Synthesis and structure–activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 4; pp. 938 - 942
• Main Authors: Tao, Ming, Park, Chung Ho, Bihovsky, Ron, Wells, Gregory J., Husten, Jean, Ator, Mark A., Hudkins, Robert L.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-02-2006; Elsevier
• Subjects: Biological and medical sciences; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; PARP-1 inhibitors; Pharmacology. Drug treatments; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Pyrrolocarbazoles; Structure-Activity Relationship; Pyrrolocarbazoles; PARP-1 inhibitors; Enzyme; Nitrogen heterocycle; Transferases; Glycosyltransferases; Enzyme inhibitor; Tetracyclic compound; In vitro; Modeling; NAD; Imide; Structure activity relation; Molecular model; Database; ADP-ribosyltransferase; Aromatic compound; Chemical synthesis; Pentosyltransferases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.10.099

Pyrrolocarbazole
1 was identified as a potent PARP-1 inhibitor (IC
50
=
36
nM) from our internal database. The synthesis and SAR optimization around this template with the aid of modeling studies led to the identification of the truncated imide.
A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole
1 was identified as a potent PARP-1 inhibitor (IC
50
=
36
nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide
14. Compound
14 (IC
50
=
40
nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor.