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)

Bioorganic & Medicinal Chemistry Letters
Bethany PurnellJohn A Hartley

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.

Citations

Dec 21, 2010·Chemical Reviews·Dyeison Antonow, David E Thurston
Apr 5, 2011·Expert Opinion on Investigational Drugs·John A Hartley
Nov 20, 2016·Angewandte Chemie·Julia MantajDavid E Thurston

Related Concepts

Cyclopropane
Indoline
Pyrrolobenzodiazepine
Benzodiazepines
Cross-Linking Reagents
Cyclopropanes
DNA, Double-Stranded
Indoles
Pyrroles
Dimerization

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis