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1.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206076

RESUMO

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4'-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.


Assuntos
Antineoplásicos/síntese química , Pirimidinas/síntese química , Pirróis/síntese química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia
2.
Eur J Med Chem ; 222: 113577, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087544

RESUMO

One of the major causes of neurodegeneration in the pathogenesis of Alzheimer's disease is the accumulation of cytotoxic amyloid species within the intercellular compartments of the brain. The efficacy of the anti-proteotoxic mechanism based on the molecular chaperones Hsp70 and Hsp90 in numerous types of neurons is often low, while its pharmacological enhancement has been shown to ameliorate the physiological and cognitive functions of the brain. Suggesting that the chemicals able to induce heat shock protein synthesis and therefore rescue neural cells from cytotoxicity associated with amyloid, we have synthesized a group of pyrrolyl- and indolylazines that cause the accumulation of heat shock proteins, using a novel method of photocatalysis that is employed in green chemistry. The selected compounds were tested in a cell model of Alzheimer's disease and demonstrated a pronounced neuroprotective effect. These substances increased the survival of neurons, blocked the activation of ß-galactosidase, and prevented apoptosis in neurons cultured in the presence of ß-amyloid.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Hidrazinas/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pirróis/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Apoptose/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Estrutura Molecular , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 220: 113497, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33957388

RESUMO

Axl has emerged as an attractive target for cancer therapy due to its strong correlation with tumor growth, metastasis, poor survival, and drug resistance. Herein, we report the design, synthesis and structure-activity relationship (SAR) investigation of a series of pyrrolo[2,3-d]pyrimidine derivatives as new Axl inhibitors. Among them, the most promising compound 13b showed high enzymatic and cellular Axl potencies. Furthermore, 13b possessed preferable pharmacokinetic properties and displayed promising therapeutic effect in BaF3/TEL-Axl xenograft tumor model. Compound 13b may serve as a lead compound for new antitumor drug discovery.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Ratos , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Molecules ; 26(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947062

RESUMO

1-Pyrrolines are important intermediates of active natural products, such as the 2,5-dialkyl-1-pyrroline derivatives found in fire ant venoms. Here, 5-hexyl-2-methyl-3,4-dihydro-2H-pyrrole was synthesized by the enzymatic transamination/cyclization of 2,5-undecadione, and enantiodifferenciation was successfully achieved by capillary electrophoresis with sulfobutyl ether-ß-cyclodextrin as the chiral selector. The rationale of the enantiomeric discrimination was based on the results of a docking simulation that revealed the higher affinity of (S)-5-hexyl-2-methyl-3,4-dihydro-2H-pyrrole for the sulfobutyl ether-ß-cyclodextrin.


Assuntos
Pirróis/química , beta-Ciclodextrinas/química , Técnicas de Química Sintética , Ciclodextrinas/química , Eletroforese Capilar , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirróis/análise , Pirróis/síntese química , beta-Ciclodextrinas/análise
5.
Bioorg Med Chem Lett ; 41: 127998, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794318

RESUMO

A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.


Assuntos
Alcaloides/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Pirróis/farmacologia , Quinonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química
6.
Eur J Med Chem ; 218: 113394, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813153

RESUMO

Herein, we describe the design, synthesis, and structure-activity relationships of a series of imidazopyrrolopyridines derivatives that selectively inhibit Janus kinase 2 (JAK2). These screening cascades revealed that 6k was a preferred compound, with IC50 values of 10 nM for JAK2. Moreover, 6k was a selective JAK2 inhibitor with 19-fold, >30-fold and >30-fold selectivity over JAK1, JAK3 and TYK2 respectively. In cytokine-stimulated cell-based assays, 6k exhibited a higher JAK2 selectivity over JAK1 isoforms. Indeed, at a dose of 20 mg/kg compound 6k, pSTAT3 and pSTAT5 expression was reduced to levels comparable to those of control animals untreated with GM-CSF. Additionally, 6k showed a relatively good bioavailability (F = 38%), a suitable half-life time (T1/2 = 1.9 h), a satisfactory metabolic stability, suggesting that 6k might be a promising inhibitor of JAK2 for further development research for the treatment of MPNs.


Assuntos
Descoberta de Drogas , Imidazóis/farmacologia , Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Janus Quinase 2/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 218: 113403, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33823396

RESUMO

Targeting P-glycoprotein (P-gp, ABCB1 transporter), which plays an essential role in multi-drug resistance (MDR) in cancers, with new cytotoxic agents is a promising strategy in cancer chemotherapy. In the current study, we report the synthesis of thirteen novel pyrimidopyrrolizine, pyrimidoindolizine, and diazepinopyrrolizine derivatives. The new compounds exhibited cytotoxic activities against MCF7, A2780 and HT29 cancer cell lines (IC50 = 0.02-19.58 µM) and MRC5 (IC50 = 0.17-20.57 µM). The six most active compounds (23b, 24a,b and, 31c-e) were evaluated for their MDR reversal activities in MCF7/ADR cells. Mechanistic study using real-time PCR revealed the ability of compound 31c to inhibit P-gp. In addition, compound 31c increased the accumulation of Rho123 inside MCF7/ADR cells in a dose-dependent manner compared to verapamil. Compound 31c arrested the cell cycle of MCF7 cells at the G1 phase. Compound 31c also caused a significant dose-dependent increase of early and late apoptotic events. Molecular docking analysis revealed a high binding affinity for compound 31c toward P-gp. Like zosuquidar, compound 31c displayed one hydrogen bond and several hydrophobic interactions with amino acids in P-gp. These results indicated that compound 31c represents a potential anticancer candidate with MDR reversal activity.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Pirimidinas/farmacologia , Pirróis/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
8.
Molecules ; 26(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918322

RESUMO

In this article, we showed the synthesis of new polycyclic aromatic compounds, such as thienotriazolopyrimidinones, N-(thienotriazolopyrimidine) acetamide, 2-mercapto-thienotriazolo-pyrimidinones, 2-(((thieno-triazolopyrimidine) methyl) thio) thieno-triazolopyrimidines, thieno-pyrimidotriazolo-thiazines, pyrrolo-triazolo-thienopyrimidines, thienopyrimido-triazolopyrrolo-quinoxalines, thienopyrimido-triazolo-pyrrolo-oxathiino-quinoxalinones, 1,4-oxathiino-pyrrolo- triazolothienopyrimidinones, imidazopyrrolotriazolothienopyrimidines and 1,2,4-triazoloimidazo- pyrrolotriazolothienopyrimidindiones, based on the starting material 2,3-diamino-6-benzoyl-5- methylthieno[2,3-d]pyrimidin-4(3H)-one (3). The chemical structures were confirmed using many spectroscopic ways (IR, 1H, 13C, -NMR and MS) and elemental analyses. A series of thiazine, imidazole, pyrrole, thienotriazolopyrimidine derivatives were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines, i.e., CNE2 (nasopharyngeal), KB (oral), MCF-7 (breast) and MGC-803 (gastric) carcinoma cells. The compounds 20, 19, 17, 16 and 11 showed significant cytotoxicity against types of human cancer cell lines.


Assuntos
Antineoplásicos/síntese química , Desenho de Fármacos , Imidazóis/síntese química , Pirimidinas/síntese química , Pirróis/química , Quinoxalinas/síntese química , Tiazinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/química , Imidazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Tiazinas/química , Tiazinas/farmacologia
9.
Eur J Med Chem ; 217: 113339, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744686

RESUMO

Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) together with nucleoside triphosphate diphosphohydrolases (NTPDases) and alkaline phosphatases (APs) are nucleotidases located at the surface of the cells. NPP1 and NPP3 are important members of NPP family that are known as druggable targets for a number of disorders such as impaired calcification, type 2 diabetes, and cancer. Sulfonylurea derivatives have been reported as antidiabetic and anticancer agents, therefore, we synthesized and investigated series of sulfonylurea derivatives 1a-m possessing pyrrolo[2,3-b]pyridine core as inhibitors of NPP1 and NPP3 isozymes that are over-expressed in cancer and diabetes. The enzymatic evaluation highlighted compound 1a as selective NPP1 inhibitor, however, 1c was observed as the most potent inhibitor of NPP1 with an IC50 value of 0.80 ± 0.04 µM. Compound 1l was found to be the most potent and moderately selective inhibitor of NPP3 (IC50 = 0.55 ± 0.01 µM). Furthermore, in vitro cytotoxicity assays of compounds 1a-m against MCF-7 and HT-29 cancer cell lines exhibited compound 1c (IC50 = 4.70 ± 0.67 µM), and 1h (IC50 = 1.58 ± 0.20 µM) as the most cytotoxic compounds against MCF-7 and HT-29 cancer cell lines, respectively. Both of the investigated compounds showed high degree of selectivity towards cancer cells than normal cells (WI-38). Molecular docking studies of selective and potent enzyme inhibitors revealed promising mode of interactions with important binding sites residues of both isozymes i.e., Thr256, His380, Lys255, Asn277 residues of NPP1 and His329, Thr205, and Leu239 residues of NPP3. In addition, the most potent antiproliferative agent, compound 1h, doesn't produce hypoglycemia as a side effect when injected to mice. This is an additional merit of the promising compound 1h.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Piridinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Diester Fosfórico Hidrolases/metabolismo , Piridinas/síntese química , Piridinas/química , Pirofosfatases/metabolismo , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 37: 127837, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33581250

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is a hardly curable disease with a high relapse rate. 20 analogs were synthesized based on the structures of two kinds of fungi-derived polyenylpyrrole products (rumbrin (1) and auxarconjugatin-B (2)) to suppress the growth of T-ALL-derived cell line CCRF-CEM and tested for growth-inhibiting activity. The octatetraenylpyrrole analog gave an IC50 of 0.27 µM in CCRF-CEM cells, while it did not affect Burkitt lymphoma-derived cell line Raji and the cervical cancer cell line HeLa, or the oral cancer cell line HSC-3 (IC50 > 10 µM). This compound will be a promising compound for developing T-ALL-specific drugs.


Assuntos
Antineoplásicos/farmacologia , Polienos/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polienos/síntese química , Polienos/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 214: 113229, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33550186

RESUMO

Three different series of cis-restricted analogues of combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed between the two aryl rings, were prepared by a palladium-mediated coupling approach and evaluated for their antiproliferative activity against six human cancer cell lines. In the two series of 1,2-diaryl pyrrole derivatives, results suggested that the presence of the 3',4',5'-trimethoxyphenyl moiety at the N-1 position of the pyrrole ring was more favorable for antiproliferative activity. In the series of 3,4-diarylpyrrole analogues, three compounds (11i-k) exhibited maximal antiproliferative activity, showing excellent antiproliferative activity against the CA-4 resistant HT-29 cells. Inhibition of tubulin polymerization of selected 1,2 pyrrole derivatives (9a, 9c, 9o and 10a) was similar to that observed with CA-4, while the isomeric 3,4-pyrrole analogues 11i-k were generally from 1.5- to 2-fold more active than CA-4. Compounds 11j and 11k were the only compounds that showed activity as inhibitors of colchicine binding comparable to that CA-4. Compound 11j had biological properties consistent with its intracellular target being tubulin. This compound was able to block the cell cycle in metaphase and to induce significant apoptosis at a concentration of 25 nM, following the mitochondrial pathway, with low toxicity for normal cells. More importantly, compound 11j exerted activity in vivo superior to that of CA-4P, being able to significantly reduce tumor growth in a syngeneic murine tumor model even at the lower dose tested (5.0 mg/kg).


Assuntos
Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Colchicina/antagonistas & inibidores , Descoberta de Drogas , Pirróis/farmacologia , Moduladores de Tubulina/farmacologia , Antimitóticos/síntese química , Antimitóticos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
12.
Eur J Med Chem ; 214: 113245, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582389

RESUMO

18F-Labelled pyrrolopyrimidines were synthesized and evaluated as positron emission tomography (PET) probes to determine leucine-rich repeat kinase 2 (LRRK2) expression in the brain. With pyrrolopyrimidine derivative PF-06447475 as the lead compound, two in vivo-stable 18F-labelled pyrrolopyrimidines ([18F]1 and [18F]2) were synthesized automatically at radiochemical yields 8-10% (non-decay-corrected) with molar activities of 0.95 and 0.5 GBq/µmol, respectively. The measured Kd of 6.90 nM for 1 and 14.27 nM for 2 demonstrated high affinities for LRRK2. The LRRK2 G2019S mice had higher uptakes (P < 0.01) of [18F]1 in the olfactory bulb, striatum, and hippocampus than WT mice during microPET/CT imaging, consistent with immunohistology results of LRRK2 distribution. [11C]CFT microPET/CT imaging demonstrated a lower expression of dopamine transporter in LRRK2 G2019S mice. Parkinson's disease-like deficits in dopamine transporter synthesis and cognitive declines were noticed along with LRRK2 expression increase in the olfactory bulb, striatum, and hippocampus. Therefore, 18F-labelled pyrrolopyrimidines can reflect real-time LRRK2 expression changes implicated in Parkinson's disease, which paves the way for LRRK2-related neurodegenerative precise therapy.


Assuntos
Encéfalo/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Sondas Moleculares/química , Doença de Parkinson/metabolismo , Pirimidinas/química , Pirróis/química , Animais , Encéfalo/patologia , Relação Dose-Resposta a Droga , Radioisótopos de Flúor , Células HEK293 , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Sondas Moleculares/síntese química , Estrutura Molecular , Doença de Parkinson/patologia , Tomografia por Emissão de Pósitrons , Pirimidinas/síntese química , Pirróis/síntese química , Relação Estrutura-Atividade
13.
Int J Mol Sci ; 22(3)2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33573356

RESUMO

In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides 2a-2p. The compounds 2a-2p were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-c]pyrrole scaffold (1a-c) with secondary amines and an excess of formaldehyde solution in C2H5OH. The structural properties of the compounds were characterized by 1H NMR, 13C NMR FT-IR, MS, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound 2h. The colorimetric inhibitor screening assay was used to obtain their potencies to inhibit COX-1 and COX-2 enzymes. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2. Theoretical modeling was also applied to describe the binding properties of compounds towards COX-1 and COX-2 cyclooxygenase isoform. The data were supported by QSAR study.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Imidas/farmacologia , Pirróis/farmacologia , Linhagem Celular , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 1/ultraestrutura , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/ultraestrutura , Inibidores de Ciclo-Oxigenase/síntese química , Desenho de Fármacos , Ensaios Enzimáticos , Humanos , Imidas/síntese química , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirróis/síntese química , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 215: 113169, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33588178

RESUMO

The study focuses on the prudent design and synthesis of anilide type class I HDAC inhibitors employing a functionalized pyrrolo[2,3-d]pyrimidine skeleton as the surface recognition part. Utilization of the bicyclic aromatic ring to fabricate the target compounds was envisioned to confer rigidity to the chemical architecture of MS-275 and chidamide. In-vitro enzymatic and cellular assays led to the identification of compound 7 as a potent inhibitor of HDAC1 and 2 isoform that exerted substantial cell growth inhibitory effects against human breast MDA-MB-231, cervical HeLa, breast MDA-MB-468, colorectal DLD1, and colorectal HCT116 cell lines with an IC50 values of 0.05-0.47 µM, better than MS-275 and chidamide. In addition, the anilide 7 was also endowed with a superior antiproliferative profile than MS275 and chidamide towards the human cutaneous T cell lymphoma (HH and HuT78), leukemia (HL60 and KG-1), and HDACi sensitive/resistant gastric cell lines (YCC11 and YCC3/7). Exhaustive exploration of the construct 7 confirmed it to be a microtubule-targeting agent that could trigger the cell-cycle arrest in mitosis. In pursuit of extracting the benefits of evidenced microtubule-destabilizing activity of the anilide 7, it was further evaluated against non-small-cell lung cancer cell lines as well as the multiple-drug resistant uterine cancer cell line (MES-SA/Dx5) and overwhelmingly positive results in context of inhibitory effects were attained. Furthermore, molecular modelling studies were performed and some key interactions of the anilide 7 with the amino acid residues of the active site of HDAC1 isoform and tubulin were figured out.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Moduladores de Tubulina/farmacologia , Aminopiridinas/química , Anilidas/síntese química , Anilidas/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Benzamidas/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirróis/síntese química , Pirróis/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo
15.
Eur J Med Chem ; 215: 113273, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33601310

RESUMO

In this study, a series of pyrrolo [2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment were synthesized and their biological activity were tested. Most of the target compounds displayed moderate to excellent activity against one or more cancer cell lines and low activity against human normal cell LO2 in vitro. The most promising compound 51, of which the IC50 values were 0.66 µM, 0.38 µM and 0.44 µM against cell lines A549, Hela and MCF-7, shown more remarkable activity and better apoptosis effect than the positive control Cabozantinib. The structure-activity relationships (SARs) indicated that double-EWGs (such as R3 = 2-Cl-4-CF3) on the terminal phenyl rings was a key factor in improving the biological activity. In addition, the further research on compound 51 mainly included c-Met kinase activity and selectivity, concentration dependence, and molecular docking.


Assuntos
Antineoplásicos/farmacologia , Naftiridinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Anilidas/metabolismo , Anilidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftiridinas/síntese química , Naftiridinas/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirróis/síntese química , Pirróis/metabolismo , Relação Estrutura-Atividade
16.
Acc Chem Res ; 54(4): 861-874, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33507727

RESUMO

Macrocyclic natural products are plentiful in the bacteria, archaea, and eukaryote domains of life. For the significant advantages that they provide to the producing organisms, evolution has learned how to implement various types of macrocyclization reactions into the different biosynthetic pathways and how to effect them with remarkable ease. Mankind greatly benefits from nature's pool, not least because naturally occurring macrocycles or derivatives thereof serve as important drugs for the treatment of many serious ailments.In stark contrast, macrocyclization reactions are usually perceived as difficult to accomplish by purely chemical means. While it is true that ring closure necessarily entails an entropic loss and may result in the buildup of (considerable) ring strain that must be compensated for in one way or the other, it is also fair to note tremendous methodological advances during the last decades that greatly alleviated this traditional "macrocycle challenge". It is therefore increasingly possible to explore the advantages provided by large as well as medium-size ring systems in a more systematic manner. This venture also holds the promise of increasing the "chemical space" amenable to drug development to a considerable extent.In consideration of this and other important long-term perspectives, it is appropriate to revisit the current state of the art. To this end, a number of vignettes are presented, each of which summarizes a total synthesis project targeting macrocyclic natural products of greatly different chemotypes using a variety of transformations to reach these goals. Although we were occasionally facing "dead ends", which are also delineated for the sake of a complete picture, these case studies illustrate the notion that the formation of a certain macrocyclic perimeter is (usually) no longer seriously limiting. In addition to substantial progress in the "classical" repertoire (macrolactonization and macrolactamization (pateamine A, spirastrellolide, and belizentrin)), various metal-catalyzed reactions have arguably led to the greatest leaps forward. Among them, palladium-catalyzed C-C bond formation (roseophilin and nominal xestocyclamine A) and, in particular, alkene and alkyne metathesis stand out (iejimalide, spirastrellolide, enigmazole, ingenamine, and sinulariadiolide). In some cases, different methods were pursued in parallel, thus allowing for a critical assessment and comparison.To the extent that the macrocyclic challenge is vanishing, the opportunity arises to focus attention on the postmacrocyclization phase. One may stipulate that a well-designed cyclization precursor does not only ensure efficient ring closure but also fosters and streamlines the steps that come after the event. One way to do so is dual (multiple) use in that the functional groups serving the actual cyclization reaction also find productive applications downstream from it rather than being subject to simple defunctionalization. In this context, better insight into the conformational peculiarities of large rings and the growing confidence in their accessibility in a stereochemically well defined format rejuvenate the implementation of transannular reactions or reaction cascades that can lead to rapid and substantial increases in molecular complexity. The examples summarized herein showcase such possibilities, with special emphasis on tranannular gold catalysis and the emerging ruthenium-catalyzed trans-hydrometalation chemistry for the selective functionalization of alkynes.


Assuntos
Produtos Biológicos/síntese química , Alcenos/química , Alcinos/química , Produtos Biológicos/química , Catálise , Ciclização , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Macrolídeos/síntese química , Macrolídeos/química , Metais/química , Pirróis/síntese química , Pirróis/química , Compostos de Espiro/síntese química , Compostos de Espiro/química
17.
Molecules ; 26(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440776

RESUMO

Natural products are rich sources of interesting scaffolds possessing a plethora of biological activity. With the isolation of the martinella alkaloids in 1995, namely martinelline and martinellic acid, the pyrrolo[3,2-c]quinoline scaffold was discovered. Since then, this scaffold has been found in two additional natural products, viz. incargranine B and seneciobipyrrolidine. These natural products have attracted attention from synthetic chemists both due to the interesting scaffold they contain, but also due to the biological activity they possess. This review highlights the synthetic efforts made for the preparation of these alkaloids and formation of analogues with interesting biological activity.


Assuntos
Alcaloides/síntese química , Pirróis/síntese química , Pirrolidinas/síntese química , Quinolinas/síntese química , Bignoniaceae/química , Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos
18.
Eur J Med Chem ; 209: 112913, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33109399

RESUMO

In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC50 = 5.9 nM, ß/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.


Assuntos
Inibidores da Angiogênese/síntese química , Antineoplásicos/síntese química , Morfolinas/síntese química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Piperazinas/síntese química , Pirróis/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
19.
Bioorg Chem ; 107: 104522, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33317838

RESUMO

A potential microtubule destabilizing series of new thirty-five Pyrrol-2-one, Pyridazin-3(2H)-one and Pyridazin-3(2H)-one/oxime derivatives has been synthesized and tested for their antiproliferative activity against a panel of 60 human cancer cell lines. Compounds IVc, IVg and IVf showed a broad spectrum of growth inhibitory activity against cancer cell lines representing renal, cancer of lung, colon, central nervous system, ovary, and kidney. Among them, compound IVg was found to have broad spectrum anti-tumor activity against the tested nine tumor subpanels with selectivity ratios ranging between 0.21 and 3.77 at the GI50 level. In vitro assaying revealed tubulin polymerization inhibition by all active compounds IVc, IVg and IVf. The results of the docking study revealed nice fitting of compounds IVc, IVf, and IVg into CA-4 binding site in tubulin. The three compounds exhibited high binding affinities (ΔGb = -12.49 to -12.99 kcal/mol) toward tubulin compared to CA-4 (-8.87 kcal/mol). Investigation of the binding modes of the three compounds IVc, IVf, and IVg revealed that they interacted mainly hydrophobically with tubulin and similar binding orientations to that of CA-4. These observations suggest that tubulin is a possible target for these compounds.


Assuntos
Antineoplásicos/farmacologia , Piridazinas/farmacologia , Pirróis/farmacologia , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Piridazinas/síntese química , Piridazinas/metabolismo , Pirróis/síntese química , Pirróis/metabolismo , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo
20.
J Enzyme Inhib Med Chem ; 36(1): 15-33, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33103497

RESUMO

In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC50 = 0.16-34.13 µM). The drug-likeness study revealed that all the new compounds conform to Lipinski's rule. Mechanistic studies of compounds 18 b, 19a, and 20a revealed the induction of apoptosis and cell cycle arrest at the G1 phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC50 = 25.53-115.30 nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
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