ABSTRACT
Synthesis and in vitro testing of a prodrug designed for the controlled delivery of the anticancer drug camptothecin within pancreatic cancer cells are reported. Our study reveals a non-conventional pharmacokinetic release characterized by an exponential pattern before reaching the half-life (t1/2) and a linear pattern thereafter. The release mechanism was triggered either by hydrolytic enzymes and/or by the acid microenvironment of cancer cells.
Subject(s)
Camptothecin , Prodrugs , Humans , Camptothecin/chemistry , Camptothecin/pharmacology , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/chemical synthesis , Cell Line, Tumor , Drug Liberation , Pancreatic Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Delayed-Action Preparations/chemistry , Molecular StructureABSTRACT
We describe the asymmetric synthesis of the most pleasant enantiomer of Jessemal fragrance. The key steps are (i) the one-pot reduction of an α-chloro-tetrasubstituted cyclohexenone to give the chlorohydrin, catalyzed by two stereoselective redox enzymes (an ene-reductase and an alcohol dehydrogenase); (ii) the regioselective epoxide ring-opening with organocuprate or organolithium nucleophiles. Density functional theory calculations together with the Curtin-Hammett principle allowed the rationalization of the regioselectivity.
Subject(s)
Acetates , Pyrans , Epoxy Compounds , StereoisomerismABSTRACT
The first total synthesis of natural (-)-clavicipitic acid from γ,γ-dimethylallyltryptophan (DMAT), its biosynthetic precursor, is described. This is done by regio- and chemoselective, remote, nondirected C(sp3)-H hydroxylation followed by aminocyclization. This study also features regio- and chemoselective Pd(0)-catalyzed linear prenylation at C4 of l-tryptophan boronic pinacol ester derivate, the latter obtained by a Lewis acid-promoted aziridine amino acid ring opening with 4-boronated indole. In addition, these results support the hypothesis that oxidative cyclization between amino acid nitrogen and the prenyl chain during clavicipitic acid biosynthesis can occur through the transient hydroxylated intermediate.
Subject(s)
Carbon/chemistry , Ergot Alkaloids/chemistry , Ergot Alkaloids/chemical synthesis , Hydrogen/chemistry , Tryptophan/chemistry , Catalysis , Chemistry Techniques, Synthetic , Cyclization , HydroxylationABSTRACT
OBJECTIVE: To assess risks associated with work-related biomechanical overloads in onset/course of carpal tunnel syndrome. METHODS: Work-groups with job tasks spanning different biomechanical exposures were evaluated at baseline in terms of American Conference of Governmental Industrial Hygienists hand-activity/peak force action limit and threshold limit values (TLV). Exposures of interest were "unacceptable" (hand-activity above TLV) and "borderline" (between action limit and TLV) overloads. Clinical/individual data were collected at baseline and 12 months. RESULTS: One-year incidence of "classic/possible" carpal tunnel syndrome symptoms as defined by consensus criteria was 7.3% (153 of 2092). "Unacceptable" overload was associated with a 3-fold increased risk of onset with respect to "acceptable" load. At ordered logistic regression analysis of symptom-status variations, increased risks were recorded for "unacceptable" and "borderline" overloads. CONCLUSIONS: Effectiveness of encouraging workplace adherence to the American Conference of Governmental Industrial Hygienists recommendations deserves investigation as a possible key to wide-scale prevention.
Subject(s)
Carpal Tunnel Syndrome/epidemiology , Occupational Diseases/epidemiology , Work , Adult , Analysis of Variance , Biomechanical Phenomena , Carpal Tunnel Syndrome/physiopathology , Carpal Tunnel Syndrome/prevention & control , Female , Humans , Logistic Models , Longitudinal Studies , Male , Middle Aged , Neural Conduction , Occupational Diseases/physiopathology , Occupational Diseases/prevention & control , Prevalence , Surveys and QuestionnairesABSTRACT
CONTEXT: Leber hereditary optic neuropathy (LHON) is a maternally inherited loss of central vision related to pathogenic mutations in the mitochondrial genome, which are a necessary but not sufficient condition to develop the disease. Investigation of precipitating environmental/occupational (and additional genetic) factors could be relevant for prevention. CASE PRESENTATION: After a 6-month period of occupational exposure to n-hexane and other organic solvents, a 27-year-old man (a moderate smoker) developed an optic neuropathy. The patient had a full ophthalmologic and neurologic investigation, including standardized cycloergometer test for serum lactic acid levels and a skeletal muscle biopsy. His exposure history was also detailed, and he underwent genetic testing for LHON mitochondrial DNA mutations. The patient suffered a sequential optic neuropathy with the hallmarks of LHON and tested positive for the homoplasmic 11778G--> A/ND4 mutation. Routine laboratory monitoring revealed increased concentrations of urinary 2.5 hexandione (n-hexane metabolite) and hippuric acid (toluene metabolite) in the period immediately preceding the visual loss. DISCUSSION: In a subject carrying an LHON mutation, the strict temporal sequence of prolonged appreciable occupational exposure followed by sudden onset of visual loss must raise a suspicion of causality (with a possible further interaction with tobacco smoke). RELEVANCE: In this article, we add to the candidate occupational/environmental triggers of LHON and highlight the need for appropriate case-control (and laboratory) studies to validate the causal effect of mixed toxic exposures.
