DNA interstrand crosslinking agents: synthesis, DNA interactions, and cytotoxicity of dimeric achiral seco-amino-CBI and conjugates of achiral seco-amino-CBI with pyrrolobenzodiazepine (PBD)

Bioorg Med Chem Lett. 2006 Nov 1;16(21):5677-81. doi: 10.1016/j.bmcl.2006.08.005.

Bethany Purnell ¹, Atsushi Sato, Amanda O'kelley, Carly Price, Kaitlin Summerville, Stephen Hudson, Caroline O'hare, Konstantinos Kiakos, Tetsuji Asao, Moses Lee, John A Hartley

Affiliations

Affiliation

1 Department of Chemistry, Furman University, 3300 Pointsett Highway, Greenville, SC 29613, USA.

PMID: 16919946 DOI: 10.1016/j.bmcl.2006.08.005

Abstract

The design and synthesis of three novel bisalkylating agents derived from the achiral seco-duocarmycin or CC-1065 analogs and Pyrrolobenzodiazepines (PBDs) are described: achiral seco-CBI (cyclopropanebenz[e]indoline)-PBD 11, achiral seco-CI-PBD 12, and achiral seco-CBI dimer 13. Compounds 11 and 12 demonstrated enhanced cytotoxicity over the monomer counterparts against the growth of P815 murine mastocytoma cells in culture. Conjugate 11 was found to covalently react with adenine-N3 positions within the minor groove at AT-rich sequences and to produce DNA interstrand crosslinks. Both compounds were found to induce Apoptosis in P815 cells. Due to its poor water solubility, dimer 13 did not give any appreciable DNA binding or cytotoxicity.

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