Synthesis of naphthalimide-carborane and metallacarborane conjugates: Anticancer activity, DNA binding ability

Nekvinda, Jan; Różycka, Daria; Rykowski, Sebastian; Wyszko, Eliza; Fedoruk-Wyszomirska, Agnieszka; Gurda, Dorota; Orlicka-Płocka, Marta; Giel-Pietraszuk, Małgorzata; Kiliszek, Agnieszka; Rypniewski, W.; Bachorz, Rafał A.; Wojcieszak, Jakub; Grüner, Bohumı́r; Olejniczak, Agnieszka B.

doi:10.1016/j.bioorg.2019.103432

Cited by 36 publications

(49 citation statements)

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“…Mitochondria are one of the main sources of intracellular ROS, which produce ROS in the form of superoxide anions (O 2 -) as a byproduct of oxidative metabolism [86]. The mitochondrial ROS generation might lead to mtDNA damage and mutations, thereby causing respiratory chain dysfunction [91]. Thus, we performed an analysis of mitochondrial ROS generation and observed a significant increase in the superoxide level when KR concentration increased, whereas, after treatment with 7-deazaKR, the superoxide level slightly increased (Figure 7C,D).…”

Section: Discussionmentioning

confidence: 99%

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

et al. 2021

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Recently, small compound-based therapies have provided new insights into the treatment of glioblastoma multiforme (GBM) by inducing oxidative impairment. Kinetin riboside (KR) and newly designed derivatives (8-azaKR, 7-deazaKR) selectively affect the molecular pathways crucial for cell growth by interfering with the redox status of cancer cells. Thus, these compounds might serve as potential alternatives in the oxidative therapy of GBM. The increased basal levels of reactive oxygen species (ROS) in GBM support the survival of cancer cells and cause drug resistance. The simplest approach to induce cell death is to achieve the redox threshold and circumvent the antioxidant defense mechanisms. Consequently, cells become more sensitive to oxidative stress (OS) caused by exogenous agents. Here, we investigated the effect of KR and its derivatives on the redox status of T98G cells in 2D and 3D cell culture. The use of spheroids of T98G cells enabled the selection of one derivative—7-deazaKR—with comparable antitumor activity to KR. Both compounds induced ROS generation and genotoxic OS, resulting in lipid peroxidation and leading to apoptosis. Taken together, these results demonstrated that KR and 7-deazaKR modulate the cellular redox environment of T98G cells, and vulnerability of these cells is dependent on their antioxidant capacity.

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Section: Discussionmentioning

confidence: 99%

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

et al. 2021

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“…We observed the increase in superoxide level when KR concentration increased. ROS production by the mitochondria leads to mtDNA damage and mutations, which in turn might lead to progressive respiratory chain dysfunction and to further increase in ROS production as a consequence of this dysfunction [54].…”

Section: Discussionmentioning

confidence: 99%

Circumventing the Crabtree effect: forcing oxidative phosphorylation (OXPHOS) via galactose medium increases sensitivity of HepG2 cells to the purine derivative kinetin riboside

et al. 2020

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Small-molecule compound-based therapies have provided new insights into cancer treatment against mitochondrial impairment. N6-furfuryladenosine (kinetin riboside, KR) is a purine derivative and an anticancer agent that selectively affects the molecular pathways crucial for cell growth and apoptosis by interfering with mitochondrial functions and thus might be a potential mitotoxicant. Metabolism of cancer cells is predominantly based on the Crabtree effect that relies on glucose-induced inhibition of cell respiration and thus on oxidative phosphorylation (OXPHOS), which supports the survival of cancer cells in metabolic stress conditions. The simplest way to circumvent this phenomenon is to replace glucose with galactose in the culture environment. Consequently, cells become more sensitive to mitochondrial perturbations caused by mitotoxicants. In the present study, we evaluated several cellular parameters and investigated the effect of KR on mitochondrial functions in HepG2 cells forced to rely mainly on OXPHOS. We showed that KR in the galactose environment is a more potent apoptosis-inducing agent. KR decreases the mitochondrial membrane potential, reduces glutathione level, depletes cellular ATP, and induces reactive oxygen species (ROS) production in the OXPHOS state, leading to the loss of cell viability. Taken together, these results demonstrate that KR directly acts on the mitochondria to limit their function and that the sensitivity of cells is dependent on their ability to cope with energetic stress.

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“…A comparison of the IC50 values is shown in Figure 2A,B. Effect of adenosine and 2 -deoxyadenosine modified with metalla bis(dicarbollides) containing Co, Fe, or Cr (compounds 14,15,16,18,19,20,22,23,and 24,IC50 [µM]) on cancer cell viability, (A) A2780 cell lines, (B) SKOV-3 and OVCAR-3 cell lines. Unmodified metalla bis(dicarbollides) (compounds 1, 2, and 3) and compound 25 were used as reference compounds; effects of cisplatin and carboplatin are shown for comparison.…”

Section: Cytotoxicity Of the Compounds In Relation To The Resistance Of The Cells To Cisplatinmentioning

confidence: 99%

“…The use of metalla bis(dicarbollides) for designing biologically active compounds has garnered increasing interest, primarily because of their extraordinary characteristic properties including their rigidity, threedimensional ellipsoidal shape, stability in the biological environment, bio-orthogonality, and hydrophobicity. Metallacarboranes and carboranes have been identified as promising therapeutically important compounds [20][21][22][23][24] including boronated nucleosides that have been extensively studied in recent years [25][26][27][28]. Several approaches have been previously proposed by us for the synthesis of adenosine and 2 -deoxyadenosine derivatives modified with boron clusters (carboranes and metallacarboranes) [29][30][31][32][33][34][35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Interaction of Adenosine, Modified Using Carborane Clusters, with Ovarian Cancer Cells: A New Anticancer Approach against Chemoresistance

Bednarska-Szczepaniak

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Kania

et al. 2021

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Platinum compounds remain the first-line drugs for the treatment of most lethal gynecological malignancies and ovarian cancers. Acquired platinum resistance remains a major challenge in gynecological oncology. Considering the unique physicochemical properties of the metallacarboranes modifier and the significant role of nucleoside derivatives as anticancer antimetabolites, we designed and synthesized a set of adenosine conjugates with metallacarboranes containing iron, cobalt, or chromium as semi-abiotic compounds that influence the cisplatin sensitivity of ovarian cancer cells. Adherent cultures of ovarian carcinoma cell lines and multicellular spheroids, ranging from sensitive to highly resistant including experimental cell lines “not responding” to platinum drugs were used. Iron-containing metallacarborane conjugates showed the best anticancer activity, especially against resistant cells. Compound modified at the C2′ nucleoside position showed the best activity in resistant cancer cells and highly resistant cancer spheroids exposed to cisplatin, increasing cell cycle arrest, apoptosis or necrosis, and reactive oxygen species production. Moreover, it showed high cellular accumulation and did not induce cross-resistance to cisplatin, carboplatin, doxorubicin, paclitaxel, or gemcitabine in long-term cultures. The reference nido-carborane derivative (no metal ions) and unmodified nucleosides were not as effective. These findings indicate that metallacarborane modification of adenosine may sensitize ovarian cancer cells to cisplatin in combination treatment.

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Synthesis of naphthalimide-carborane and metallacarborane conjugates: Anticancer activity, DNA binding ability

Cited by 36 publications

References 47 publications

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

Implications of Oxidative Stress in Glioblastoma Multiforme Following Treatment with Purine Derivatives

Circumventing the Crabtree effect: forcing oxidative phosphorylation (OXPHOS) via galactose medium increases sensitivity of HepG2 cells to the purine derivative kinetin riboside

Interaction of Adenosine, Modified Using Carborane Clusters, with Ovarian Cancer Cells: A New Anticancer Approach against Chemoresistance

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