Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization.

The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC50 values against a variety of human cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as anticancer therapeutic agents.

Oxygen-Sensing Chemiluminescent Iridium(III) 1,2-Dioxetanes: Unusual Coordination and Activity.

Next generation chemiluminescent iridium 1,2-dioxetane complexes have been developed which consist of the Schaap's 1,2-dioxetane scaffold directly attached to the metal center. This was achieved by synthetically modifying the scaffold precursor with a phenylpyridine moiety, which can act as a ligand. Reaction of this scaffold ligand with the iridium dimer [Ir(BTP)2(µ-Cl)]2 (BTP = 2-(benzo[b]thiophen-2-yl)pyridine) yielded isomers which depict ligation through either the cyclometalating carbon or, interestingly, the sulfur atom of one BTP ligand. Their corresponding 1,2-dioxetanes display chemiluminescent responses in buffered solutions, exhibiting a single, red-shifted peak at 600 nm. This triplet emission was effectively quenched by oxygen, yielding in vitro Stern-Volmer constants of 0.1 and 0.009 mbar-1 for the carbon-bound and sulfur compound, respectively. Lastly, the sulfur-bound dioxetane was further utilized for oxygen sensing in muscle tissue of living mice and xenograft models of tumor hypoxia, depicting the ability of the probe chemiluminescence to penetrate biological tissue (total flux ~ 106 p/s).

GPR84-mediated signal transduction affects metabolic function by promoting brown adipocyte activity.

The G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within brown adipose tissue (BAT). Mice lacking GPR84 exhibited increased lipid accumulation in BAT, rendering them more susceptible to cold exposure and displaying reduced BAT activity compared with their WT counterparts. Our in vitro experiments with primary brown adipocytes from GPR84-KO mice revealed diminished expression of thermogenic genes and reduced O2 consumption. Furthermore, the application of the GPR84 agonist 6-n-octylaminouracil (6-OAU) counteracted these effects, effectively reinstating the brown adipocyte activity. These compelling in vivo and in vitro findings converge to highlight mitochondrial dysfunction as the primary cause of BAT anomalies in GPR84-KO mice. The activation of GPR84 induced an increase in intracellular Ca2+ levels, which intricately influenced mitochondrial respiration. By modulating mitochondrial Ca2+ levels and respiration, GPR84 acts as a potent molecule involved in BAT activity. These findings suggest that GPR84 is a potential therapeutic target for invigorating BAT and ameliorating metabolic disorders.

GPR92 activation in islet macrophages controls ß cell function in a diet-induced obesity model.

The molecular mechanisms underlying obesity-induced increases in ß cell mass and the resulting ß cell dysfunction need to be elucidated further. Our study revealed that GPR92, expressed in islet macrophages, is modulated by dietary interventions in metabolic tissues. Therefore, we aimed to define the role of GPR92 in islet inflammation by using a high-fat diet-induced (HFD-induced) obese mouse model. GPR92-KO mice exhibited glucose intolerance and reduced insulin levels - despite the enlarged pancreatic islets - as well as increased islet macrophage content and inflammation level compared with WT mice. These results indicate that the lack of GPR92 in islet macrophages can cause ß cell dysfunction, leading to disrupted glucose homeostasis. Alternatively, stimulation with the GPR92 agonist farnesyl pyrophosphate results in the inhibition of HFD-induced islet inflammation and increased insulin secretion in WT mice, but not in GPR92-KO mice. Thus, our study suggests that GPR92 can be a potential target to alleviate ß cell dysfunction via the inhibition of islet inflammation associated with the progression of diabetes.

Pênfigo Foliáceo Endêmico (Fogo Selvagem) e sua associação com fatores ambientais e ocupacionais em Ouro Preto, Minas Gerais, Brasil / Endemic Pemphigus Foliaceus (Fogo Selvagem) and its association with environmental and occupational factors in Ouro Preto, Minas Gerais, Brazil

Resumo Pênfigo compreende grupo de doenças bolhosas autoimunes que possuem tendência à progressão, com evolução ilimitada e crônica e com prognóstico potencialmente fatal. O tipo mais comum é o Pênfigo Foliáceo Endêmico (PFE), caracterizado pela presença de lesões cutâneas com formação de bolhas na face, no couro cabeludo e na região interescapular. Fatores de ordem ambiental, genéticos e imunológicos podem desencadear a enfermidade. Entre os fatores ambientais, exposição a mercúrio, poeiras minerais e a picada do mosquito Simulium nigrimanum devem ser considerados. Buscou-se, neste artigo, relatar a ocorrência do PFE entre a população de Antônio Pereira, distrito rural de Ouro Preto, Minas Gerais, bem como identificar possíveis associações da doença com fatores ocupacionais e ambientais locais. Foi constatada uma prevalência de 4,57 casos de PFE/1.000 habitantes, considerada bastante elevada. Observou-se associação estatística entre a doença e contato com barragem de rejeitos de mineração (p = 0,048) e exposição ao mercúrio (p = 0,008). Os resultados indicam a necessidade de vigilância epidemiológica eficaz das comunidades afetadas, assim como adequada assistência à saúde dos pacientes acometidos pela doença.

Abstract Pemphigus comprises a group of autoimmune bullous diseases, which have a tendency of progression, with unlimited and chronic development and with a potentially to fatal disease prognosis. The most common type is the Endemic Pemphigus Foliaceus (EPF), characterized by the presence of skin lesions with blistering located on the face, scalp and interscapular region. Environmental, genetic and immunological factors may trigger the disease. Among the environmental factors, exposure to mercury, mineral dust and Simulium nigrimanum mosquitoes bite should be considered. Sought to, in this article, it is reported the occurrence of PFE among the population of Antonio Pereira, rural district of Ouro Preto, Minas Gerais, and identify their possible association with occupational and environmental local factors. A prevalence of 4.57 cases of EPF/1.000 inhabitants, considered high was found. There was association between the disease and contact with dam tailings mining (p=0.048); and exposure to mercury (p=0.008). The results indicate the need for effective surveillance of the affected communities, as well as adequate health care of patients affected by the disease.