Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer

Bioorganic & Medicinal Chemistry Letters
Stephen J GregsonDavid E Thurston

Abstract

We report the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 16 synthesised through a new and efficient route, thus establishing that C2-C3-endo unsaturation enhances both cytotoxicity and DNA-binding affinity in A-Ring-linked PBD dimers but to a lesser extent than C2/C2'-exo-unsaturation. This new route has allowed the preparation of multi-gram quantities of the related clinical candidate 1 and should lead to more structurally diverse PBD dimer analogues.

References

Mar 1, 1985·Journal of Medicinal Chemistry·T KanekoW T Bradner
Sep 25, 1968·Journal of the American Chemical Society·W LeimgruberR C Czajkowski
Sep 2, 2000·Bioorganic & Medicinal Chemistry Letters·S J GregsonD E Thurston
Nov 15, 1996·The Journal of Organic Chemistry·David E. ThurstonLaurence H. Hurley

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Citations

Nov 1, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Jul 13, 2002·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalP Ramulu
Sep 25, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Mar 7, 2012·ACS Chemical Biology·Isaac T YonemotoBarbara Gerratana
Dec 21, 2010·Chemical Reviews·Dyeison Antonow, David E Thurston
Jun 15, 2010·Medicinal Research Reviews·Barbara Gerratana
Apr 10, 2003·Journal of Enzyme Inhibition and Medicinal Chemistry·Wei-Qun JiangStéphane Léonce

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