Design, synthesis, and evaluation of mixed imine-amine pyrrolobenzodiazepine dimers with efficient DNA binding affinity and potent cytotoxicity

Bioorganic & Medicinal Chemistry
Ahmed KamalH A Nagarajaram

Abstract

Synthesis of mixed imine-amine pyrrolobenzodiazepine (PBD) dimers that are comprised of DC-81 and secondary amine (N10) of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three and five carbons) is described. These noncross-linking unsymmetrical molecules exhibit significant DNA minor groove binding ability and one of them 5b linked through the pentanedioxy chain exhibits efficient DNA binding ability (DeltaTm=11.0 degrees C) when compared to naturally occurring DC-81, 1 (DeltaTm=0.7 degrees C). The imine-amine PBD dimers exhibit promising in vitro antitumor activity in a number of human cancer cell lines.

References

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Mar 12, 1998·Nature·D J WithersM F White
Jul 18, 2001·Journal of the American Chemical Society·Q ZhouL H Hurley
Oct 13, 2001·Bioorganic & Medicinal Chemistry Letters·S J GregsonD E Thurston
Nov 15, 1996·The Journal of Organic Chemistry·David E. ThurstonLaurence H. Hurley
Jul 13, 2002·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalP Ramulu
Jul 13, 2002·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Aug 29, 2002·Chemical Communications : Chem Comm·Nectaroula CooperDavid E Thurston
Sep 25, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Nov 1, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalG Ramesh
Dec 31, 2003·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalP Ramulu
Jul 1, 2004·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalP Praveen Kumar

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Citations

Dec 21, 2010·Chemical Reviews·Dyeison Antonow, David E Thurston
Jun 15, 2010·Medicinal Research Reviews·Barbara Gerratana
Feb 1, 2006·Expert Opinion on Therapeutic Patents·Jinxia DengNouri Neamati
Feb 25, 2005·Bioorganic & Medicinal Chemistry·Ahmed KamalM Shiva Kumar

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