Synthesis of a Novel C2‐Aryl Substituted 1,2‐Unsaturated Pyrrolobenzodiazepine.

Abstract

For Abstract see ChemInform Abstract in Full Text.

Structure−Activity Relationships of Monomeric C2-Aryl Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Antitumor Agents

“…We found that a C1/C2-enol-triflate analogue of 7 could be obtained under kinetic conditions which allowed further elaboration to C2-aryl PBDs (e.g., 29, Table 1) via Suzuki coupling. 36 To fully understand the impact of unsaturation in the C-ring, we also synthesized the novel fully saturated C2-aryl PBD-imine 27 (Scheme 2). The synthesis started from the C-ring building block 17, 39 which was oxidized to the C2-ketone (18) using TEMPO and BAIB.…”

“…Molecular modeling analysis involving a conformational search (Macro-Model, version 9.6) indicated that 27 and 29 are unlikely to bind effectively to double-stranded DNA (a model 14-mer DNA duplex 43 was studied; data not shown) due to their overall shape and lack of isohelicity with the DNA minor groove. In addition, it was observed that 29 is prone to undergo C-ring aromatization 36 which may also reduce its overall cytotoxicity. In vitro data generated for the parallelsynthesized C2/C3-endo-unsaturated C2-aryl and C2-styryl PBD imines, and the PBD C11-(sodium bisulfite) adducts are collected in Tables 1, 3, and 4).…”

“…35 We also reported a synthetic procedure to obtain C1/C2-endo-unsaturated C2-aryl PBD imines. 36 We now report biological (in vitro cytotoxicity and xenograft) and biophysical (DNA thermal denaturation) data for a library of 80 C2-aryl-substituted PBD-imine compounds synthesized via three different routes. The library includes a number of novel C2-heteroaryl and C2-styryl analogues, and some C1/C2-endo unsaturated C2-aryl PBD analogues (Tables 1 and 3).…”

“…In a follow-up study we reported the synthesis of a novel C2-aryl PBD-imine library in which a parallel approach was employed to obtain 66 structurally unique C2-aryl-substituted PBDs containing A-ring electron-donating substituents and N10−C11 imine functionalities . We also reported a synthetic procedure to obtain C1/C2- endo -unsaturated C2-aryl PBD imines …”

An Isomerization Approach to Tesirine and Pyrrolobenzodiazepines

“…Earlier internal work on the formation of the triflate as part of the conversion of 5 to 6 showed that, under kinetic deprotonation conditions (−78 °C and use of hard bases), the enol forms with the double bond in the 3,4-position (analogous to 11), whereas under thermodynamic conditions the double bond forms in the 4,5-position (analogous to 6). 27 In the isomerization reaction, the fast initial kinetically driven conversion of 8 to 11 is followed by a slower thermodynamically driven conversion to 6. Conversion of 11 to 13 is energetically disfavored (18.7 kJ/ mol for the conversion); thus, only very small amounts of this intermediate are likely to form, which will rapidly convert back to 11 or further isomerize onto 12.…”