Natural products as new antimitotic compounds for anticancer drug development

Cell cycle control genes are frequently mutated in cancer cells, which usually display higher rates of proliferation than normal cells. Dysregulated mitosis leads to genomic instability, which contributes to tumor progression and aggressiveness. Many drugs that disrupt mitosis have been studied because they induce cell cycle arrest and tumor cell death. These antitumor compounds are referred to as antimitotics. Vinca alkaloids and taxanes are natural products that target microtubules and inhibit mitosis, and their derivatives are among the most commonly used drugs in cancer therapy worldwide. However, severe adverse effects such as neuropathies are frequently observed during treatment with microtubule-targeting agents. Many efforts have been directed at developing improved antimitotics with increased specificity and decreased likelihood of inducing side effects. These new drugs generally target specific components of mitotic regulation that are mainly or exclusively expressed during cell division, such as kinases, motor proteins and multiprotein complexes. Such small molecules are now in preclinical studies and clinical trials, and many are products or derivatives from natural sources. In this review, we focused on the most promising targets for the development of antimitotics and discussed the advantages and disadvantages of these targets. We also highlighted the novel natural antimitotic agents under investigation by our research group, including combretastatins, withanolides and pterocarpans, which show the potential to circumvent the main issues in antimitotic therapy.

Therapeutic approaches for tumor necrosis factor inhibition

Tumor necrosis factor (TNF) consists of an inflammatory cytokine essential for homeostasis and organism defense. Despite its physiological relevance, both increased biosynthesis and release of TNF lead to the exacerbation of inflammatory and oxidative responses, which are related to the pathogenesis of a host of diseases of an inflammatory, autoimmune and/or infectious nature. In this context, effective therapeutic approaches for the modulation of TNF have been the focus of research efforts. Approximately one million individuals worldwide have been treated with biotechnological inhibitors of this cytokine, the so-called anti-TNF biopharmaceuticals. However, given the high risk of infection and the limitations related to cost and administration routes, new therapeutic approaches aimed at biological targets that directly or indirectly modulate the production and/or activation of TNF appear promising alternatives for the discovery of new anti-inflammatory and immunomodulatory orally active drugs and are therefore discussed in this paper.

O fator de necrose tumoral (do inglês, tumor necrosis factor - TNF) consiste em uma citocina inflamatória essencial para a homeostase e defesa do organismo. A despeito de sua relevância fisiológica, o aumento da biossíntese e liberação do TNF conduzem à exacerbação das respostas inflamatória e oxidativa, as quais estão relacionadas à patogênese de várias doenças de natureza inflamatória, auto-imune e/ou infecciosa. A busca por abordagens terapêuticas eficientes na modulação do TNF tem sido alvo de diversos esforços de pesquisa. Aproximadamente um milhão de pessoas ao redor do mundo já foi tratado com inibidores biotecnológicos desta citocina, os chamados biofármacos anti-TNF. Entretanto, em face ao elevado risco de infecções e as limitações relacionadas ao custo e a via de administração, novas abordagens terapêuticas com foco em alvos que modulem, de forma direta ou indireta, a produção e/ou ativação do TNF surgem como alternativas promissoras para a descoberta de novos fármacos antiinflamatórios e imunomoduladores ativos por via oral e serão discutidas neste trabalho.

Antiplasmodial activity of 3-trifluoromethyl-2-carbonylquinoxaline di-N-oxide derivatives

The in vitro antiplasmodial activity of some 3-trifluoromethyl-2-carbonylquinoxaline di-N-oxide derivatives is reported. The evaluation was performed on cultures of FcB1 strain (chloroquine-resistant) of P. falciparum and the most interesting compounds were then evaluated on MCF7 tumor cells in order to evaluate an index of selectivity. The 7-methyl (2b, 4b, 5b, 6b) and nonsubstituted (3c, 4c, 5c) quinoxaline 1,4-dioxide derivatives presented the best level of activity.

Neste artigo descreve-se a atividade anti-Plasmodium falciparum de derivados 3-trifluorometil-2-carbonilquinoxalinas di-N-óxidos (2a-6g). A avaliação das propriedades farmacológicas dos derivados 2a-6g foi realizada em modelo in vitro de inibição de cepas P. falciparum FcB1 (cloroquina resistente) em cultura celular, e sobre culturas de células tumorais MCF7, com a finalidade de estabelecer o índice de seletividade para os compostos mais promissores. Os derivados 7-metil (2b, 4b, 5b, 6b) e não-substituído (3c, 4c, 5c) apresentaram o melhor perfil de atividade.