Design and Synthesis of a Luminescent Cyclometalated Iridium(III) Complex Having N,N-Diethylamino Group that Stains Acidic Intracellular Organelles and Induces Cell Death by Photoirradiation

Macroautophagy, often referred to as autophagy, designates the process by which portions of the cytoplasm, intracellular organelles and long-lived proteins are engulfed in double-membraned vacuoles (autophagosomes) and sent for lysosomal degradation. Basal levels of autophagy contribute to the maintenance of intracellular homoeostasis by ensuring the turnover of supernumerary, aged and/or damaged components. Under conditions of starvation, the autophagic pathway operates to supply cells with metabolic substrates, and hence represents an important pro-survival mechanism. Moreover, autophagy is required for normal development and for the protective response to intracellular pathogens. Conversely, uncontrolled autophagy is associated with a particular type of cell death (termed autophagic, or type II) that is characterized by the massive accumulation of autophagosomes. Regulators of apoptosis (e.g. Bcl-2 family members) also modulate autophagy, suggesting an intimate cross-talk between these two degradative pathways. It is still unclear whether autophagic vacuolization has a causative role in cell death or whether it represents the ultimate attempt of cells to cope with lethal stress. For a multicellular organism, autophagic cell death might well represent a pro-survival mechanism, by providing metabolic supplies during whole-body nutrient deprivation. Alternatively, type II cell death might contribute to the disposal of cell corpses when heterophagy is deficient. Here, we briefly review the roles of autophagy in cell death and its avoidance.

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Alterations to the structure of Leishmania major induced by N-arylisoquinolines correlate with compound accumulation and disposition

Journal of Medical Microbiology ◽

10.1099/jmm.0.014241-0 ◽

2010 ◽

Vol 59 (1) ◽

pp. 69-75 ◽

Cited By ~ 6

Author(s):

Alicia Ponte-Sucre ◽

Tanja Gulder ◽

Tobias A. M. Gulder ◽

Gerina Vollmers ◽

Gerhard Bringmann ◽

...

Keyword(s):

Cell Death ◽

Host Cell ◽

Mechanism Of Action ◽

Structural Changes ◽

Leishmania Major ◽

Ultrastructural Changes ◽

Synthetic Analogues ◽

Intracellular Compartments ◽

Intracellular Organelles ◽

Fluorescent Derivative

Naphthylisoquinoline alkaloids equipped with a N,C-hetero-‘biaryl’ axis, and, in particular, simplified synthetic analogues thereof, kill intracellular Leishmania major at concentrations in the low submicromolar range, while being significantly less toxic to their major host cell, the macrophage, at the same concentrations. To further investigate their mechanism of action we evaluated the morphological and ultrastructural changes induced by specific N-arylisoquinolines in L. major, and the correlation of these changes with compound accumulation and disposition by the parasite. After 24 h of treatment with the synthetic arylisoquinolinium salts 3 or 4, dramatic structural changes and cell death were observed. Furthermore, the auto-fluorescent derivative salt 3 accumulates continually in intracellular compartments. Our results thus suggest that the leishmanicidal effect of arylisoquinolinium salts may involve their ability to accumulate and precipitate in intracellular organelles, form a huge vacuole and eventually promote cell lysis.

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14-helical β-peptides Elicit Toxicity againstC. albicansby Forming Pores in the Cell Membrane and Subsequently Disrupting Intracellular Organelles

10.1101/430850 ◽

2018 ◽

Cited By ~ 1

Author(s):

Myung-Ryul Lee ◽

Namrata Raman ◽

Patricia Ortiz-Bermudez ◽

David M. Lynn ◽

Sean P. Palecek

Keyword(s):

Cell Death ◽

Partition Coefficient ◽

Peptide Binding ◽

Membrane Disruption ◽

Bacterial Membranes ◽

Drug Candidates ◽

Small Unilamellar Vesicle ◽

Proteolytic Stability ◽

Intracellular Organelles ◽

Insight Into

SummarySynthetic peptidomimetics of antimicrobial peptides are promising as antimicrobial drug candidates because they promote membrane disruption and exhibit greater structural and proteolytic stability. We previously reported selective antifungal 14-helical β-peptides, but the mechanism of antifungal toxicity of β-peptides remains unknown. To provide insight into the mechanism, we studied antifungal β-peptide binding to artificial membranes and livingCandida albicanscells. We investigated the ability of β-peptides to interact with and permeate small unilamellar vesicle models of fungal and bacterial membranes. The partition coefficient supported a pore-mediated mechanism characterized by the existence of a critical β-peptide concentration separating low and high partition coefficient regimes. Live cell intracellular tracking of β-peptides showed that β-peptides translocated into the cytoplasm, and then disrupted the nucleus and vacuole sequentially, leading to cell death. This understanding of the mechanisms of antifungal activity will facilitate design and development of peptidomimetic AMPs, including 14-helical β-peptides, for antifungal applications.Graphical Abstract

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Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis

Cancers ◽

10.3390/cancers12092574 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2574 ◽

Cited By ~ 2

Author(s):

Roberta Peruzzo ◽

Roberto Costa ◽

Magdalena Bachmann ◽

Luigi Leanza ◽

Ildikò Szabò

Keyword(s):

Cell Death ◽

Calcium Signaling ◽

Intracellular Signaling ◽

Cellular Respiration ◽

Special Focus ◽

Symbiotic Relationship ◽

Contact Sites ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Intracellular Organelles

Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling.

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Design and synthesis of Pictet–Spengler condensation products that exhibit oncogenic-RAS synthetic lethality and induce non-apoptotic cell death

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2012.06.077 ◽

2012 ◽

Vol 22 (17) ◽

pp. 5707-5713 ◽

Cited By ~ 25

Author(s):

Rachid Skouta ◽

Miki Hayano ◽

Kenichi Shimada ◽

Brent R. Stockwell

Keyword(s):

Cell Death ◽

Synthetic Lethality ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Design And Synthesis ◽

Oncogenic Ras ◽

Condensation Products

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Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19

International Journal of Molecular Sciences ◽

10.3390/ijms22158180 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8180

Author(s):

Shailendra Pratap Singh ◽

Salomon Amar ◽

Pinky Gehlot ◽

Sanjib K. Patra ◽

Navjot Kanwar ◽

...

Keyword(s):

Cell Death ◽

Essential Role ◽

Viral Infections ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Innate Immune ◽

Innate Immune Signaling ◽

Promising Target ◽

Intracellular Organelles ◽

Viral Proliferation

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.

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Design and Synthesis of Novel Peptidomimetics for Cancer Immunotherapy

10.26434/chemrxiv.12936827.v1 ◽

2020 ◽

Author(s):

Ceyda Köse ◽

Esra Uysal ◽

Büşra Yazıcı ◽

Zeynep Tuğay ◽

Serap İpek Dingiş Birgül ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cancer Immunotherapy ◽

Mononuclear Cells ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Peripheral Blood Mononuclear ◽

Design And Synthesis ◽

Viability Assay ◽

Immune Mediated

Tumor cells benefit from some certain signals, which are referred to as “immune checkpoints”, to escape immune-mediated destruction. With that in mind, it is believed that the blockade of these points, such as programmed cell death Ligand-1 (PD-L1) and programmed cell death 1 (PD-1), can restore an adaptative immune response against tumoral cells. In this study, we have designed and synthesized some novel peptidomimetics with a 2-aminobenzathiazole scaffold, which targets the PD-1/PDL-1 pathway. In the viability assay, it was found that these compounds decreased the proliferation of peripheral blood mononuclear cells in the concentration of 10 uM. Overall, our results indicate that these novel compounds are potential checkpoint inhibitors for cancer immunotherapy.

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Luminescent Iridium Complex-Peptide Hybrids (IPHs) for Therapeutics of Cancer: Design and Synthesis of IPHs for Detection of Cancer Cells and Induction of Their Necrosis-Type Cell Death

Bioinorganic Chemistry and Applications ◽

10.1155/2018/7578965 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 5

Author(s):

Abdullah-Al Masum ◽

Yosuke Hisamatsu ◽

Kenta Yokoi ◽

Shin Aoki

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Anticancer Agents ◽

Cyclic Peptide ◽

Death Receptors ◽

Iridium Complex ◽

Peptide Motifs ◽

Design And Synthesis ◽

Cancer Cell Death ◽

Promising Tool

Death receptors (DR4 and DR5) offer attractive targets for cancer treatment because cancer cell death can be induced by apoptotic signal upon binding of death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with death receptors. Cyclometalated iridium(III) complexes such asfac-Ir(tpy)3(tpy = 2-(4-tolyl)pyridine) possess aC3-symmetric structure like TRAIL and exhibit excellent luminescence properties. Therefore, cyclometalated Ir complexes functionalized with DR-binding peptide motifs would be potent TRAIL mimics to detect cancer cells and induce their cell death. In this study, we report on the design and synthesis ofC3-symmetric and luminescent Ir complex-peptide hybrids (IPHs), which possess cyclic peptide that had been reported to bind DR5. The results of 27 MHz quartz-crystal microbalance (QCM) measurements of DR5 with IPHs and costaining experiments of IPHs and anti-DR5 antibody, suggest that IPHs bind with DR5 and undergo internalization into cytoplasm, possibly via endocytosis. It was also found that IPHs induce slow cell death of these cancer cells in a parallel manner to the DR5 expression level. These results indicate that IPHs may offer a promising tool as artificial luminescent mimics of death ligands to develop a new category of anticancer agents that detect and kill cancer cells.

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Design and Synthesis of Novel Peptidomimetics for Cancer Immunotherapy

10.26434/chemrxiv.12936827 ◽

2020 ◽

Author(s):

Ceyda Köse ◽

Esra Uysal ◽

Büşra Yazıcı ◽

Zeynep Tuğay ◽

Serap İpek Dingiş Birgül ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cancer Immunotherapy ◽

Mononuclear Cells ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Peripheral Blood Mononuclear ◽

Design And Synthesis ◽

Viability Assay ◽

Immune Mediated

Tumor cells benefit from some certain signals, which are referred to as “immune checkpoints”, to escape immune-mediated destruction. With that in mind, it is believed that the blockade of these points, such as programmed cell death Ligand-1 (PD-L1) and programmed cell death 1 (PD-1), can restore an adaptative immune response against tumoral cells. In this study, we have designed and synthesized some novel peptidomimetics with a 2-aminobenzathiazole scaffold, which targets the PD-1/PDL-1 pathway. In the viability assay, it was found that these compounds decreased the proliferation of peripheral blood mononuclear cells in the concentration of 10 uM. Overall, our results indicate that these novel compounds are potential checkpoint inhibitors for cancer immunotherapy.

Download Full-text