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Self-Assembled Molecular Complexes of 1,10-Phenanthroline and 2-Aminobenzimidazoles: Synthesis, Structure Investigations, and Cytotoxic Properties.

ABSTRACT: Three new molecular complexes (phen)₃(2-amino-Bz)₂(H⁺)(BF₄^-)·3H₂O 5, (phen)₃(2-amino-5(6)-methyl-Bz)₂(H⁺)(BF₄^-)·H₂O 6, and (phen)(1-methyl-2-amino-Bz)(H⁺)(BF₄^-) 7, were prepared by self-assembly of 1,10-phenanthroline (phen) and various substituted 2-aminobenzimidazoles. Confirmation of their structures was established through spectroscopic methods and elemental analysis. The X-ray diffraction analysis revealed that the crystal structure of 7 is stabilized by the formation of hydrogen bonds and short contacts. In addition, the molecular geometry and electron structure of molecules 5 and 6 were theoretically evaluated using density functional theory (DFT) methods. According to the DFT B3LYP/6-311+G* calculations, the protonated benzimidazole (Bz) units act as NH hydrogen bond donors, binding two phenanthrolines and a BF₄^- ion. Non-protonated Bz unit form hydrogen bonds with the N-atoms of a third molecule phen. The molecular assembly is held together by π-π stacking between benzimidazole and phenanthroline rings, allowing for N-atoms to associate with water molecules. The complexes were tested in vitro for their tumor cell growth inhibitory effects on prostate (PC3), breast (MDA-MB-231 and MCF-7), and cervical (HeLa) cancer cell lines using MTT-dye reduction assay. The in vitro cytotoxicity analysis and spectrophotometric investigation in the presence of ct-DNA, showed that self-assembled molecules 5-7 are promising DNA-binding anticancer agents warranting further in-depth exploration.

SUBMITTER: Anichina K

PROVIDER: S-EPMC10856035 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Self-Assembled Molecular Complexes of 1,10-Phenanthroline and 2-Aminobenzimidazoles: Synthesis, Structure Investigations, and Cytotoxic Properties.

Anichina Kameliya K Kaloyanov Nikolay N Zasheva Diana D Rusew Rusi R Nikolova Rositsa R Yancheva Denitsa D Bakov Ventsislav V Georgiev Nikolai N

Molecules (Basel, Switzerland) 20240124 3

Three new molecular complexes (phen)3(2-amino-Bz)2(H+)(BF4-)·3H2O 5, (phen)3(2-amino-5(6)-methyl-Bz)2(H+)(BF4-)·H2O 6, and (phen)(1-methyl-2-amino-Bz)(H+)(BF4-) 7, were prepared by self-assembly of 1,10-phenanthroline (phen) and various substituted 2-aminobenzimidazoles. Confirmation of their structures was estab ...[more]

PMID: 38338328

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Project description:Eight rhenium(I) tricarbonyl aqua complexes with the general formula fac-[Re(CO)3(N,N'-bid)(H2O)][NO3] (1-8), where N,N'-bid is (2,6-dimethoxypyridyl)imidazo[4,5-f]1,10-phenanthroline (L1), (indole)imidazo[4,5-f]1,10-phenanthroline (L2), (5-methoxyindole)-imidazo[4,5-f]1,10-phenanthroline (L3), (biphenyl)imidazo[4,5-f]1,10-phenanthroline (L4), (fluorene)imidazo[4,5-f]1,10-phenanthroline (L5), (benzo[b]thiophene)imidazo[4,5-f]1,10-phenanthroline (L6), (5-bromothiazole)imidazo[4,5-f]1,10-phenanthroline (L7), and (4,5-dimethylthiophene)imidazo[4,5-f]1,10-phenanthroline (L8), were synthesized and characterized using 1H and 13C{1H} NMR, FT-IR, UV/Vis absorption spectroscopy, and ESI-mass spectrometry, and their purity was confirmed by elemental analysis. The stability of the complexes in aqueous buffer solution (pH 7.4) was confirmed by UV/Vis spectroscopy. The cytotoxicity of the complexes (1-8) was then evaluated on prostate cancer cells (PC3), showing a low nanomolar to low micromolar in vitro cytotoxicity. Worthy of note, three of the Re(I) tricarbonyl complexes showed very low (IC50 = 30-50 nM) cytotoxic activity against PC3 cells and up to 26-fold selectivity over normal human retinal pigment epithelial-1 (RPE-1) cells. The cytotoxicity of both complexes 3 and 6 was lowered under hypoxic conditions in PC3 cells. However, the compounds were still 10 times more active than cisplatin in these conditions. Additional biological experiments were then performed on the most selective complexes (complexes 3 and 6). Cell fractioning experiments followed by ICP-MS studies revealed that 3 and 6 accumulate mostly in the mitochondria and nucleus, respectively. Despite the respective mitochondrial and nuclear localization of 3 and 6, 3 did not trigger the apoptosis pathways for cell killing, whereas 6 can trigger apoptosis but not as a major pathway. Complex 3 induced a paraptosis pathway for cell killing while 6 did not induce any of our other tested pathways, namely, necrosis, paraptosis, and autophagy. Both complexes 3 and 6 were found to be involved in mitochondrial dysfunction and downregulated the ATP production of PC3 cells. To the best of our knowledge, this report presents some of the most cytotoxic Re(I) carbonyl complexes with exceptionally low nanomolar cytotoxic activity toward prostate cancer cells, demonstrating further the future viability of utilizing rhenium in the fight against cancer.

Project description:Herein we report the synthesis and structural elucidation of two novel imine-based ligands, 2-(1,10-phenanthrolin-5-yl)imino)methyl)-5-bromophenol (PIB) and N-(1,10-phenanthrolin-5-yl)-1-(thiophen-3-yl)methanimine (PTM) ligands. An in vitro cytotoxicity assay of the synthesized molecules was carried out against breast, cervical, colorectal, and prostate cancer cell lines as well as immortalized human keratinocytes. The observations indicated that both the molecules possesses dose-dependent selective cytotoxicity of cancer cells with no detrimental effect on the normal cell lines. Furthermore, the detailed computational analysis of newly synthetized ligands (PIB and PTM) has been conducted in order to identify their most important parts from the perspective of local reactivity. The IC50 values of PIB treatment on MCF-7, HeLa, HCT-116 and PC-3 were 15.10, 16.25, 17.88, 17.55 and 23.86 micromoles, respectively. Meanwhile, the IC50 values of PTM on MCF-7, HeLa, HCT-116, PC-3 and HaCat were observed to be 14.82, 15.03, 17.88, 17.28 and 21.22 micromoles, respectively. For computational analysis, we have employed the combination of Density Functional Theory (DFT) calculations and MD simulations. DFT calculations provided us with information about structure and reactivity descriptors based on the electron distribution. Surfaces of molecular electrostatic potential (MEP) and averaged local ionization energy (ALIE) indicated the sites within studied molecules that are most reactive. These results indicated the importance of nitrogen atoms and OH group. Additionally, the values of bond dissociation for hydrogen abstraction showed that both molecules, especially the PTM, are stable toward the influence of autoxidation mechanism. On the other side, MD simulations gave us an insight how ligands interact with water molecules. Namely, the radial distribution functions (RDF) indicated that the hydrogen atom of the OH group in the case of the PIB has the most pronounced interactions with water.

Dataset Information

Self-Assembled Molecular Complexes of 1,10-Phenanthroline and 2-Aminobenzimidazoles: Synthesis, Structure Investigations, and Cytotoxic Properties.

Publications

Self-Assembled Molecular Complexes of 1,10-Phenanthroline and 2-Aminobenzimidazoles: Synthesis, Structure Investigations, and Cytotoxic Properties.

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