Investigation of dual anti-HIV/HSV activity of oxoquinoline-acylhydrazone derivatives by molecular docking

Abstract Someoxoquinoline-acylhydrazonederivativesshowedactivityagainst HumanImmunodeficiency Virus type 1 (HIV-1). These compounds must also be active against Herpes Simplex Virus type 1 (HSV-1) by an inhibition mechanism where they interact with the HSV-DNA-polymerase/DNA-duplex complex. There are several treatment options for HSV-1 but there is no cure for the disease, which may represent a life risk for individuals co-infected with HIV. In this work molecular docking studies were carried out in an attempt to understand the dual activity of these oxoquinoline-acyhydrazone derivatives. The compounds were docked in two possible situations: (i) in the polymerase domain of HIV-1 Reverse Transcriptase (RT) enzyme in order to verify whether the inhibition occurs similarly to the proposed mechanism for HSV-1 inhibition, where the ligand would form a complex with the enzyme and the DNA; (ii) in the allosteric site of RT in order to verify if the inhibition occur in a similar way to non-nucleoside RT inhibitors (NNRTI). The studied compounds showed higher binding affinity to the allosteric site of RT and the results indicate that the inhibition should occur in a mechanism similar to that of NNRTI, which produces an allosteric inhibition that induces structural changes in the enzymatic active site.

Desenvolvimento de inibidores duais de histona desacetilase 6 (HDAC6) e tirosina quinase (TQ) com vistas ao tratamento do câncer / Design of histone deacetylase 6 (HDAC6) and tyrosine kinase (TK) dual inhibitors for cancer treatment

Câncer é a denominação atribuída a um conjunto de doenças que são responsáveis pela segunda maior causa de morte no Brasil e no mundo. A quimioterapia figura entre uma das estratégias utilizadas para o tratamento e cura do câncer, sendo amplamente empregada em estratégias terapêuticas isoladas, ou em associação à radioterapia e cirurgia. A enzima histona desacetilase 6 (HDAC6) é responsável por desacetilar a cadeia lateral de N-acetillisinas em -tubulinas, desempanhando papel crítico na dinâmica do citoesqueleto celular, estando superexpressa em uma série de neoplasias. Neste sentido, na última década os receptores tirosina quinase (TQ) foram os principais alvos de fármacos aprovados para o tratamento do câncer e de doenças autoimunes e continuam atraindo a atenção de grupos de pesquisa dada a exorbitante diversidade do quinoma humano. É sabido que a monoterapia seja com inibidores de HDAC, seja com inibidores TQ, apresenta problemas de toxicidade, reações adversas, ineficácia, resistência e/ou recidiva. Diversos estudos relatam o desenvolvimento de inibidores duais de HDAC-TQ, almejando tanto a simplificação do tratamento, quanto sinergismo terapêutico e redução de efeitos adversos. Assim, o presente trabalho apresenta o planejamento, síntese e avaliação da citotoxicidade de inibidores duais, potencialmente seletivos para HDAC6 e receptores TQ. No total, 23 compostos foram sintetizados entre 2 a 4 etapas. Todos os compostos finais foram caracterizados por RMN (1H e 13C) e espectrometria de massas de alta resolução (HRMS). A citotoxicidade foi determinada pelo ensaio de MTT, em linhagens derivadas de tumores sólidos (HCT116 e MCF-7) e hematológicos (Jurkat e Namalwa). Os compostos apresentaram citotoxicidade em concentrações micro e nanomolares em todas as linhagens testadas, sendo que a linhagem MCF-7 foi a mais resistente à ação dos compostos, e as linhagens hematológicas foram as mais sensíveis. Os inibidores 4d-f foram os mais ativos na triagem por MTT, com IC50 iguais a 20, 30 e 50 nM, respectivamente, em células Jurkat. Estudos mecanísticos do efeito citotóxico indicaram que os compostos 4d-f exercem atividade de forma tempo-dependente, e majoritariamente por ação antiproliferativa, embora estímulos apoptóticos também tenham sido observados nos estudos. Simulações de ancoramento molecular (docking) e de relação entre as estruturas químicas dos compostos e suas respectivas atividades biológicas (REA) permitiram identificar padrões moleculares, propriedades físico-químicas e eletrônicas que potencialmente possuem relação com a atividade biológica dos compostos, permitindo futuras otimizações do arcabouço molecular desta série de compostos. Tomados em conjunto, os resultados deste trabalho revelam o potencial terapêutico de inibidores duais de HDAC6-TQ. Notadamente, os compostos apresentados aqui podem ser os primeiros potenciais inibidores duais de HDAC6-TQ a serem reportados na literatura

Cancer is the name of a series of diseases that are the second main cause of death in Brazil and worldwide. Chemotherapy is one of the main strategies to treat and cure cancer, and has been widely applied as a single therapeutic agent, and in association with radiotherapy and surgery. Histone deacetylase 6 (HDAC6) deacetylates N-acetyllysine side chains of tubulin, playing crucial role on cytoskeletal dynamics, and could be overexpressed in several cancers. Tyrosine kinase receptors (TK) have been the main targets of FDA-approved drugs through the last decade for both cancer and autoimmune diseases, and have been attracting special attention of research groups due to the exorbitant diversity of the human kinome. It is known that either HDAC or TK single therapy have toxicity issues, adverse effects, inefficacy, resistance and/or recidive. Therefore, many studies report the design of HDAC-TK dual inhibitors aiming simpler treatments, synergism of action and side effects reduction. Herein, the design, synthesis and cytotoxic evaluation of dual and selective HDAC6-TK inhibitors are presented. A total of 23 compounds were designed and synthesized through 2 to 4 steps. All final compounds were characterized by 1H/13C NMR and high-resolution mass spectrometry (HRMS). The cytotoxicity of compounds was determined by MTT assay for both solid (HCT116 and MCF-7 cells) and hematological cancers (Jurkat and Namalwa cells). Compounds exhibited micro and nanomolar ranges of cytotoxicity for all cell lines tested. MCF-7 cells were the most resistant against the treatment, and hematological cells were more susceptible to the cytotoxic effect of the compounds. Compounds 4d-f were the most actives in the MTT screening against Jurkat cells (IC50 = 20, 30 and 50 nM, respectively). Mechanistic studies regarding the cytotoxic effects of 4d-f indicated that the compounds induced cell death in a time-dependent manner mainly via cytostatic activity even though apoptotic stimuli were observed also. Molecular docking and structure-activity relationships (SARs) allowed the identification of molecular patterns, and physicochemical and electronic properties that potentially modulate the biological activity of these compounds, allowing further optimizations of the molecular scaffold for these series of compounds. Taken together, the results of this study reveal the therapeutic potential of HDAC6-TK dual inhibitors. Noteworthy, the compounds reported herein could be the first HDAC6-TK dual inhibitors ever reported in literature

Planejamento, síntese, modelagem molecular e avaliação biológica de novos potenciais inibidores duais HDAC/ MMP não-hidroxamatos / Design, synthesis, molecular modeling and biological evaluation of novel potential non-hydroxamate dual HDAC/ MMP inhibitors

A inibição de alvos específicos como metaloproteinase de matriz (MMP) e histona desacetilase (HDAC) é amplamente estudada para impedir o progresso do câncer. Foi estabelecido que a inibição concomitante de MMP e HDAC é eficaz no combate de tumores sólidos e hematológicos. Ambos os alvos possuem um íon Zn2+ em seu sítio ativo, fundamental para a atividade destas enzimas. A alta afinidade dos inibidores conhecidos de MMP e de HDAC é conferida, principalmente, por um potente grupo ligante de zinco (ZBG). O ácido hidroxâmico é o ZBG mais potente conhecido atualmente, entretanto, este apresenta instabilidade farmacocinética, levando a ineficácia e genotoxicidade em testes clínicos. Frente a este contexto, o presente trabalho teve como objetivo o planejamento, síntese, modelagem molecular e avaliação biológica de novos inibidores duais MMP/HDAC não-hidroxamatos. Os compostos foram planejados utilizando estratégias de hibridação molecular, a partir de arcabouços provenientes inibidores de HDAC e MMP, gerando compostos arilsulfonamídicos com variações no tipo de ZBG inserido e na sua respectiva posição relativa na estrutura geral. Foram sintetizados sete análogos, em duas a três etapas reacionais, utilizando métodos de sulfonilação e acoplamento com agentes condensantes, partindo dos ésteres para e meta aminobenzoicos. Os rendimentos globais variaram de 25% a 55% e os produtos obtidos foram caracterizados por RMN 1H e 13C, LC/MS, CLAE e ponto de fusão. Os compostos tiveram sua atividade citotóxica avaliada em células HOG (oligodendroma) e T98G (glioblastoma), dentre os quais o 6a, que possui o ZBG 2-amino anilida, foi o mais promissor, apresentando atividade nas duas linhagens na casa de nM. Ensaios de coordenação com Fe2+ comprovaram a capacidade quelante dos análogos contendo ácido hidroxâmico e dos demais compostos citotóxicos, 4a e 4b (ZBG-2, salicilal-hidrazona), o que não foi observado para o composto 6a. Os estudos de ancoramento molecular permitiram sugerir um modo de interação para todos os ZBG propostos frente aos respectivos alvos (HDAC e MMP), sendo observado que o ZBG 4 (2-amino anilida) faria a interação de modo monodentado com a HDAC, enquanto não seria possível o encaixe no sítio catalítico da MMP. Conclui-se, portanto, que o planejamento proposto permitiu a obtenção de compostos promissores como antitumorais, e que a substituição do ácido hidroxâmico por outros ZBG fornece moléculas ativas frente a células tumorais. Entretanto, a avaliação biológica frente à MMP e HDAC é necessária para confirmar o mecanismo de ação proposto

Inhibition of specific targets such as matrix metalloproteinase (MMP) and histone deacetylase (HDAC) is extensively studied regarding arrest cancer growth. Particularly, concomitant inhibition of MMP and HDAC is effective against solid and hematologic tumors. Both targets have an ion Zn2+ at their catalytic site, which is essential for respective enzymatic activity. High affinity of known MMP and HDAC inhibitors is mainly provided by a potent zinc binding group (ZBG). Hydroxamic acid is the most potent ZBG currently known; however, it presents low pharmacokinetics stability, which results in its ineffectiveness and genotoxicity along clinical trial. So, the aim of this work comprised the design, synthesis, molecular modeling and biological evaluation of novel potential non-hydroxamate dual HDAC/ MMP inhibitors. Compounds were designed by molecular hybridation, employing scaffolds from HDAC and MMP inhibitors, which provided arylsulfonamides with variation about the ZBG type and its respective relative position in the general structure. Seven compounds were synthesized, in two to three reaction steps, through methods that comprise sulfonilation and coupling with condensing agents, using para and meta-aminobenzoic esters as starting material. Compounds showed global yields around 25-55 % and were characterized by 1H and 13C NMR, LC/MS, HPLC and melting point. Compounds were evaluated about their cytotoxicity against HOG (oligodendroma) and T98G (glioblastoma) cells, which 6a, with ZBG 2-aminobenzamide, was the most promising molecules, presenting activity against both cell lines at nM range. Coordination assays with Fe2+ proved the chelating capacity of hydroxamate analogues as well as the cytotoxic compounds, 4a and 4b (ZBG-2, salicylal-hydrazone), which was not observed about 6a. Molecular docking allowed to suggest an interaction model for all proposed ZBG with the respective targets (MMP and HDAC), showing that (ZBG-4) 2-aminobenzamide interacts with HDAC by monodentate way, but does not docks at MMP catalytic site. We conclude that the proposed design allowed obtaining promising compounds as antitumors agents, and the replacement of hydroxamic acid by other ZBG provide active molecules against tumor cells. However, biological evaluation against MMP and HDAC is necessary to confirm the proposed action mechanism

Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity: selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® assays. Studies in glioblastoma cell lines showed that the most active compound induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.

Research progress of dual topoisomerase Ⅰ and Ⅱ inhibitors / 药学实践杂志

DNA topoisomerases (Tops) are essential enzymes that regulate the cellular processes such as replication , transcription ,recombination and repair .DNA Tops can be classified into two types ,topoisomerase Ⅰ (TopⅠ ) and topoi-somerase Ⅱ (TopⅡ) .They catalyze the breakage and religation of DNA ,maintaining the topological changes of DNA and va-rious DNA metabolic processes .Due to their important role in DNA metabolism ,the ability to interfere with the functions of Tops or generating Top-mediated DNA damage is an effective strategy for cancer chemotherapy .Tops have been considered as the most important targets for tumor chemotherapy .In this review ,we used examples to describe the development of dual to-poisomerase Ⅰ and Ⅱ inhibitors .

Review of research on dual PI3K-mTOR small molecular inhibitors / 药学实践杂志

Objective The phosphoinositide 3-kinase (PI3K) constituted an important family of lipid kinase enzymes that control a range of cellular proliferation , differentiation and apoptosis through their regulation of a network of signal transduction path -ways, which had emerged as important therapeutic targets in the context of cancer and inflammation .Considerable progress had been made in the discovery and development of small molecular inhibitors targeting PI 3K.Progress in dual PI3K-mTOR inhibitors, a number of which had entered early phase clinical trials over recent years was summarized .

Synthesis and anti-inflammatory activity of p-(sulfamyl) benzylidene-linked heterocyclic ketone derivatives / 中国药科大学学报

Aim: To study the synthesis and anti-inflammatory activity of p-(sulfamyl) benzylidene-linked hetero-cyclic ketone derivatives. Methods: A series of p-(sulfamyl) benzylidene-linked heterocyclic ketone derivatives were synthesized. Anti-inflammatory activity was evaluated against xylene-induced ear oedema in mice and against carrageenan-induced paw oedema in rats. Gastrointestinal side effects in the rats were also examined after continu-ous introgastric administration of these compounds once daily for 7 days. Results: Twelve compounds( LHZ-101-LHZ-112) were synthesized and their structures were confirmed by IR, ~1H NMR, MS and elemental analysis. LHZ-105, LHZ-106 and LHZ-111 exhibited marked anti-inflammatory activity in xylene-induced mice ear swelling model. LHZ-106 and LHZ-111 showed significant anti-inflammatory activity in carrageenan-induced rat paw ede-ma model. LHZ-105, LHZ-106 and LHZ-111 had less gastrointestinal side effects than diclofenac sodium and CI-1004. Conclusion: These results suggest that some of these compounds have the potential for anti-inflammatory activity with few gastrointestinal side effects.