New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

Regina, Giuseppe La; Bai, Ruoli; Coluccia, Antonio; Famiglini, Valeria; Pelliccia, Sveva; Passacantilli, Sara; Mazzoccoli, Carmela; Ruggieri, Vitalba; Sisinni, Lorenza; Bolognesi, Alessio; Rensen, Whilelmina Maria; Miele, Andrea; Nalli, Marianna; Alfonsi, Romina; Marcotullio, Lucia Di; Gulino, Alberto; Brancale, Andrea; Novellino, Ettore; Dondio, Giulio; Vultaggio, Stefania; Varasi, Mario; Mercurio, Ciro; Hamel, Ernest; Lavia, Patrizia; Silvestri, Romano

doi:10.1021/jm500561a

Cited by 81 publications

(59 citation statements)

References 36 publications

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“…The second model is composed of one hydrogen bond acceptor (Asnα101), one hydrogen bond donor, one hydrophobic feature, and one aromatic ring feature while the third model is made up of three hydrogen bond acceptors (Valα181, Leuβ252, and Cysβ241), a hydrogen bond donor (Thrα179), and a hydrophobic skeleton with four hydrophobic centers . There are many reports about the critical role of Cysβ241 for formation of H‐bond and/or hydrophobic interactions of the TMP ring containing structures . So, in the present study interaction between Cysβ241 and TMP ring (designated as Cysβ241‐TMP interaction) of the designed compounds together with docking binding energy were considered to select the most appropriate compounds.…”

Section: Resultsmentioning

confidence: 88%

Novel Aldimine‐Type Schiff Bases of 4‐Amino‐5‐[(3,4,5‐trimethoxyphenyl)methyl]‐1,2,4‐triazole‐3‐thione/thiol: Docking Study, Synthesis, Biological Evaluation, and Anti‐Tubulin Activity

Ameri

Khodarahmi

Hassanzadeh

et al. 2016

Archiv der Pharmazie

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The present study was planned to design some novel aldimine-type Schiff bases bearing 3,4,5-trimethoxyphenyl and 1,2,4-triazole-3-thione/thiol as potential tubulin polymerization inhibitors. The obtained results of the molecular docking study using the tubulin complex (PDB code: 1SA0) showed that compounds H-25 and H-26 were well fitted in the colchicine binding site of tubulin with binding energies of -8.68 and -8.40 kcal/mol, respectively, in comparison to the main ligand (-8.20 kcal/mol). In parallel, molecular simulations were also performed on five other 3,4,5-trimethoxyphenyl-containing ligand targets including hsp90, VEGFR2, and human and microbial (Staphylococcus aureus and Candida albicans) dihydrofolate reductase, among which H-17, H-45, H-27, H-02, and H-19 were the most suitable compounds, respectively. Evaluation of the cytotoxic effect of the most efficient compounds of the docking steps (H-25) revealed IC50 values of 12.48 ± 1.10, 4.25 ± 0.22, 3.33 ± 0.31, and 9.71 ± 0.75 µM against the HT1080, HT29, MCF-7, and A549 cell lines, respectively, compared to doxorubicin (12.69 ± 1.23, 6.12 ± 0.47, 3.51 ± 0.32, and 6.40 ± 0.31 µM, respectively). The in vitro tubulin polymerization investigation launched compounds H-25 and H-26 as potent antitubulin agents due to their IC50 values of 0.17 ± 0.01 and 10.93 ± 0.43 µM, respectively.

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Section: Resultsmentioning

confidence: 88%

Novel Aldimine‐Type Schiff Bases of 4‐Amino‐5‐[(3,4,5‐trimethoxyphenyl)methyl]‐1,2,4‐triazole‐3‐thione/thiol: Docking Study, Synthesis, Biological Evaluation, and Anti‐Tubulin Activity

Ameri

Khodarahmi

Hassanzadeh

et al. 2016

Archiv der Pharmazie

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“…In this study, we introduced on the phenyl rings substituents that were associated with the best biological activity in the ARAP series. 16 The new ARDAP derivatives were synthesized starting from chalcones 25−31, which were converted to the corresponding pyrrole derivatives 32 16 In an initial screen, ARDAP 1 proved to be superior to 3 as an inhibitor of MCF-7 cell growth (Table 1). Besides the ability to inhibit tubulin polymerization, for which they were originally …”

Section: * S Supporting Informationmentioning

confidence: 99%

3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin

Regina

Bai

Coluccia

et al. 2017

ACS Med. Chem. Lett.

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We designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential anticancer agents having different substituents at the 1-or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARDAP derivative 10 inhibited the proliferation of BCR/ABL-expressing KU812 and LAMA84 cells from chronic myeloid leukemia (CML) patients in blast crisis and of hematopoietic cells ectopically expressing the imatinib mesylate (IM)-sensitive KBM5-WT or its IM-resistant KBM5-T315I mutation. Compound 10 minimally affected the proliferation of normal blood cells, indicating that it may be a promising agent to overcome broad tyrosine kinase inhibitor resistance in relapsed/refractory CML patients. Compound 10 significantly decreased CML proliferation by inducing G2/M phase arrest and apoptosis via a mitochondria-dependent pathway. ARDAP 10 augmented the cytotoxic effects of IM in human CML cells. Compound 10 represents a robust lead compound to develop tubulin inhibitors with potential as novel treatments for CML.

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“…The CBSIs 4-substituted methoxybenzoyl-aryl-thiazole (SMART, 5 ), 2-aryl-4-benzoyl-imidazole (ABI, 6 ), 4-aryl-2-benzoyl-imidazoles (RABI, 7 ) and 3-aroyl-1-arylpyrrole (ARAP, 8 ) are the representative synthetic CBSIs that exhibit potent antiproliferative activity (Fig 1A) [14–17]. Furthermore, a set of oxadiazole CBSIs with an oxime linker between the A-ring and the B-ring was previously reported by our group ( 9 , Fig 1A) [18].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and bioevaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity

Sun

et al. 2017

PLoS ONE

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A series of N,4-diaryl-1,3-thiazole-2-amines containing three aromatic rings with an amino linker were designed and synthesized as tubulin inhibitors and evaluated for their antiproliferative activity in three human cancer cell lines. Most of the target compounds displayed moderate antiproliferative activity, and N-(2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1,3-thiazol-2-amine (10s) was determined to be the most potent compound. Tubulin polymerization and immunostaining experiments revealed that 10s potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Moreover, 10s effectively induced SGC-7901 cell cycle arrest at the G2/M phase in both concentration- and time-dependent manners. The molecular docking results revealed that 10s could bind to the colchicine binding site of tubulin.

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New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

Cited by 81 publications

References 36 publications

Novel Aldimine‐Type Schiff Bases of 4‐Amino‐5‐[(3,4,5‐trimethoxyphenyl)methyl]‐1,2,4‐triazole‐3‐thione/thiol: Docking Study, Synthesis, Biological Evaluation, and Anti‐Tubulin Activity

Novel Aldimine‐Type Schiff Bases of 4‐Amino‐5‐[(3,4,5‐trimethoxyphenyl)methyl]‐1,2,4‐triazole‐3‐thione/thiol: Docking Study, Synthesis, Biological Evaluation, and Anti‐Tubulin Activity

3-Aroyl-1,4-diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin

Synthesis and bioevaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity

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