ArticleJournal of medicinal chemistry2018
Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity.
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Oxetane-to-azetidine skeletal editing.Nature chemistry · 2026Article
- Chemical Upcycling of Expired Pharmaceuticals as a Source of Value-Added Chemicals for Organic Synthesis and Medicinal Chemistry.Molecules (Basel, Switzerland) · 2024Article
- Dual-target EZH2 inhibitor: latest advances in medicinal chemistry.Future medicinal chemistry · 2024Review
- Improved QSAR models for PARP-1 inhibition using data balancing, interpretable machine learning, and matched molecular pair analysis.Molecular diversity · 2024Article
- Access to 3-Azetidines via Halogenation of Titanacyclobutanes.Advanced synthesis & catalysis · 2024Article
- Olaparib Conjugates with Selenopheno[3,2-Pharmaceutics · 2022Article
- Exploration of Diazaspiro Cores as Piperazine Bioisosteres in the Development of σ2 Receptor Ligands.International journal of molecular sciences · 2022Article
- Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson's Disease.Molecular neurobiology · 2021Article
- Article
- Lowering Lipophilicity by Adding Carbon: AzaSpiroHeptanes, a logACS medicinal chemistry letters · 2019Article
- Small-Molecule Poly(ADP-ribose) Polymerase and PD-L1 Inhibitor Conjugates as Dual-Action Anticancer Agents.ACS omega · 2019Article
- Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine DJournal of medicinal chemistry · 2019Article
- Synthesis and evaluation of an AZD2461 [Bioorganic chemistry · 2019Article
- Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Development of poly(ADP-ribose) polymerase inhibitors (PARPi's) continues to be an attractive area of research due to synthetic lethality in DNA repair deficient cancers; however, PARPi's also have potential as therapeutics to prevent harmful inflammation. We investigated the pharmacological impact of incorporating spirodiamine motifs into the phthalazine architecture of FDA approved PARPi olaparib. Synthesized analogues were screened for PARP-1 affinity, enzyme specificity, catalytic inhibition, DNA damage, and cytotoxicity. This work led to the identification of 10e (12.6 ± 1.1 nM), which did not induce DNA damage at similar drug concentrations as olaparib. Interestingly, several worst in class compounds with low PARP-1 affinity, including 15b (4397 ± 1.1 nM), induced DNA damage at micromolar concentrations, which can explain the cytotoxicity observed in vitro. This work provides further evidence that high affinity PARPi's can be developed without DNA damaging properties offering potential new drugs for treating inflammatory related diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.