RESUMO
Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense (Tbg) or Trypanosoma brucei rhodesiense (Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC50 for over 24 h and achieving peak brain concentrations exceeding 7 µM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.
Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Humanos , Animais , Camundongos , Tripanossomíase Africana/tratamento farmacológico , Trypanosoma brucei rhodesiense , Trypanosoma brucei gambiense , Tripanossomicidas/toxicidade , Tripanossomicidas/uso terapêuticoRESUMO
Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.
Assuntos
Antiprotozoários , Leishmania , Leishmaniose , Humanos , Animais , Camundongos , Leishmaniose/tratamento farmacológico , Leishmaniose/induzido quimicamente , Leishmaniose/parasitologia , Antiprotozoários/química , Benzamidas/farmacologia , Benzamidas/uso terapêuticoRESUMO
Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F-, Cl-, Br-, CF3- and OCF3-)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl-, Br-, and CF3- groups at the 2-phenyl ring conferred a strong dual topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent topoisomerase inhibition and antiproliferative effects, which showed dependency upon the topoisomerase gene expression level of diverse cancer cells. In particular, as a DNA minor groove-binding non-intercalative topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the anticancer efficacy of clinically applied topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.
Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Halogênios/farmacologia , Indenos/farmacologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Piridonas/farmacologia , Inibidores da Topoisomerase/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Halogênios/química , Humanos , Indenos/síntese química , Indenos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química , Células Tumorais CultivadasRESUMO
Several anticancer agents have been developed and innovative approaches have been made toward cancer type-specific medicines for cancer treatment. As a continuous effort to develop potential chemotherapeutic agents, a novel series of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines containing amino groups, hydroxyphenyl and fluorine functionalities were designed and synthesized. The compounds were evaluated for topo IIα inhibitory and cytotoxicity against HCT15, and HeLa human cancer cell lines. Among synthesized thirty compounds, the majority exhibited strong topo IIα inhibition and anti-proliferation against HCT15 colorectal adenocarcinoma cell line. The structure-activity relationship study revealed that compounds with -CF3 and -OCF3 substituents at 4- position and 3' or 4'-hydroxyphenyl at 2-position attached to the central pyridine ring displayed potent topo IIα and anti-proliferative activity in colorectal and cervix cancer cell line. In vitro studies provided the evidence that compounds 16, 19, 22, and 28 possess excellent topo IIα inhibition and antiproliferative activity. For a better understanding, topo IIα cleavage complex, EtBr displacement, KI quenching assays and molecular docking of compound 19 was performed and the results revealed the mode of action as a DNA intercalative topo IIα poison inhibitor. The results obtained from this study provide insight into the DNA binding mechanism of 2,4-diphenyl-5,6-dihydrobenzo(h)quinolin-8-amines and alteration in topo IIα inhibitory and antiproliferative activity with modifications in the rigid structure.
Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Descoberta de Drogas , Inibidores da Topoisomerase II/farmacologia , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais CultivadasRESUMO
Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Antineoplásicos/química , Inibidores Enzimáticos/química , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Estrogen-related receptor gamma (ERRγ) is the NR3B subgroup of associated transcription factors. In this report, a new generation of a potent and selective ERRγ inverse agonist (25) with good biocompatibility was proposed. We also explored the potential of the newly developed compound 25 in the PDTC model to expand the original indications from ATC. In addition, an X-ray crystallographic study of the ligand and ERRγ co-complex showed that 25 completely binds to the target protein (PDB 6KNR). Its medicinal chemistry, including a distinctive structural study to in vivo results, denotes that 25 may be directed towards the development of a pivotal treatment for ERRγ-related cancers.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Agonismo Inverso de Drogas , Radioisótopos do Iodo/uso terapêutico , Receptores de Estrogênio/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Receptores de Estrogênio/química , Receptores de Estrogênio/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARß or PPARδ. PPARδ is crucial to pathophysiological processes, including metabolic disorders, liver diseases, and cardiovascular diseases. In the past, the clinical development of PPARδ-selective agonist drugs has been stalled due to potential safety-related issues. Despite the elusiveness of such a drug, efforts continue in developing drugs that target PPARδ due to advances in the knowledge of the PPARδ receptor's structure and functions. While several preclinical and clinical studies are reported on PPARδ agonists, there is limited data with no clinical evidence available for PPARδ-selective antagonists. In this review, we mainly focus on the challenges of PPARδ selectivity and the medicinal chemistry of most active agonists discovered by different pharmaceutical companies and institutes. With this in mind, we also provide an update on the development status of PPARδ agonists that are undergoing clinical trials and their therapeutic promise for the treatment of various diseases.
Assuntos
Compostos Orgânicos/uso terapêutico , PPAR delta/agonistas , Animais , Química Farmacêutica , Humanos , Estrutura Molecular , Compostos Orgânicos/química , Compostos Orgânicos/farmacologia , PPAR delta/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
With the aim of developing new effective topoisomerase IIα-targeted anticancer agents, we synthesized a series of hydroxy- and halogenated 2,4-diphenyl indeno[1,2-b]pyridinols using a microwave-assisted single step synthetic method and investigated structure-activity relationships. The majority of compounds with chlorophenyl group at 2-position and phenol group at the 4-position of indeno[1,2-b]pyridinols exhibited potent antiproliferative activity and topoisomerase IIα-selective inhibition. Of the 172 compounds tested, 89 showed highly potent and selective topoisomerase IIα inhibition and antiproliferative activity in the nanomolar range against human T47D breast (2.6 nM) cancer cell lines. In addition, mechanistic studies revealed compound 89 is a nonintercalative topoisomerase II poison, and in vitro studies showed it had promising cytotoxic effects in diverse breast cancer cell lines and was particularly effective at inducing apoptosis in T47D cells. Furthermore, in vivo administration of compound 89 had significant antitumor effects in orthotopic mouse model of breast cancer.
Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Neoplasias da Mama/tratamento farmacológico , DNA Topoisomerases Tipo II/metabolismo , Descoberta de Drogas , Piridinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos ICR , Micro-Ondas , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais CultivadasRESUMO
The convergent and enantioselective synthesis of a highly potent human peroxisome proliferator-activated receptor delta agonist is presented. More specifically, the thiazoline structure, which constitutes the biosynthetically distinctive core structure of pulicatin (a secondary metabolite of symbiotic bacteria), was synthesized from a commercially available and inexpensive chiral pool of l-threonine.
RESUMO
In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6â¯nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50â¯=â¯0.7â¯nM) shows much more potent activity than S isomer (EC50â¯=â¯6.1â¯nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.
Assuntos
Acetatos/química , Compostos de Bifenilo/síntese química , PPAR delta/agonistas , Acetatos/síntese química , Acetatos/farmacocinética , Administração Oral , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Camundongos , Microssomos/metabolismo , Simulação de Acoplamento Molecular , PPAR delta/metabolismo , Estrutura Terciária de Proteína , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/metabolismoRESUMO
A series of pyridine-linked indanone derivatives were designed and synthesized to discover new small molecules for the treatment of inflammatory bowel disease (IBD). Compounds 5b and 5d exhibited strongest inhibitory activity against TNF-α-induced monocyte adhesion to colon epithelial cells (an in vitro model of colitis). In TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced rat colitis model, oral administration of the compounds 5b and 5d ameliorated colitis with significant recovery in altered expressions of E-cadherin, TNF-α and IL-1ß expressions, indicating 5b and 5d as potential agents for therapeutics development against IBD.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Indanos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Piridinas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/síntese química , Adesão Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células HT29 , Humanos , Indanos/administração & dosagem , Indanos/síntese química , Doenças Inflamatórias Intestinais/patologia , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Piridinas/administração & dosagem , Piridinas/química , Ratos , Relação Estrutura-Atividade , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
As part of our effort to develop potential topoisomerase IIα (topo IIα) targeting anticancer agents, we systematically designed a new series of hydroxy and chloro-substituted 2,4-diphenyl 5H-chromeno[4,3-b]pyridines. Total eighteen compounds were synthesized and tested for their ability to inhibit the function of topo I and IIα, and proliferation of human breast (T47D), colorectal (HCT15), and cervix (HeLa) cancer cells. Except compound 11, all of the tested compounds displayed selective topo IIα inhibitory activity. Compounds 8-18, 22, 24, and 25 showed excellent topo IIα inhibitory activity than a positive control, etoposide. Most of the compounds appeared to be superior to reference compounds in their antiproliferative activity. Structure-activity relationship (SAR) study has shown that it is better to place the hydroxyphenyl group at the 4-position of the central pyridine for superior topo IIα inhibition and antiproliferative activity. Similarly, the 3'-, or 4'-hydroxyphenyl substitution at the 2- and 4-positon of pyridine ring is important for better activity than 2'-substitution.
Assuntos
Antineoplásicos/síntese química , DNA Topoisomerases Tipo II/metabolismo , Piridinas/química , Inibidores da Topoisomerase II/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Benzopiranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/química , Células HeLa , Humanos , Ligação Proteica , Piridinas/metabolismo , Piridinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologiaRESUMO
The pathogenesis of inflammatory bowel disease (IBD) is associated with production of immense pro-inflammatory cytokines including TNF-α. Once generated, TNF-α stimulates production of various pro-inflammatory cytokines and disrupts mucosal barrier by inducing inflamed mucosal epithelial cell death. In the present study, we investigated inhibitory effects of TI-1-162, a hydroxyindenone derivative, against TNF-α-induced and TNBS-induced colon inflammation. TI-1-162 showed inhibitory effect on the TNF-α-induced adhesion of U937 monocytic cells to HT-29 colonic epithelial cells (IC50 =â¯0.83⯱â¯0.12⯵M), which is an in vitro model representing the initial step of colitis. In addition, TI-1-162 suppressed TNF-α-stimulated caspase-3 activation and HT-29 cell apoptosis. These in vitro inhibitory activities of TI-1-162 correlated to recovery changes in in vivo colon tissues, such as downregulation of adhesion molecules (ICAM-1, VCAM-1) and chemokines (CCL11, CXCL1, CXCL2, CXCL3, CX3CL1) revealed by gene expression array and Western blot analyses. Such molecular recovery of colon epithelium from TNBS-treated rats corresponded to the recovery in body weight, colon weight/length, and myeloperoxidase level by TI-1-162 (10 and 30â¯mg/kg/day, orally). In relation to action mechanism, TI-1-162 did not disturb TNF-α binding to its receptor, but suppressed phosphorylation of RIP-1, ASK-1, JNK and p38, and nuclear translocation of NF-kB and AP-1, which corresponded to down regulation of inflammatory cytokines in TNF-α-treated cells (HT-29 and U937) and TNBS-treated rat colon tissues. Taken together, the results indicate that the protective effects of TI-1-162 against colon inflammation and epithelial cell death are associated with its inhibitory action in RIP/ASK-1/MAPK signaling pathway downstream to TNF receptor 1.
Assuntos
Compostos de Benzilideno/farmacologia , Colite/tratamento farmacológico , Colite/patologia , Indenos/uso terapêutico , MAP Quinase Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ácido Trinitrobenzenossulfônico/efeitos adversos , Animais , Compostos de Benzilideno/uso terapêutico , Adesão Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Citocinas/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Indenos/farmacologia , RatosRESUMO
To develop effective therapeutics for inflammatory bowel disease (IBD), 2-benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives, were designed and synthesized and their structure-activity relationships (SAR) were investigated. Compounds 7, 25, 26, 32, 39, 41, 52, 54, and 55 showed potent inhibitory effect (>70%) on the TNF-α-induced adhesion of monocytes to colon epithelial cells, which is one of the hallmark events leading to IBD. Such inhibitory activity of the compounds correlated with their suppressive activities against the TNF-α-induced production of ROS; ICAM-1 and MCP-1 expression, critical molecules involved in monocyte-epithelial adhesion; and NF-κB transcriptional activity. In addition, compounds 41 and 55 significantly suppressed the lipopolysaccharide (LPS)-induced expression of the TNF-α gene, with compound 55 showing better efficacy. This inhibition of TNF-α expression by compounds 41 and 55 corresponded to their additional inhibitory activity against AP-1 transcriptional activity, which is another transcription factor required for high level TNF-α expression. The strong inhibitory activity of compound 55 against an in vivo colitis model was confirmed by its dose-dependent inhibitory activity in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, demonstrating compound 55 as a new potential candidate for the development of therapeutics against IBD.
Assuntos
Benzofuranos/farmacologia , Descoberta de Drogas , Indenos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/síntese química , Benzofuranos/química , Colite/induzido quimicamente , Colite/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Indenos/síntese química , Indenos/química , Doenças Inflamatórias Intestinais/genética , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/genética , Ácido Trinitrobenzenossulfônico , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Células U937RESUMO
A new series of 2-chloropheny-substituted benzofuro[3,2-b]pyridines were designed, synthesized, and evaluated for topoisomerase I and II inhibition and antiproliferative activity. Compounds 17-19, 23, 24, 26, and 27 exhibited excellent topo II inhibitory activity. A systematic structure-activity relationship study revealed the important role of chlorine substitution in the strong topoisomerase inhibitory activity.
Assuntos
Benzofuranos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Piridinas/farmacologia , Inibidores da Topoisomerase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Halogenação , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Piridinas/síntese química , Piridinas/química , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
Novel series of conformationally constrained 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-b]pyridines were rationally designed and synthesized. Their biological activities were evaluated for topoisomerase I and II inhibitory activity, and antiproliferative activity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with phenol moiety at 4-position of central pyridine exhibited significant dual topoisomerase I and II inhibitory activities, and strong antiproliferative activity in low micromolar range. Structure activity relationship study suggested that phenol moiety at 4-position of the central pyridine regardless of chlorophenyl moiety at 2-position of the central pyridine has an important role in dual topoisomerase inhibitory activity as well as antiproliferative activity. For investigation of mode of action for compound 14 which displayed the most strong dual topoisomerase I and II inhibitory activity and antiproliferative activity against HCT15 cell, we performed cleavable complex assay, band depletion assay, comet assay, and competitive EtBr displacement assay. Compound 14 functioned as non-intercalative catalytic topo I and II dual inhibitor. In addition, compound 14 induced apoptosis in HCT15 cells through increase of Bax, decrease of Bcl-2 and increase of PARP cleavage.
Assuntos
Benzofuranos/química , Biocatálise , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Piridinas/síntese química , Piridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , DNA/metabolismo , Humanos , Piridinas/química , Piridinas/metabolismo , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/metabolismo , Inibidores da Topoisomerase II/farmacologiaRESUMO
On the basis of previous reports on the importance of thienyl, furyl or phenol group substitution on 5H-indeno[1,2-b]pyridine skeleton, a new series of rigid 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridine derivatives were systematically designed and synthesized. Topoisomerase inhibitory activity and antiproliferative activity of all the synthesized compounds were determined using human colorectal (HCT15), breast (T47D), prostate (DU145) and cervix (HeLa) cancer cells. Compounds 9, 10, 12, 13, 15, 16, 18 and 19 with thienyl or furyl moiety at the 2-position and hydroxyl group at the meta or para positions of 4-phenyl ring displayed strong to moderate topoisomerase IIα (topo IIα) inhibitory activity and significant antiproliferative activity. The evaluation of compound 16 to determine its mechanism of action was performed with topo IIα-DNA cleavable complex, topo IIα-mediated ATPase assay, DNA unwinding and in vitro and ex vivo topo IIα relaxation assay. Compound 16 functioned as a DNA non-intercalative topo IIα catalytic inhibitor with better potency than etoposide in T47D breast cancer cells. Molecular docking study revealed that compound 16 cannot intercalate into regularly stacked base-pairs of DNA duplex but can interact or intercalate to topo IIα-bound DNA.
Assuntos
Antineoplásicos/síntese química , Proteínas de Ligação a DNA/antagonistas & inibidores , Piridinas/síntese química , Inibidores da Topoisomerase II/síntese química , Antígenos de Neoplasias , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , DNA Topoisomerases Tipo II , Humanos , Simulação de Acoplamento Molecular , Piridinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/farmacologiaRESUMO
A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100µM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27-37, and 39 which showed excellent cytotoxicity (IC50=0.68-1.25µM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.
Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Fenóis/farmacologia , Piridinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
In continuation of our previous work, six hydroxylated 2,4-diphenyl-5H-indeno[1,2-b]pyridine analogs were modified by introducing one chlorine functionality at ortho, meta or para position of the 2- or 4-phenyl ring. Eighteen new chlorinated compounds were thus prepared and assessed for topoisomerase inhibitory activity and cytotoxicity against HCT15, T47D, and HeLa cancer cell lines. All of the chlorinated compounds displayed significant cytotoxic effect, revealing potent anticancer activity against T47D breast cancer cells. This functional group modification allowed us to explore the importance of chlorine group substitution for the cytotoxic properties. The information reported here provides valuable insight for further study to develop new anticancer agents using related scaffolds.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Indenos/química , Indenos/farmacologia , Piridinas/química , Piridinas/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Mama/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Feminino , Halogenação , Células HeLa , Humanos , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologiaRESUMO
As a continuous effort to develop novel antitumor agents, a new series of forty-five 2-phenol-4-aryl-6-chlorophenyl pyridine compounds were synthesized and evaluated for cytotoxicity against four different human cancer cell lines (DU145, HCT15, T47D, and HeLa), and topoisomerase I and II inhibitory activity. Several compounds (10-15, 20, 22, 24, 28, 42, and 49) displayed strong to moderate dual topoisomerase I and II inhibitory activity at 100 µM. It was observed that hydroxyl and chlorine moiety at meta or para position of phenyl ring is favorable for dual topoisomerase inhibitory activity and cytotoxicity. Most of the compounds displayed stronger cytotoxicities than those of all positive controls against the HCT15 and T47D cell lines. For investigation of the structure-activity relationships, a 3D-QSAR analysis using the method of comparative molecular field analysis (CoMFA) was performed. The generated 3D contour maps can be used for further rational design of novel terpyridine derivatives as highly selective and potent cytotoxic agents.