Exploring the 1,3-benzoxazine chemotype for cannabinoid receptor 2 as a promising anti-cancer therapeutic.

The discovery of selective agonists of cannabinoid receptor 2 (CB2) is strongly pursued to successfully tuning endocannabinoid signaling for therapeutic purposes. However, the design of selective CB2 agonists is still challenging because of the high homology with the cannabinoid receptor 1 (CB1) and for the yet unclear molecular basis of the agonist/antagonist switch. Here, the 1,3-benzoxazine scaffold is presented as a versatile chemotype for the design of CB2 agonists from which 25 derivatives were synthesized. Among these, compound 7b5 (CB2 EC50 = 110 nM, CB1 EC50 > 10 µM) demonstrated to impair proliferation of triple negative breast cancer BT549 cells and to attenuate the release of pro-inflammatory cytokines in a CB2-dependent manner. Furthermore, 7b5 abrogated the activation of extracellular signal-regulated kinase (ERK) 1/2, a key pro-inflammatory and oncogenic enzyme. Finally, molecular dynamics studies suggested a new rationale for the in vitro measured selectivity and for the observed agonist behavior.

Recent Advances on Type-2 Cannabinoid (CB2) Receptor Agonists and their Therapeutic Potential.

In the last decade, selective modulators of type-2 cannabinoid receptor (CB2) have become a major focus to target endocannabinoid signaling in humans. Indeed, heterogeneously expressed within our body, CB2 actively regulates several physio-pathological processes, thus representing a promising target for developing specific and safe therapeutic drugs. If CB2 modulation has been extensively studied since the very beginning for the treatment of pain and inflammation, the more recent involvement of this receptor in other pathological conditions has further strengthened the pursuit of novel CB2 agonists in the last five years. Against this background, here we discuss the most recent evidence of the protective effects of CB2 against pathological conditions, emphasizing central nervous system disorders, bone and synovial diseases, and cancer. We also summarize the most recent advances in the development of CB2 agonists, focusing on the correlation between different chemical classes and diverse therapeutic applications. Data mining includes a review of the CB2 ligands disclosed in patents also released in the last five years. Finally, we discuss how the recent elucidation of CB2 tertiary structure has provided new details for the rational design of novel and more selective CB2 agonists, thus supporting innovative strategies to develop effective therapeutics. Our overview of the current knowledge on CB2 agonists provides pivotal information on the structure and function of different classes of molecules and opens possible avenues for future research.

Design, Synthesis, and Biological Evaluation of Tetrahydro-ß-carboline Derivatives as Selective Sub-Nanomolar Gelatinase Inhibitors.

Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro-ß-carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f, 9 g, 9 h and 9 i show sub-nanomolar IC50 values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC50 =0.15 nm for both toward MMP-2 and IC50 =0.63 and 0.58 nm, respectively, toward MMP-9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1' and S3' domains. Taken together, these studies indicate that tetrahydro-ß-carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.

Cervicites agudas / Acute cervicitis

A Cervicite é a inflamação do epitélio colunar do colo uterino, cujos principais agentes etiológicos são: Chalamydia trachomatis e Neisseria gonorrhoeae, sendo considerada pela Organização Mundial de Saúde como doença sexualmente transmissível. É na maioria das vezes assintomática podendo, no entanto, causar fluxo vaginal anormal, sinusorragia, dispareunia. E o colo apresenta-se hiperemiado, edemaciado, friável e sangrante. O diagnóstico varia de acordo com o agente causador. Devemos sempre considerar o tratamento associado de clamídia e neisséria, sendo que a droga de escolha é a ciprofloxacina 250 mg e azitromicina 1 g, ambas em dose única. Em mulheres grávidas a droga de escolha é o estearato de eritromicina por 7 dias. O tratamento tem como objetivo fundamental evitar complicações futuras, desde doença inflamatória pélvica até infecções neonatais com mortalidade fetal