Design, Synthesis, and Biological Evaluation of Novel Mitochondria-Targeting Fluorescent Phenothiazine Derivatives as Potential Anticancer Agents

Abstract

In this research, we synthesized a novel mitochondrial-targeted antitumor lead compound named phenolthiazide-4C-Pvi (PCP) by modifying a phenothiazine with 3-(2-pyridin-4-ylvinyl)-1H-indole (Pvi) as a mitochondrial-targeted fluorescent cargo. Our preliminary findings indicated that PCP exhibits remarkable cell imaging and mitochondrial localization ability, and can induce apoptosis by influencing the membrane potential and reactive oxygen species levels in mitochondria. Compared with phenothiazines, PCP has an excellent ability to target the mitochondria of cancer cells, and its selectivity and toxicity to tumor cells are stronger than those toward normal cells. These results demonstrated that PCP possesses strong antitumor effects with excellent selectivity, making it a promising candidate as a mitochondrial-targeted antitumor drug.

Key words

phenothiazines - pyridinylvinylindole - mitochondria targeting - anticancer drugs - medicinal chemistry

Publication History

Received: 05 May 2024

Accepted after revision: 19 June 2024

Accepted Manuscript online:
19 June 2024

Article published online:
03 July 2024

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• 18 1-[4-(2-Chloro-10H-phenothiazin-10-yl)butyl]-4-[(E)-2-(1H-indol-3-yl)vinyl]pyridinium bromide (PCP) A mixture of Pvi (220 mg, 1.0 mmol), 10-(4-bromobutyl)-2-chloro-10H-phenothiazine (367 mg, 1.0 mmol), and anhyd toluene (5.0 mL) was stirred at r.t. for 48 h. The mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography [neutral alumina, CH₂Cl₂–MeOH (50:1 to 10:1 gradient)] to give a yellow solid; yield: 320 mg (63%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.13 (s, 1 H), 8.72 (d, J = 6.7 Hz, 2 H), 8.34–7.91 (m, 5 H), 7.60–7.45 (m, 1 H), 7.31–7.09 (m, 6 H), 7.06–6.89 (m, 4 H), 4.44 (t, J = 6.7 Hz, 2 H), 3.90 (t, J = 6.5 Hz, 2 H), 2.10–1.87 (m, 2 H), 1.78–1.48 (m, 2 H). ¹³C NMR(101 MHz, DMSO-d ₆): δ = 155.0, 146.5, 143.9, 137.5, 132.9, 128.6, 127.8, 125.3, 123.5, 123.0, 121.6, 120.9, 117.2, 116.3, 114.0, 113.1, 58.9, 46.3, 28.1, 23.0. LC-MS (ESI⁺): m/z [M⁺] calcd for C₃₁H₂₇ClN₃S: 508.16; found: 508.33.