-turns [ 43 – 45 ] and are also known to bind to a number of biological targets [ 46 – 48 ].…”