Insight on [1,3]thiazolo[4,5-e]isoindoles as tubulin polymerization inhibitors

Spanò, Virginia; Barreca, Marilia; Rocca, Roberta; Bortolozzi, Roberta; Bai, Ruoli; Carbone, Anna; Raimondi, Maria Valeria; Piccionello, Antonio Palumbo; Montalbano, Alessandra; Alcaro, Stefano; Hamel, Ernest; Viola, Giampietro; Barraja, Paola

doi:10.1016/j.ejmech.2020.113122

Cited by 32 publications

(16 citation statements)

References 62 publications

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“…Others, like combretastatin A‐4 phosphate (CA‐4P, Figure 1), a prodrug of combretastatin A‐4 (CA‐4), have been recently approved by the European Medicines Agency and the US Food and Drug Administration as orphan drugs for the treatment of anaplastic thyroid cancer and ovarian cancer. [ 2 ] CA‐4 interacts with the colchicine binding site of tubulin, and during the past decades, several of its analogs were synthesized and tested in vitro and in vivo. [ 1–3 ] Many of these analogs were obtained by isosteric replacement of double bond and/or aromatic rings with aromatic heterocycles, including pyrrole, imidazole, isoxazole, and so forth, aiming to improve the activity, stability, pharmacokinetic properties, and toxicological profile of the lead molecule.…”

Section: Introductionmentioning

confidence: 99%

Novel substituted 5‐methyl‐4‐acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells

Sadovnikov

Vasilenko

Gracheva

et al. 2022

Archiv der Pharmazie

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A series of novel antimitotic agents was designed using the replacement of heterocyclic cores in two tubulin‐targeting lead molecules with the acylated 4‐aminoisoxazole moiety. Target compounds were synthesized via heterocyclization of β‐aryl‐substituted vinylketones by tert‐butyl nitrite in the presence of water as a key step. 4‐Methyl‐N‐[5‐methyl‐3‐(3,4,5‐trimethoxyphenyl)isoxazol‐4‐yl]benzamide (1aa) was found to stimulate partial depolymerization of microtubules of human lung carcinoma A549 cells at a high concentration of 100 µM and to totally inhibit cell growth (IC50 = 0.99 µM) and cell viability (IC50 = 0.271 µM) in the nanomolar to submicromolar concentration range. These data provide evidence of the multitarget profile of the cytotoxic action of compound 1aa. The SAR study demonstrated that the 3,4,5‐trimethoxyphenyl residue is the key structural parameter determining the efficiency both towards tubulin and other molecular targets. The cytotoxicity of 3‐methyl‐N‐[5‐methyl‐3‐(3,4,5‐trimethoxyphenyl)isoxazol‐4‐yl]benzamide (1ab) to the androgen‐sensitive human prostate adenocarcinoma cancer cell line LNCaP (IC50 = 0.301 µM) was approximately one order of magnitude higher than that to the conditionally normal cells lines WI‐26 VA4 (IC50 = 2.26 µM) and human umbilical vein endothelial cells (IC50 = 5.58 µM) and significantly higher than that to primary fibroblasts (IC50 > 75 µM).

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Section: Introductionmentioning

confidence: 99%

Novel substituted 5‐methyl‐4‐acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells

Sadovnikov

Vasilenko

Gracheva

et al. 2022

Archiv der Pharmazie

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“…These molecules are involved in different cellular processes, such as cell signaling, secretion, and motility, and they play an important role in cell proliferation because they constitute the mitotic spindle, an essential structure for chromosome segregation during mitosis. Agents acting on microtubule‐associated proteins interfere with their functions and, thus, can be highly effective in cancer treatment 1‐4 . By interfering with microtubule dynamics during mitosis, these compounds induce mitotic dysfunction and apoptotic cell death 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Agents acting on microtubule‐associated proteins interfere with their functions and, thus, can be highly effective in cancer treatment. 1 , 2 , 3 , 4 By interfering with microtubule dynamics during mitosis, these compounds induce mitotic dysfunction and apoptotic cell death. 5 Hence, identifying new therapeutic molecular targets that regulate microtubule assembly and function specifically in cancer cells is critical.…”

Section: Introductionmentioning

confidence: 99%

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

et al. 2021

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Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti–apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC.

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“…For many years, we have been involved in studies dealing with nitrogen heterocycles and much of our attention has been paid to tricyclic pyrrolo-fused systems [21][22][23][24][25][26][27][28][29][30][31][32]. Based on our past experience, we decided to investigate the effect on corrector activity of the replacement of one thiazole unit with a pyrrole moiety, which could have allowed the incorporation of some common structural features with constrained bithiazoles, aiming at the identification of new correctors.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein

et al. 2021

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Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named “correctors”. So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.

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Insight on [1,3]thiazolo[4,5-e]isoindoles as tubulin polymerization inhibitors

Cited by 32 publications

References 62 publications

Novel substituted 5‐methyl‐4‐acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells

Novel substituted 5‐methyl‐4‐acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein

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