UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Design and Synthesis of Novel N10 Protected Pyrrolobenzodiazepines for Use in ADEPT and GDEPT

Von Bulow, Christina; (2009) Design and Synthesis of Novel N10 Protected Pyrrolobenzodiazepines for Use in ADEPT and GDEPT. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[thumbnail of 10104786.pdf] Text

Download (20MB)


The PBDs are a family of naturally occurring antitumor antibiotics that bind in a sequence selective manner in the minor groove of DNA, interrupting processes such as transcription and replication. A PBD dimer, SJG-136, is currently undergoing Phase I clinical trials. The mechanism of action of the PBDs requires that the N10-position remains unsubstituted in order to maintain antitumor activity. This makes the PBDs excellent candidates for prodrug therapies, as potentiating groups can be introduced at other positions in the molecule while labile substituents at the N10-position can block DNA interaction and act as an "on/off" switch. The aim of this project was to significantly increase the cytotoxic differential between prodrug and released parent PBD. In particular, SAR data suggest that the cytotoxicity of both PBD monomers and dimers can be greatly enhanced by the introduction of unsaturation between the C2 and C3 positions of the C-ring and inclusion of an aryl moiety at C2. Therefore, an initial objective was to design and synthesize novel prodrugs for use in ADEPT therapy with enhanced differential and potency. A 4-methoxyphenyl C2-substituted PBD was selected as the initial prodrug target, as the Suzuki coupling reaction is known to proceed smoothly and the products can be readily characterised by NMR. A robust 13-step synthesis has been developed to provide a C2-ketone N10-protected PBD intermediate (225). However, the critical triflation reaction, a prerequisite for the Suzuki coupling of the C2-aryl group, produced a mixture of C1-C2 and C2-C3 unsaturated isomers (255 and 222) which could only be separated by preparative LC-MS affording only low yields of products. An alternative strategy of installing the N10-progroup at a later stage of the synthesis was explored. This was potentially highly advantageous as the progroup could be introduced in a variety of substituted PBD structures. Unfortunately, the complex glutamate protecting group required for ADEPT was unstable to the conditions required to introduce it to the N10 position of the N10-C11 imine moiety of a PBD. Both prodrug isomers were evaluated in vitro but were found to be inherently unstable and thus cytotoxic (i.e. 255, IC 50 = 2.5 μM and 0.19 μM after 1 hour exposure or continuous exposure, respectively; 222, IC50 = 0.17 μM and 0.015 μM for 1 hour exposure or continuous exposure, respectively) in LS174T, K562 and SW1222 cells. As it was not possible to synthesize stable prodrugs for use in ADEPT, attention turned to a new family of prodrugs suitable for nitroreductase-based GDEPT therapies. A range of N10-protected molecules sensitive to nitroreductase were synthesized. Four N10-carbamates (the benzyl carbamate 263, p-nitrobenzyl carbamate 265, p-methoxy benzyl carbamate 288 and the p-nitrophenyl carbamate 287) were evaluated in LS174T, K562, SWI222, A2780, A549, C33a and 5637 cell lines. It was found that p-nitrobenzyl carbamate 265 had up to a 18.4-fold greater potency in a nitroreductase-expressing CMV NRT A2780 cell line compared to the parent A2870 cell line, and this prodrug has been progressed to further in vitro and in vivo studies.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Design and Synthesis of Novel N10 Protected Pyrrolobenzodiazepines for Use in ADEPT and GDEPT
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; ADEPTand; GDEPT; N10; Novel; Protected; Pyrrolobenzodiazepines
URI: https://discovery.ucl.ac.uk/id/eprint/10106811
Downloads since deposit
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item