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Title: Triorganotin (IV) carboxylates as potential anticancer agents: Their synthesis, physiochemical characterization, and cytotoxic activity against HeLa and MCF‐7 cancer cells

Three triorganotin (IV) cyclopentane carboxylates were synthesized and structurally characterized by in solid state by Fourier‐transform infrared spectroscopy and single crystal diffraction, and in solution by NMR (1H,13C, and119Sn) spectroscopy. The complexes were tested for their anticancer activity against MCF‐7 and HeLa cells along with normal BHK‐21 cells. As revealed by MTT assay, complex2was identified as the most potent derivative with an IC50value of 2.59 and 0.051 μM against HeLa and MCF‐7 cells, respectively. The results were compared with cisplatin as reference drug. Fluorescent microscopic studies using 4′,6‐diamidino‐2‐phenylindole (DAPI) and propidium iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active complex2. The complex2also triggered the release of lactate dehydrogenase (LDH) in treated HeLa and MCF‐7 cells whereas a luminescence assay displayed a remarkable increase in the activity of caspase‐9 and ‐3. Moreover, flow cytometric results revealed that complex2caused G0/G1 arrest in the treated HeLa cells. The complexes were further screened for DNA binding studies through UV‐vis spectroscopy and cyclic voltammetry. The high activity of complex2was attributed to its higher Lewis acidity as indicated by natural bond orbital (NBO) analysis. Theoretical modelling and molecular docking studies were also conducted to study the reactivity of complexes againstVEGFR 2 Kinase.

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Author(s) / Creator(s):
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Publisher / Repository:
Wiley Blackwell (John Wiley & Sons)
Date Published:
Journal Name:
Applied Organometallic Chemistry
Medium: X
Sponsoring Org:
National Science Foundation
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  1. Three new organotin( iv ) carboxylate compounds were synthesized and structurally characterized by elemental analysis and FT-IR and multinuclear NMR ( 1 H, 13 C, 119 Sn) spectroscopy. Single X-ray crystallography reveals that compound C2 has a monoclinic crystal system with space group P 2 1 / c having distorted bipyramidal geometry defined by C 3 SnO 2 . The synthesized compounds were screened for drug-DNA interactions via UV-Vis spectroscopy and cyclic voltammetry showing good activity with high binding constants. Theoretical investigations also support the reactivity of the compounds as depicted from natural bond orbital (NBO) analysis using Gaussian 09. Synthesized compounds were initially evaluated on two cancer (HeLa and MCF-7) cell lines and cytotoxicity to normal cells was evaluated using a non-cancerous (BHK-21) cell line. All the compounds were found to be active, with IC 50 values less than that of the standard drug i.e. cisplatin. The cytotoxic effect of the most potent compound C2 was confirmed by LDH cytotoxicity assay and fluorescence imaging after PI staining. Apoptotic features in compound C2 treated cancer cells were visualized after DAPI staining while regulation of apoptosis was observed by reactive oxygen species generation, binding of C2 with DNA, a change in mitochondrial membrane potential and expression of activated caspase-9 and caspase-3 in cancer cells. Results are indicative of activation of the intrinsic pathway of apoptosis in C2 treated cancer cells. 
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  2. Rationale

    Coordinatively driven self‐assembly of transition metal ions and bidentate ligands gives rise to organometallic complexes that usually contain superimposed isobars, isomers, and conformers. In this study, the double dispersion ability of ion mobility mass spectrometry (IM‐MS) was used to provide a comprehensive structural characterization of the self‐assembled supramolecular complexes by their mass and charge, revealed by the MS event, and their shape and collision cross‐section (Ω), revealed by the IM event.


    Self‐assembled complexes were synthesized by reacting a bis(terpyridine) ligand exhibiting a 60odihedral angle between the two ligating terpyridine sites (T) with divalent Zn, Ni, Cd, or Fe. The products were isolated as (Metal2+[T])n(PF6)2nsalts and analyzed using IM‐MS after electrospray ionization (ESI) which produced several charge states from eachn‐mer, depending on the number of PF6ˉ anions lost upon ESI. Experimental Ω data, derived using IM‐MS, and computational Ω predictions were used to elucidate the size and architecture of the complexes.


    Only macrocyclic dimers, trimers, and tetramers were observed with Cd2+, whereas Zn2+formed the same plus hexameric complexes. These two metals led to the simplest product distributions and no linear isomers. In sharp contrast, Ni2+and Fe2+formed all possible ring sizes from dimer to hexamer as well as various linear isomers. The experimental and theoretical Ω data indicated rather planar macrocyclic geometries for the dimers and trimers, twisted 3D architectures for the larger rings, and substantially larger sizes with spiral conformation for the linear congeners. Adding PF6ˉ to the same complex was found to mainly cause size contraction due to new stabilizing anion–cation interactions.


    Complete structural identification could be accomplished using ESI‐IM‐MS. Our results affirm that self‐assembly with Cd2+and Zn2+proceeds through reversible equilibria that generate the thermodynamically most stable structures, encompassing exclusively macrocyclic architectures that readily accommodate the 60oligand used. In contrast, complexation with Ni2+and Fe2+, which form stronger coordinative bonds, proceeds through kinetic control, leading to more complex mixtures and kinetically trapped less stable architectures, such as macrocyclic pentamers and linear isomers.

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  3. Abstract

    The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca2+) into the mitochondria, a process that is vital for maintaining normal cellular function. Inhibitors of the MCU, the most promising of which are dinuclear ruthenium coordination compounds, have found use as both therapeutic agents and tools for studying the importance of this ion channel. In this study, six Co3+cage compounds with sarcophagine‐like ligands were assessed for their abilities to inhibit MCU‐mediated mitochondrial Ca2+uptake. These complexes were synthesized and characterized according to literature procedures and then investigated in cellular systems for their MCU‐inhibitory activities. Among these six compounds, [Co(sen)]3+(3, sen=5‐(4‐amino‐2‐azabutyl)‐5‐methyl‐3,7‐diaza‐1,9‐nonanediamine) was identified to be a potent MCU inhibitor, with IC50values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound3was determined, revealing moderate accumulation in cells. Most notably,3was demonstrated to operate in intact cells as an MCU inhibitor. Collectively, this work presents the viability of using cobalt coordination complexes as MCU inhibitors, providing a new direction for researchers to investigate.

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  4. Key points

    Association of plasma membrane BKCachannels with BK‐β subunits shapes their biophysical properties and physiological roles; however, functional modulation of the mitochondrial BKCachannel (mitoBKCa) by BK‐β subunits is not established.

    MitoBKCa‐α and the regulatory BK‐β1 subunit associate in mouse cardiac mitochondria.

    A large fraction of mitoBKCadisplay properties similar to that of plasma membrane BKCawhen associated with BK‐β1 (left‐shifted voltage dependence of activation,V1/2 = −55 mV, 12 µmmatrix Ca2+).

    In BK‐β1 knockout mice, cardiac mitoBKCadisplayed a lowPoand a depolarizedV1/2of activation (+47 mV at 12 µmmatrix Ca2+)

    Co‐expression of BKCawith the BK‐β1 subunit in HeLa cells doubled the density of BKCain mitochondria.

    The present study supports the view that the cardiac mitoBKCachannel is functionally modulated by the BK‐β1 subunit; proper targeting and activation of mitoBKCashapes mitochondrial Ca2+handling.


    Association of the plasma membrane BKCachannel with auxiliary BK‐β1–4 subunits profoundly affects the regulatory mechanisms and physiological processes in which this channel participates. However, functional association of mitochondrial BK (mitoBKCa) with regulatory subunits is unknown. We report that mitoBKCafunctionally associates with its regulatory subunit BK‐β1 in adult rodent cardiomyocytes. Cardiac mitoBKCais a calcium‐ and voltage‐activated channel that is sensitive to paxilline with a large conductance for K+of 300 pS. Additionally, mitoBKCadisplays a high open probability (Po) and voltage half‐activation (V1/2 = −55 mV,n = 7) resembling that of plasma membrane BKCawhen associated with its regulatory BK‐β1 subunit. Immunochemistry assays demonstrated an interaction between mitochondrial BKCa‐α and its BK‐β1 subunit. Mitochondria from the BK‐β1 knockout (KO) mice showed sparse mitoBKCacurrents (five patches with mitoBKCaactivity out of 28 total patches fromn = 5 different hearts), displaying a depolarizedV1/2of activation (+47 mV in 12 µmmatrix Ca2+). The reduced activity of mitoBKCawas accompanied by a high expression of BKCatranscript in the BK‐β1 KO, suggesting a lower abundance of mitoBKCachannels in this genotype. Accordingly, BK‐β1subunit increased the localization of BKDEC (i.e. the splice variant of BKCathat specifically targets mitochondria) into mitochondria by two‐fold. Importantly, both paxilline‐treated and BK‐β1 KO mitochondria displayed a more rapid Ca2+overload, featuring an early opening of the mitochondrial transition pore. We provide strong evidence that mitoBKCaassociates with its regulatory BK‐β1 subunit in cardiac mitochondria, ensuring proper targeting and activation of the mitoBKCachannel that helps to maintain mitochondrial Ca2+homeostasis.

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