Benzothienoquinazolinones as new multi-target scaffolds: Dual inhibition of human Topoisomerase I and tubulin polymerization

Ceramella, Jessica; Caruso, Anna; Occhiuzzi, Maria Antonietta; Iacopetta, Domenico; Barbarossa, Alexia; Rizzuti, Bruno; Dallemagne, Patrick; Rault, Syl­vain; El‐Kashef, Hussein; Saturnino, Carmela; Grande, Fedora; Sinicropi, Maria Stefania

doi:10.1016/j.ejmech.2019.111583

Cited by 40 publications

(27 citation statements)

References 52 publications

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“…The expression of CB2-Rs in the central nervous system is increased in neurodegenerative pathologies, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and in some tumours like gliomas [14]. In addition to the involvement in physiological functions, CB2-Rs are implied in numerous pathological processes, so they can represent an interesting target in order to obtain agonist molecules for the treatment of many pathological conditions, including neuropathic pain, inflammation, neuroinflammatory and neurodegenerative pathologies (Parkinson's disease, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis), spinal and brain injuries, stroke, ischemia, anxiety disorder, depression, colitis, fibrosis and liver ischemia, atherosclerosis, osteoporosis, osteoarthritis, diabetes, obesity, and some types of cancer [9,[12][13][14][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

β-Caryophyllene: A Sesquiterpene with Countless Biological Properties

et al. 2019

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β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, is a selective phytocannabinoid agonist of type 2 receptors (CB2-R). It isn’t psychogenic due to the absence of an affinity to cannabinoid receptor type 1 (CB1). Among the various biological activities, BCP exerts anti-inflammatory action via inhibiting the main inflammatory mediators, such as inducible nitric oxide synthase (iNOS), Interleukin 1 beta (IL-1β), Interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-α), nuclear factor kapp a-light-chain-enhancer of activated B cells (NF-κB), cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2). Peroxisome proliferator-activated receptors alpha (PPAR-α) effects are also mediated by the activation of PPAR-α and PPAR-γ receptors. In detail, many studies, in vitro and in vivo, suggest that the treatment with β-caryophyllene improves the phenotype of animals used to model various inflammatory pathologies, such as nervous system diseases (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke), atherosclerosis, and tumours (colon, breast, pancreas, lymphoma, melanoma and glioma cancer). Furthermore, pre-clinical data have highlighted that BCP is potentially useful in Streptococcus infections, osteoporosis, steatohepatitis, and exerts anticonvulsant, analgesic, myorelaxing, sedative, and antidepressive effects. BCP is non-toxic in rodents, with a Lethal dose, 50% (LD50) greater than 5000 mg/kg. Nevertheless, it inhibits various cytochrome P450 isoforms (above all, CYP3A4), which metabolise xenobiotics, leading to adverse effects, due to drug levels over therapeutic window. All the reported data have highlighted that both pharmacological and toxicological aspects need to be further investigated with clinical trials.

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Section: Introductionmentioning

confidence: 99%

β-Caryophyllene: A Sesquiterpene with Countless Biological Properties

et al. 2019

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“…Tubulin polymerization inhibition was evaluated using an in vitro tubulin Polymerization Assay Kit purchased from EMD Millipore, employing the manufacturer's instructions with some modifications. [6,47] Briefly, polymerization reactions were realized in 70 μL final volumes, in which 60 μL is represented by the 60 μM tubulin in 1x PB-GTP and 10 μL contain the tested molecules dissolved in the same buffer. Paclitaxel, vinblastine and nocodazole (used as controls) and each tested compound are dissolved in DMSO and used at final concentration of 10 μM.…”

Section: In Vitro Tubulin Polymerization Assaymentioning

confidence: 99%

“…[5] Due to the above reasons, microtubules have become a preferred target in cancer treatment. [6][7][8][9] Nowadays, the microtubule-targeted agents (MTAs) represent a class of drugs commonly used in cancer chemotherapy. They are employed for the treatment of solid tumors and malignant hemopathies, being able to suppress the microtubule dynamics, leading to mitotic arrest and cell death.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, being essential components of mitotic spindles, microtubules are implicated in all those functions vital for cell growth and proliferation, such as intracellular trafficking, preservation of cellular shape and cell movement and migration [5] . Due to the above reasons, microtubules have become a preferred target in cancer treatment [6–9] …”

Section: Introductionmentioning

confidence: 99%

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α–ω Alkenyl‐bis‐S‐Guanidine Thiourea Dihydrobromide Affects HeLa Cell Growth Hampering Tubulin Polymerization

et al. 2020

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Cancer is going to be the first cause of mortality worldwide in the 21th century. It is considered a multifactorial disease that results from the combined influence of many genetic aberrations, leading to abnormal cell proliferation. As microtubules are strongly implicated in cellular growth, they represent an important target for cancer treatment. The well-known microtubule-targeting agents (MTAs) including paclitaxel, colchicine and vinca alkaloids are commonly used in the treatment of various cancers. However, adverse effects and drug resistance are major limitations in their clinical use. To find new candidates able to induce microtubule alteration with reduced toxic effects or drug resistance, we studied a small new series of derivatives that present imidazolinic, guanidinic, thioureidic and hydrazinic groups (1-9). All the compounds were tested for their antitumor activity against a panel of six tumoral cell models. In particular, compound 8 (nonane-1,9diyl-bis-S-amidinothiourea dihydrobromide) showed the lowest IC 50 value against HeLa cells, together with a low cytotoxicity for normal cells. This compound was able to induce the apoptotic mitochondrial pathway and inhibited tubulin polymerization with a similar efficacy to vinblastine and nocodazole. Taken together, these promising biological properties make compound 8 useful for the development of novel therapeutic approaches in cancer treatment.

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“…A large body of studies has been performed in order to characterize the mechanisms of action of the above-mentioned compounds. Certain agents are able to inhibit the human topoisomerases I and II (hTopoI and II), crucial enzymes involved in the DNA replication, transcription, recombination and chromatin remodeling [ 3 , 4 , 5 , 6 ]. For instance, cisplatin is known for its ability to interact with many types of proteins regulating the DNA replication and cell division like DNA topoisomerase II [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Newly Synthesized Imino-Derivatives Analogues of Resveratrol Exert Inhibitory Effects in Breast Tumor Cells

Iacopetta

Lappano

Mariconda

et al. 2020

IJMS

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Breast cancer represents the most frequently diagnosed malignancy in women worldwide. Various therapeutics are currently used in order to halt the progression of breast tumor, even though certain side effects may limit the beneficial effects. In recent years, many efforts have been addressed to the usefulness of natural compounds as anticancer agents due to their low toxicity. Resveratrol, a stilbene found in grapes, berries, peanuts and soybeans, has raised a notable interest for its antioxidant, anti-inflammatory, and antitumor properties. Here, we report the design, the synthesis and the characterization of the anticancer activity of a small series of imino N-aryl-substituted compounds that are analogues of resveratrol. In particular, the most active compound, named 3, exhibited anti-tumor activity in diverse types of breast cancer cells through the inhibition of the human topoisomerase II and the induction of apoptotic cell death. Therefore, the abovementioned compound maybe considered as a promising agent in more comprehensive treatments of breast cancer.

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Benzothienoquinazolinones as new multi-target scaffolds: Dual inhibition of human Topoisomerase I and tubulin polymerization

Cited by 40 publications

References 52 publications

β-Caryophyllene: A Sesquiterpene with Countless Biological Properties

β-Caryophyllene: A Sesquiterpene with Countless Biological Properties

α–ω Alkenyl‐bis‐S‐Guanidine Thiourea Dihydrobromide Affects HeLa Cell Growth Hampering Tubulin Polymerization

Newly Synthesized Imino-Derivatives Analogues of Resveratrol Exert Inhibitory Effects in Breast Tumor Cells

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