Current medicinal chemistry
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Studies on fluorinated inhalation anesthetics, including synthesis, physical chemistry and pharmacology, have been summarized in this review. Retrospecting the history of inhalation anesthetics revealed their increasing reliance on fluorine and ether structures. Halothane causes a rare but severe immune-based hepatotoxicity, which was replaced by enflurane in the 1970s. ⋯ Moreover, the anesthetic activity cannot be simply predicted from the molecular structures but has to be inferred from the experiments. Several regularities were found by experimental studies: 1) the potency and toxicity of the saturated linear chain halogenated ether are enhanced when its molecular weight is increased; 2) the margin of safety decreases and the recovery time is prolonged when the boiling point of the candidate increases; and 3) compounds with an asymmetric carbon terminal exhibit good anesthesia. Nevertheless, the development of new inhalation anesthetics, better than desflurane and sevoflurane, is still challenging not only because of the poor structure/activity relationship known so far but also due to synthetic issues.
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The immune system actively counteracts the tumorigenesis process; a breakout of the immune system function, or its ability to recognize transformed cells, can favor cancer development. Cancer becomes able to escape from immune system control by using multiple mechanisms, which are only in part known at a cellular and molecular level. Among these mechanisms, in the last decade, the role played by the so-called "inhibitory immune checkpoints" is emerging as pivotal in preventing the tumor attack by the immune system. ⋯ An outline of the immune checkpoint targeting approaches, also including combined immunotherapies and the existing trials, is also provided. Notwithstanding the great efforts devoted by researchers in the field of biomarkers of response, to date, no validated FDA-approved immunological biomarkers exist for cancer patients. We highlight relevant studies on predictive biomarkers and attempt to discuss the challenges in this field, due to the complex and largely unknown dynamic mechanisms that drive the tumor immune tolerance.