Steroidal Pyrimidines and Dihydrotriazines as Novel Classes of Anticancer Agents against Hormone-Dependent Breast Cancer Cells

Most breast and prostate tumors are hormone-dependent, making it possible to use hormone therapy in patients with these tumors. The design of effective endocrine drugs that block the growth of tumors and have no severe side effects is a challenge. Thereupon, synthetic steroids are promising therapeutic drugs for the treatment of diseases such as hormone-dependent breast and prostate cancers. Here, we describe novel series of steroidal pyrimidines and dihydrotriazines with anticancer activities. A flexible approach to unknown pyrimidine and dihydrotriazine derivatives of steroids with selective control of the heterocyclization pattern is disclosed. A number of 18-nor-5α-androsta-2,13-diene[3,2-d]pyrimidine, androsta-2-ene[3,2-d]pyrimidine, Δ1, 3, 5(10)-estratrieno[16,17-d]pyrimidine, and 17-chloro-16-dihydrotriazine steroids were synthesized by condensations of amidines with β-chlorovinyl aldehydes derived from natural hormones. The synthesized compounds were screened for cytotoxicity against breast cancer cells and showed IC50 values of 7.4 μM and higher. Compounds were tested against prostate cancer cells and exhibited antiproliferative activity with IC50 values of 9.4 μM and higher comparable to that of cisplatin. Lead compound 4a displayed selectivity in ERα-positive breast cancer cells. At 10 μM concentration, this heterosteroid inhibited 50% of the E2-mediated ERα activity and led to partial ERα down-regulation. The ERα reporter assay and immunoblotting were supported by the docking study, which showed the probable binding mode of compound 4a to the estrogen receptor pocket. Thus, heterosteroid 4a proved to be a selective ERα modulator with the highest antiproliferative activity against hormone-dependent breast cancer and can be considered as a candidate for further anticancer drug development. In total, the synthesized heterosteroids may be considered as new promising classes of active anticancer agents

A Straightforward Approach toward Multifunctionalized Pyridazines via Imination/Electrocyclization

A facile synthesis of functionalized 3-carbamide pyridazines starting from readily available chlorovinyl aldehydes and oxamic acid thiohydrazides via cascade imination/electrocyclization is reported. In the presence of <i>p</i>-toluenesulfuric acid, various ketones have been efficiently incorporated into the pyridazine derivatives through a two-step sequence involving a Vilsmeier–Haack reaction and imination. The synthetic value of this method has been demonstrated by efficient synthesis of steroidal pyridazines

Multi-risk governance for natural hazards in Naples and Guadeloupe

Technical and institutional capacities are strongly related and must be jointly developed to guarantee effective natural risk governance. Indeed, the available technical solutions and decision support tools influence the development of institutional frameworks and disaster policies. This paper analyses technical and institutional capacities, by providing a comparative evaluation of governance systems in Italy and France. The focus is on two case studies: Naples and Guadeloupe. Both areas are exposed to multiple hazards, including earthquakes, volcanic eruptions, landslides, floods, tsunamis, fires, cyclones, and marine inundations Cascade and conjoint effects such as seismic swarms triggered by volcanic activity have also been taken into account. The research design is based on a documentary analysis of laws and policy documents informed by semi-structured interviews and focus groups with stakeholders at the local level. This leads to the identification of three sets of governance characteristics that cover the key issues of: (1) stakeholders and governance level; (2) decision support tools and mitigation measures; and (3) stakeholder cooperation and communication. The results provide an overview of the similarities and differences as well as the strengths and weaknesses of the governance systems across risks. Both case studies have developed adequate decision support tools for most of the hazards of concern. Warning systems, and the assessment of hazards and exposure are the main strengths. While technical/scientific capacities are very well developed, the main weaknesses involve the interagency communication and cooperation, and the use and dissemination of scientific knowledge when developing policies and practices. The consequences for multi-risk governance are outlined in the discussion