{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T06:25:01Z","timestamp":1778394301277,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EU Recovery and Resilience Facility project","award":["07\/OSI\/ZG"],"award-info":[{"award-number":["07\/OSI\/ZG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>PARP inhibitors are a clinically validated class of anticancer therapeutics that exploit synthetic lethality to target homologous recombination-deficient tumors, such as those carrying BRCA1\/2 mutations. Nevertheless, the rational design of mitochondria-targeted PARP inhibitors capable of selective mitochondrial accumulation and organelle-specific PARP modulation remains an unresolved objective. To enable organelle-specific modulation of PARP activity, we synthesized a series of trialkyl(aryl)phosphonium conjugates of olaparib and rucaparib designed to target mitochondria by cardiolipin binding. Their activity was evaluated by PARP1 inhibition, cardiolipin affinity, and cytotoxicity in BRCA1-deficient HCC1937 breast cancer cells and non-malignant H9C2 cardiomyocytes. All conjugates retained potent PARP1 inhibition (IC50 = 3.4\u201317 nM), comparable to the parent drugs. Several derivatives, particularly compounds 2d and 6c, exhibited strong cardiolipin binding (EC50 = 12.99 \u00b5M and 6.77 \u00b5M, respectively) and significantly enhanced cytotoxicity in HCC1937 cells (IC50 = 0.93 and 2.01 \u00b5M), outperforming olaparib and rucaparib. Notably, cytotoxicity toward H9C2 cells was lower, indicating a favorable selectivity profile. Phosphonium conjugation preserves PARP1 inhibitory activity while conferring mitochondrial targeting and enhanced anticancer potency. These findings support the development of mitochondria-targeted PARP inhibitors as a next-generation therapeutic strategy with the potential to improve efficacy and overcome resistance in HR-deficient tumors.<\/jats:p>","DOI":"10.3390\/biom16010165","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T14:58:54Z","timestamp":1768834734000},"page":"165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of Mitochondria-Targeted PARP Inhibitors"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6332-2395","authenticated-orcid":false,"given":"Pavels","family":"Dimitrijevs","sequence":"first","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4549-1993","authenticated-orcid":false,"given":"Marina","family":"Makrecka-Kuka","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5875-2799","authenticated-orcid":false,"given":"Pavel","family":"Arsenyan","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV1006 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/nrm.2017.53","article-title":"The Multifaceted Roles of PARP1 in DNA Repair and Chromatin Remodelling","volume":"18","author":"Nussenzweig","year":"2017","journal-title":"Nat. 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