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1.
Bioorg Chem ; 143: 107094, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199139

RESUMO

Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI50 values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Tubulina (Proteína) , Animais , Humanos , Camundongos , Amidas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Microtúbulos/metabolismo , Mitose , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
2.
J Nat Prod ; 85(6): 1503-1513, 2022 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-35687347

RESUMO

Aurora kinases (Aurora A, B, and C) are a family of serine/threonine kinases that play critical roles during mitotic initiation and progression. Aurora A and B kinases are ubiquitously expressed, and their overexpression and/or amplification in many cancers have been associated with poor prognosis. Several inhibitors that target Aurora kinases A, B, or both have been developed during the past decade with efficacy in different in vitro and in vivo models for a variety of cancers. Recent studies have also identified Aurora A as a synthetic lethal target for different tumor suppressors, including RB1, SMARCA4, and ARID1A, which signifies the need for Aurora-A-selective inhibitors. Here, we report the screening of a small library of quinones (nine naphthoquinones, one orthoquinone, and one anthraquinone) in a biochemical assay for Aurora A kinase that resulted in the identification of several quinones as inhibitors. IC50 determination against Aurora A and B kinases revealed the inhibition of both kinases with selectivity toward Aurora A. Two of the compounds, natural quinone naphthazarin (1) and a pseudo anthraquinone, 2-(chloromethyl)quinizarin (11), potently inhibited the proliferation of various cancer cell lines with IC50 values ranging from 0.16 ± 0.15 to 1.7 ± 0.06 and 0.15 ± 0.04 to 6.3 ± 1.8 µM, respectively. Treatment of cancer cells with these compounds for 24 h resulted in abrogated mitosis and apoptotic cell death. Direct binding of both the compounds with Aurora A kinase was also confirmed through STD NMR analysis. Docking studies predicted the binding of both compounds to the ATP binding pocket of Aurora A kinase. We have, therefore, identified quinones as Aurora kinase inhibitors that can serve as a lead for future drug discovery endeavors.


Assuntos
Aurora Quinase A , Aurora Quinase B , Neoplasias , Inibidores de Proteínas Quinases , Quinonas , Antraquinonas , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Linhagem Celular Tumoral , DNA Helicases , Humanos , Proteínas Nucleares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinonas/química , Quinonas/farmacologia , Fatores de Transcrição
3.
J Nat Prod ; 83(10): 3111-3121, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-32975953

RESUMO

Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2'-allyloxy-4,4'-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1-3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2'-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Chalconas/farmacologia , Microtúbulos/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Antibióticos Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Chalconas/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/farmacologia , Células HCT116 , Humanos , Células K562 , Leucemia Mieloide Aguda/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Polimerização , Tirosina Quinase 3 Semelhante a fms/genética
4.
Bioorg Med Chem Lett ; 27(17): 4101-4106, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28743509

RESUMO

Tumor suppressor protein p53 induces cell cycle arrest and apoptotic cell death in response to various cellular stresses thereby preventing cancer development. Activation and stabilization of p53 through small organic molecules is, therefore, an attractive approach for the treatment of cancers retaining wild-type p53. In this context, a series of nineteen chalcones with various substitution patterns of functional groups including chloro, fluoro, methoxy, nitro, benzyloxy, 4-methyl benzyloxy was prepared using Claisen-Schmidt condensation. The compounds were characterized using NMR, HRMS, IR and melting points. Evaluation of synthesized compounds against human colorectal (HCT116) and breast (CAL-51) cancer cell lines revealed potent antiproliferative activities. Nine compounds displayed GI50 values in the low micromolar to submicromolar range; for example (E)-1-phenyl-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (SSE14108) showed GI50 of 0.473±0.043µM against HCT116 cells. Further analysis of these compounds revealed that (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (SSE14105) and (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (SSE14106) caused rapid (4 and 8-h post-treatment) accumulation of p53 in HCT116 cells similar to its induction by positive control, Nutlin-3. Such activities were absent in 3-(4-methoxyphenyl)propiophenone (SSE14106H2) demonstrating the importance of conjugated ketone for antiproliferative and p53 stabilizing activity of the chalcones. We further evaluated p53 levels in the presence of cycloheximide (CHX) and the results showed that the p53 stabilization was regulated at post-translational level through blockage of its degradation. These chalcones can, therefore, act as fragment leads for further structure optimization to obtain more potent p53 stabilizing agents with enhanced anti-proliferative activities.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Estrutura Molecular , Estabilidade Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
5.
Cell Cycle ; 18(18): 2281-2292, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31318643

RESUMO

Oral cancer is the most prevalent subtype of head and neck cancers and arises mainly from squamous cells of the oral cavity. Patients with advanced metastatic disease have poor overall survival resulting primarily from limited treatment options. Recent advances in the understanding of molecular basis of oral tumorigenesis provide an opportunity for identification and validation of new drug targets. The deregulated expression of the Aurora family of mitotic kinases, for example, has been associated with pathogenesis and poor prognosis in oral cancer. Here, we have evaluated the efficacy of the pan-Aurora inhibitor (CCT137690) alone and in combination with different chemotherapeutic and targeted drugs to identify its synergistic partners in oral cancer cell lines (ORL-48 and ORL-115). CCT137690 effectively inhibits Aurora kinases in both the cell lines and displays potent antiproliferative activity towards them. Prolonged treatment of these cells with CCT137690 results in abrogated mitotic spindle formation, misaligned chromosome attachment and polyploidy that ultimately leads to apoptotic cell death. We further identified that inhibitors of EGFR (gefitinib) and PI3-kinase (pictilisib) synergize with CCT137690 to inhibit the proliferation of the oral cancer cell lines. Moreover, we demonstrate that polyethylene glycol-based nanocapsules harboring combinations of CCT137690 with gefitinib or pictilisib inhibit the growth of oral cancer cell lines in 3D spheroid cultures and induce apoptosis that is comparable to free drug combinations. In conclusion, we have demonstrated the in vitro efficacy of CCT137690 in oral cancer cell lines, identified novel drug combinations with CCT137690 and synthesized nanocapsules containing these drug combinations for co-administration.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinase A/antagonistas & inibidores , Aurora Quinase B/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos/métodos , Gefitinibe/farmacologia , Imidazóis/farmacologia , Indazóis/farmacologia , Neoplasias Bucais/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Neoplasias Bucais/patologia , Nanocápsulas
6.
Sci Rep ; 8(1): 3305, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29459693

RESUMO

Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Microtúbulos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Pirazóis/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Microtúbulos/genética , Mitose/efeitos dos fármacos , Neoplasias/patologia , Pirazóis/farmacologia
7.
Sci Rep ; 8(1): 6427, 2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29666376

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

8.
Nat Prod Res ; 31(5): 583-587, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27450325

RESUMO

Parasitic Cuscuta reflexa Roxb. possesses many medicinal properties and is a rich source of a variety of biologically relevant natural products. Natural products are the prime source of leads, drugs, and drug templates, and many of the anticancer and antiviral drugs are either based on natural product or derived from them. Cancer is a devastating disease and one of the leading causes of death worldwide despite improvements in patient survival during the past 50 years; new and improved treatments for cancer are therefore actively sought. Colorectal cancer is the fourth most prevalent cancer worldwide and is responsible for nearly 9% of all cancer deaths. Our search for anticancer natural products from C. reflexa has yielded four natural products: Scoparone (1), p-coumaric acid (2), stigmasta-3,5-diene (3) and 1-O-p-hydroxycinnamoylglucose (4) and among them 1-O-p-hydroxycinnamoyldlucose (4) showed promising antiproliferative activities in HCT116 colorectal cell lines, whereas compounds 1-3 showed moderate activities.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Cuscuta/química , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Humanos
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