Elkafoury, E M, El-Hamamsy, M H, El-Bastawissy, E A, Afarinkia, K ORCID: https://orcid.org/0000-0003-2819-4364 and Aboukhatwa, S M (2024) Synergy Trap for Guardian Angels of DNA: Unraveling the Anticancer Potential of Phthalazinone -Thiosemicarbazone Hybrids through Dual PARP-1 and TOPO-I Inhibition. Bio-Organic Chemistry, 153 (107924).

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Abstract

Targeting DNA repair, like PARP-1 and TOPO-I, shows promise in cancer therapy. However, resistance to
single agents requires complex and costly combination strategies with significant side effects. Thus, there's an
urgent need for single agents with dual inhibition. Current dual inhibitors focusing on the C-4 position of the
phthalazinone core for PARP inhibition often have high molecular weights. Clinical use of PARP inhibitors is
limited by hematological and other toxicities from concurrent PARP-2 inhibition. They're mainly effective in
gynecological cancers, despite high PARP-1 and TOPO-I expression in various cancers. Moreover, their efficacy
is limited to BRCA1-expressing breast cancer. In this study, we synthesized 27 dual inhibitors for PARP-1 and
TOPO-I with molecular weights below 500 g/mol through hybridizing a phthalazinone core with a
thiosemicarbazone linker. Among these, 6c demonstrated exceptional broad spectrum and potency against the
NCI 60 cancer cell lines, with GI50 values from 1.65 to 5.63 µM. Notably, 6c exposed the highest PARP-1
inhibition (IC50 = 32.2 ± 3.26 nM) and a selectivity over PARP-2 (IC50 = 2844 ± 111 nM). Furthermore, 6c's
inhibition of TOPO-I (IC50 = 46.2 ± 3.3 nM) surpassed the control camptothecin by eleven-fold. Mechanistically,
6c disrupted the cell cycle at the S phase, induced apoptosis, and displayed a favorable safety profile against
normal cells. Compound 6c induced PARP trapping and synthetic lethality and showed high efficacy on BRCA1-
expressing cell lines. So, decreasing the likelihood of cancer cell resistance to chemotherapy. Drug-likeness
predictions and molecular modeling were also performed.

Item Type:	Article
Identifier:	10.1016/j.bioorg.2024.107924
Subjects:	Medicine and health > Clinical medicine > Therapeutics Medicine and health > Pharmacology
Depositing User:	Kamyar Afarinkia
Date Deposited:	04 Nov 2024 09:29
Last Modified:	04 Nov 2024 10:35
URI:	https://repository.uwl.ac.uk/id/eprint/12825

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