Discovery of a Novel [6–6–5–5–6] Pentacyclic Tetrahydrocyclopentaphthalazinone as a Promising PARP Inhibitor Scaffold
Inhibitors of poly(ADP-ribose) polymerases (PARPs) have revolutionized the treatment of cancers with DNA repair deficiencies. Here we describe the structure-based discovery and synthesis of 6-6-5-5-6-fused pentacyclic scaffolds <b>5</b> and <i>cis</i>-(±)-<b>6</b> as a novel class of PARP1 inhibitors. Chiral supercritical fluid chromatographic separation of <i>cis</i>-(±)-<b>6</b> afforded inactive <i>ent</i>-<b>6_P1</b> and active <i>ent</i>-<b>6_P2</b>. Compound <b>5</b> (P-gp ER = 0.9) and <i>ent</i>-<b>6_P2</b> (P-gp ER = 1.1) demonstrated good Caco-2 permeability and are not actively effluxed by ABC transporters. <i>In vitro</i> analysis in HEK293T cells found that <b>5</b>, <i>cis</i>-(±)-<b>6</b>, and <i>ent</i>-<b>6_P2</b> showed near complete inhibition of PARP1 activity at 10 μM. Furthermore, compounds <b>5</b>, <i>cis</i>-(±)-<b>6</b>, and <i>ent</i>-<b>6_P2</b> displayed selective cytotoxic activity in <i>BRCA</i> mutant cancer cells but not isogenic <i>BRCA</i>-proficient cells. Taken together, <b>5</b> and <i>ent</i>-<b>6_P2</b> define a novel class of lead PARP inhibitors for further development.
Authors
- Morgan E. Diolaiti (ORCID: https://orcid.org/0000-0001-5900-3060)
- Yagmur Umay Doruk (ORCID: https://orcid.org/0000-0002-3388-7803)
- Tanaji T. Talele (ORCID: https://orcid.org/0000-0002-5938-6505)
- Alan Ashworth
Institutions
- Massachusetts College of Pharmacy and Health Sciences (US)
- University of California System (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00603
- Citations
- 1
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- V Foundation for Cancer Research
- Gray Foundation
- University of California, San Francisco