Citation: Hanxue LIU, Shijie LI, Meng REN, Xuling XUE, Hongke LIU. Design and antitumor properties of dehydroabietic acid functionalized cyclometalated iridium(Ⅲ) complex[J]. Chinese Journal of Inorganic Chemistry, ;2025, 41(8): 1483-1494. doi: 10.11862/CJIC.20250031 shu

Design and antitumor properties of dehydroabietic acid functionalized cyclometalated iridium(Ⅲ) complex

Hanxue LIU ¹ ,
Shijie LI ¹ ,
Meng REN ¹ ,
Xuling XUE ^{1, 2,,} ,
Hongke LIU ^{1, 2,,}

1.
School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
2.
State Key Laboratory of Coordination Chemistry, Nanjing 210023, China

Corresponding author: Xuling XUE, xuexuling87@163.com Hongke LIU, liuhongke@njnu.edu.cn
Received Date: 25 January 2025
Revised Date: 16 June 2025

Figures(8)

A novel cyclometalated iridium complex, CycIr-DHA, was successfully synthesized by incorporating the natural product dehydroabietic acid (DHA) into the cyclometalated iridium framework, and the ligand and complex were characterized by ¹H NMR. The complex showed strong antitumor effects on various cancer cells, especially michigan cancer foundation-7 (MCF-7) cells, with a half maximal inhibitory concentration (IC₅₀) of 2.5 μmol·L^-1, superior to that of the traditional chemotherapeutic drug cisplatin. Experimental results indicated that CycIr-DHA primarily accumulated in the mitochondria of MCF-7, leading to a significant increase in intracellular reactive oxy- gen species levels and subsequent mitochondrial dysfunction. Furthermore, the complex modulated the expression of apoptosis - related proteins (Bax and Bcl - 2), promoting apoptosis, and upregulates LC3 - Ⅱ protein, inducing autophagy. In a 3D cell spheroid model, CycIr-DHA significantly inhibited the growth of the spheroids.
- dehydroabietic acid,
- cyclometalated iridium complex,
- apoptosis,
- autophagy,
- antitumor
1. [1]
  XIONG X L, LIU L Y, MAO Z W, ZOU T T. Approaches towards understanding the mechanism-of-action of metallodrugs[J]. Coord. Chem. Rev., 2022,453214311.
2. [2]
  GHOSH S. Cisplatin: The first metal based anticancer drug[J]. Bioorganic Chem., 2019,88102925.
3. [3]
  YANG J, WANG M M, DENG D P, LIN H, SU Y, SHAO C X, LI S H, YU Z H, LIU H K, SU Z. Consolidating organometallic complex Ir-CA empowers mitochondria-directed chemotherapy against resistant cancer via stemness and metastasis inhibition[J]. Inorg. Chem., 2024,63(11):5235-5245.
4. [4]
  WANG Z G, XU Z F, ZHU G Y. A platinum(Ⅳ) anticancer prodrug targeting nucleotide excision repair to overcome cisplatin resistance[J]. Angew. Chem.-Int. Edit., 2016,55(50):15564-15568.
5. [5]
  WU Y P, LI S M, CHEN Y C, HE W J, GUO Z J. Recent advances in noble metal complex based photodynamic therapy[J]. Chem. Sci., 2022,13(18):5085-5106.
6. [6]
  GU Y Q, YANG K, YANG Q Y, LI H Q, HU M Q, MA M X, CHEN N F, LIU Y H, LIANG H, CHEN Z F. Rhodium (Ⅲ) -picolinamide complexes act as anticancer and antimetastasis agents via inducing apoptosis and autophagy[J]. J. Med. Chem., 2023,66(14):9592-9606.
7. [7]
  SU X X, WANG W J, CAO Q, ZHANG H, LIU B, LING Y Y, ZHOU X T, MAO Z W. A carbonic anhydrase Ⅸ (CAIX)- anchored rhenium (Ⅰ) photosensitizer evokes pyroptosis for enhanced anti-tumor immunity[J]. Angew. Chem.-Int. Edit., 2022,61(8)e202115800.
8. [8]
  XUE X L, FU Y, HE L, SALASSA L, HE L F, HAO Y Y, KOH M J, SOULIÉ C, NEEDHAM R J, HABTEMARIAM A, GARINO C, LOMACHENKO K A, SU Z, QIAN Y, PATERSON M J, MAO Z W, LIU H K, SADLER P J. Photoactivated osmium arene anticancer complexes[J]. Inorg. Chem., 2021,60(23):17450-17461.
9. [9]
  ZAMORA A, VIGUERAS G, RODRíGUEZ V, SANTANA M D, RUIZ J. Cyclometalated iridium (Ⅲ) luminescent complexes in therapy and phototherapy[J]. Coord. Chem. Rev., 2018,360:34-76.
10. [10]
  LI S J, QIAN X T, HUANG Y L, XUE X L, QIAN Y, SU Z, LIU H K. Click-chemistry synthesis and antitumor properties of cyclometalated iridium (Ⅲ) complex based on oleanolic acid[J]. Chinese J. Inorg. Chem., 2023,39(2):317-326. doi: 10.11862/CJIC.2022.289
11. [11]
  LIU L, CHEN J, WANG M M, HUANG Y L, QIAN Y, XUE X L, SU Z, LIU H K. The cyclometalated iridium (Ⅲ) complex based on 9-Anthracenecarboxylic acid as a lysosomal-targeted anticancer agent[J]. J. Inorg. Biochem., 2022,235111913.
12. [12]
  WANG M M, XU F J, SU Y, GENG Y, QIAN X T, XUE X L, KONG Y Q, YU Z H, LIU H K, SU Z. A new strategy to fight metallodrug resistance: Mitochondria-relevant treatment through mitophagy to inhibit metabolic adaptations of cancer cells[J]. Angew. Chem.-Int. Edit., 2022,61(27)e202203843.
13. [13]
  ZENG Y L, LIU L Y, MA T Z, LIU Y, LIU B, LIU W T, SHEN Q H, WU C, MAO Z W. Iridium (Ⅲ) photosensitizers induce simultaneous pyroptosis and ferroptosis for multi-network synergistic tumor immunotherapy[J]. Angew. Chem.-Int. Edit., 2024,63(49)e202410803.
14. [14]
  LI J, CHEN H M, ZENG L L, REES T W, XIONG K, CHEN Y, JI L N, CHAO H. Mitochondria-targeting cyclometalated iridium(Ⅲ) complexes for tumor hypoxic imaging and therapy[J]. Inorg. Chem. Front., 2019,6(4):1003-1010.
15. [15]
  LV M D, QIAN X T, LI S J, GONG J, WANG Q, QIAN Y, SU Z, XUE X L, LIU H K. Unlocking the potential of iridium and ruthenium arene complexes as anti-tumor and anti-metastasis chemotherapeutic agents[J]. J. Inorg. Biochem., 2023,238112057.
16. [16]
  TAO Q, WU J, GE C, WANG M M, LÜ M D, XUE X L, LIU H K. Synthesis, characterization, fluorescence and interactions with DNA/BSA properties of ruthenium ferulate complexes[J]. Chinese J. Inorg. Chem., 2020,36(10):1853-1864.
17. [17]
  LIU L, KONG Y Q, HE L, WANG X X, WANG M M, XU H J, YANG C G, SU Z, ZHAO J, MAO Z W, HUANG Y, LIU H K. A rhein-based Rh(Ⅲ) arene complex with anti-tumor cell proliferative activity inhibits RNA demethylase FTO[J]. Chin. J. Chem., 2022,40(10):1156-1164.
18. [18]
  WANG M M, XUE X L, SHENG X X, SU Y, KONG Y Q, QIAN Y, BAO J C, SU Z, LIU H K. Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(Ⅲ)-based complexes with functionalized α-lipoic acid[J]. RSC Adv., 2020,10(9):5392-5398.
19. [19]
  LI F Y, WANG X, DUAN W G, LIN G S. Synthesis and in vitro anticancer activity of novel dehydroabietic acid-based acylhydrazones[J]. Molecules, 2017,22(7)1087.
20. [20]
  LV M D, ZHENG Y, WU J, SHEN Z Q, GUO B L, HU G J, HUANG Y L, ZHAO J Y, QIAN Y, SU Z, WU C, XUE X L, LIU H K, MAO Z W. Evoking ferroptosis by synergistic enhancement of a cyclopentadienyl iridium-betulin immune agonist[J]. Angew. Chem.-Int. Edit., 2023,62(48)e202312897.
21. [21]
  LV M D, ZHENG Y, DAI X Y, ZHAO J Y, HU G J, REN M, SHEN Z Q, SU Z, WU C, LIU H K, XUE X L, MAO Z W. Ruthenium(Ⅱ)- arene complex triggers immunogenic ferroptosis for reversing drug resistance[J]. J. Med. Chem., 2024,67(22):20156-20171.
22. [22]
  ZHOU J, LI J L, ZHANG K Y, LIU S J, ZHAO Q. Phosphorescent iridium(Ⅲ) complexes as lifetime-based biological sensors for photoluminescence lifetime imaging microscopy[J]. Coord. Chem. Rev., 2022,453214334.
23. [23]
  LIAO K Y, HSU C W, CHI Y, HSU M K, WU S W, CHANG C H, LIU S H, LEE G H, CHOU P T, HU Y, ROBERTSON N. Pt(Ⅱ) metal complexes tailored with a newly designed spiro-arranged tetradentate ligand; harnessing of charge-transfer phosphorescence and fabrication of sky blue and white OLEDs[J]. Inorg. Chem., 2015,54(8):4029-4038.
24. [24]
  YANG X L, XU S P, ZHANG Y, ZHU C Y, CUI L S, ZHOU G J, CHEN Z, SUN Y H. Narrowband pure near-infrared (NIR) Ir(Ⅲ) complexes for solution-processed organic light-emitting diode (OLED) with external quantum efficiency over 16%[J]. Angew. Chem. - Int. Edit., 2023,62(41)e202309739.
25. [25]
  NAYLOR M R, LY A M, HANDFORD M J, RAMOS D P, PYE C R, FURUKAWA A, KLEIN V G, NOLAND R P, EDMONDSON Q, TURMON A C, HEWITT W M, SCHWOCHERT J, TOWNSEND C E, KELLY C N, BLANCO M J, LOKEY R S. Lipophilic permeability efficiency reconciles the opposing roles of lipophilicity in membrane permeability and aqueous solubility[J]. J. Med. Chem., 2018,61(24):11169-11182.
26. [26]
  LI Z, ZOU J H, CHEN X Y. In response to precision medicine: Current subcellular targeting strategies for cancer therapy[J]. Adv. Mater., 2023,35(21)2209529.
27. [27]
  SABHARWAL S S, SCHUMACKER P T. Mitochondrial ROS in cancer: Initiators, amplifiers or an Achilles' heel?[J]. Nat. Rev. Cancer, 2014,14(11):709-721.
28. [28]
  TANIDA I, MINEMATSU-IKEGUCHI N, UENO T, KOMINAMI E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy[J]. Autophagy, 2005,1(2):84-91.
29. [29]
  LU Y, WANG S S, LI M Y, LIU R, ZHU M F, YANG L M, WANG F Y, HUANG K B, LIANG H. Cyclometalated iridium (Ⅲ) complex based on isoquinoline alkaloid synergistically elicits the ICD response and IDO inhibition via autophagy-dependent ferroptosis[J]. Acta Pharm. Sin. B, 2024,15(1):424-437.
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