53631-75-7Relevant academic research and scientific papers
Design, synthesis, and evaluation of a novel sequence-selective epoxide- containing DNA cross-linking agent based on the pyrrolo[2,1- c][1,4]benzodiazepine system
Wilson, Stuart C.,Howard, Philip W.,Forrow, Stephen M.,Hartley, John A.,Adams, Lesley J.,Jenkins, Terence C.,Kelland, Lloyd R.,Thurston, David E.
, p. 4028 - 4041 (1999)
Synthetic routes have been investigated to prepare a novel C8-epoxide- functionalized pyrrolo[2,1-c][1,4]benzodiazepine 6 as a potential sequence- selective DNA cross-linking agent (Wilson et al. Tetrahedron Lett. 1995, 36, 6333-6336). A successful synthesis was accomplished via a 10-step route involving a pro-N10-Fmoc cleavage method that should have general applicability to other pyrrolobenzodiazepine (PBD) molecules containing acid- or nucleophile-sensitive groups. During the course of this work, a one-pot reductive cyclization procedure for the synthesis of PBD N10-C11 imines from nitro dimethyl acetals was also discovered, although this method results in C11a racemization which can reduce DNA binding affinity and cytotoxicity. The target epoxide 6 was shown by thermal denaturation studies to have a significantly higher DNA-binding affinity than the parent DC-81 (3) or the C8-propenoxy-PBD (15), which is structurally similar but lacks the epoxide moiety. The time course of effects upon thermal denaturation indicated a rapid initial binding phase followed by a slower phase consistent with the stepwise cross-linking of DNA observed for a difunctional agent. This was confirmed by an electrophoretic assay which demonstrated efficient induction of interstrand cross-links in plasmid DNA at concentrations > 1 μM. Higher levels of interstrand cross-linking were observed at 24 h compared to 6 h incubation. A Taq polymerase stop assay indicated a preference for binding to guanine-rich sequences as predicted for bis-alkylation in the minor groove of DNA by epoxide and imine moieties. The pattern of stop sites could be partly rationalized by molecular modeling studies which suggested low-energy models to account for the observed binding behavior. The epoxide PBD 6 was shown to have significant cytotoxicity (45-60 nM) in the A2780, CH1, and CH1cis(R) human ovarian carcinoma cell lines and an IC50 of 0.2 μM in A2780cis(R). The significant activity of 6 in the cisplatin-resistant CH1cis(R) cell line (IC50 = 47 nM) gave a resistance factor of 0.8 compared to the parent cell line, demonstrating no cross-resistance with the major groove cross-linking agent cisplatin.
Design and synthesis of a novel epoxide-containing pyrrolo[2,1-c[]1,4]benzodiazepine (PBD) via a new cyclization procedure
Wilson,Howard,Thurston
, p. 6333 - 6336 (2007/10/02)
The synthesis of a potential DNA-crosslinking pyrrolo[2,1-c]-[1,4]benzodiazepine (PBD) substituted at the C8-position with a 2,3-epoxypropaneoxy moiety using a new cyclization procedure is described.
