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Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

ABSTRACT: A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.

SUBMITTER: Morese PA

PROVIDER: S-EPMC10510387 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

Morese Pasquale A PA Anthony Nahoum N Bodnarchuk Michael M Jennings Claire C Martin Mathew P MP Noble Richard A RA Phillips Nicole N Thomas Huw D HD Wang Lan Z LZ Lister Andrew A Noble Martin E M MEM Ward Richard A RA Wedge Stephen R SR Stewart Hannah L HL Waring Michael J MJ

Journal of medicinal chemistry 20230830 17

A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the β-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol a ...[more]

PMID: 37647129

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Project description:The toxicity that was caused by the developed medications for anticancer treatment is, unfortunately, an earnest problem stemming from the various involved targets, and accordingly, intense research for overcoming such a phenomenon remains indispensable. In the current inquiry, an innovative category of substituted quinazoline-based glycosides incorporating a core of 1,2,3-triazole and attached to distinct acetylated likewise deprotected sugar segments are created and produced synthetically. The resulted 1,2,3-triazolyl-glycosides products were investigated for their ability to cause cytotoxicity to several human cancer cell lines. The quinazoline based glycosyl-1,2,3-triazoles 10-13 with free hydroxy sugar moiety revealed excellent potency against (IC50 range = 5.70-8.10 µM, IC50 Doxorubicin = 5.6 ± 0.30 µM, IC50 Erlotinib = 4.3 ± 0.1 µM). against MCF-7 cancer cell line. In addition, the derived glycosides incorporating quinazolinone and triazole core 6-13 with acetylated and deprotected sugar parts showed excellent and superior potency against HCT-116 (IC50 range = 2.90-6.40 µM). The potent products were revealed as safe cytotoxic agents as indicated by their studied safety profiles. Additional research of promising candidates inhibitory analysis performed against EGFR and VEGFR-2. The hydroxylated glycosides incorporating triazole and quinazoline system 11 and 13 with N-methyl substitution of quinazolinone, gave excellent potency against EGFR (IC50 = 0.35 ± 0.11 and 0.31 ± 0.06 µM, correspondingly) since glycoside 13 revealed comparable IC50 (3.20 ± 0.15 µM) to sorafenib against VEGFR-2. For more understanding of its action mode, it was analyzed how the 1,2,3-triazolyl glycoside 13 made an effect on the apoptosis induction and the arrest of the cell cycle. It was revealed that it had the ability to stop HCT-116 cells in their cell cycle's G1 stage. Moreover, the influence of quinazolinone-1,2,3-triazole-glycoside 13 upon p53, Bax, and Bcl-2 levels in HCT-116 units was also studied for future approaches toward its behavior. Additionally, the latter derivative may trigger apoptosis, as indicated by a significant increase in apoptotic cells. Furthermore, molecular docking was simulated to make an obvious validation and comprehension acquirement of the binding's characteristics also attractions among the most forceful compounds side by side with their aimed enzymes.

Dataset Information

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

Publications

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

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