Drug design and synthesis of novel heteroanthracycline antitumor drugs

Novel heteroanthracycline antitumor drugs were designed based on structure activity relationship studies and known mechanisms of drug action. Their preparation required the development of a general synthetic approach.After extensive studies, three methodologies were developed for the general synthetic plan. The first method involved photoenolisation of 2,5-dimethoxybenzaldehyde and SO$sb2$ entrapment of the o-quinodimethane to give 4,7-dimethoxy-1-hydroxy-1,3-dihydrobenzo(2,3-c) thiophene-2,2-dioxide. This compound served as a general intermediate towards the synthesis of several heteroanthracyclinones. It could be reduced to the oxathiin-2-oxide derivative which thermally extruded SO$sb2$ to yield the o-quinodimethane. Reentrapment of this latter intermediate with various glyoxalates gave key isochroman derivatives. The second method is an improvement over the first. Isochromandiones with a C-1 hydroxyl functionality were prepared from oxidative demethylation of 1-hydroxyisochromans. These were obtained after acid hydrolysis of the coupling products between epoxides and the cuprate of 2,5-dimethoxy-6-methylbenzaldehydedioxane acetal. The third method involved a sequential cycloaddition routine with two o-quinodimethanes.By combining newly developed techniques with known methods, a general synthetic plan was developed. Consequently, the total synthesis of six tetracyclic structural hybrids of the naphthoquinone(2,3-c) pyranyl class of antibiotics was accomplished; along with the total synthesis of (R) and (S) 1-(4$sp prime$-O-p-nitrobenzoyl-N-trifluoroacetyldaunosamine)-$1,3$-dihydrothioxantho(2,3-c) thiophene-2,2-dioxide, p-nitrobenzyl(5,12-dihydroxy-3,4-dihydrothioxantho(2,3-c) and (3,2-c) pyran-3-yl)formate, and eight novel heteroanthracyclines with the 5,12-dioxo-2,3,5,12-tetrahydroanthraceno(2,3-c) pyranyl backbone. The diastereomeric mixture of (1$sp prime$S, 1R, 3S) and (1$sp prime$S, 1S, 3R) methyl(11-hydroxy-1-$(2 sp prime,3 sp prime,6 sp prime$-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-$5,12$-dioxo-3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3-yl) formate was found to possess equipotent antileukemic activity to doxorubicin with no cross resistance

Facile Route to 2‑Fluoropyridines via 2‑Pyridyltrialkylammonium Salts Prepared from Pyridine <i>N</i>‑Oxides and Application to ¹⁸F‑Labeling

Among known precursors for 2-[¹⁸F]­fluoropyridines, pyridyltrialkylammonium salts have shown excellent reactivity; however, their broader utility has been limited because synthetic methods for their preparation suffer from poor functional group compatibility. In this paper, we demonstrate the regioselective conversion of readily available pyridine <i>N</i>-oxides into 2-pyridyltrialkylammonium salts under mild and metal-free conditions. These isolable intermediates serve as effective precursors to structurally diverse 2-fluoropyridines, including molecules relevant to PET imaging. In addition to providing access to nonradioactive analogues, this method has been successfully applied to ¹⁸F-labeling in the radiosynthesis of [¹⁸F]­AV-1451 ([¹⁸F]­T807), a PET tracer currently under development for imaging tau

[¹⁸F]Fluorobenzoyl­lysine­pentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA)

Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four ¹⁸F-labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2-[¹⁸F]­fluorobenzoyl­lysineoxy­pentanedioic acid (OPA) carbamate [¹⁸F]<b>23</b> and 4-iodo-2-[¹⁸F]­fluorobenzoyl­lysine OPA carbamate [¹⁸F]<b>24</b> in particular exhibited high target-selective uptake in PSMA+ PC3 PIP tumor xenografts, with tumor-to-kidney ratios of >1 by 4 h postinjection, an important benchmark. Because of its high tumor uptake (90% injected dose per gram of tissue at 2 h postinjection) and high tumor-to-organ ratios, [¹⁸F]<b>23</b> is promising for clinical translation. Prolonged tumor-specific uptake demonstrated by [¹⁸F]<b>24</b>, which did not reach equilibrium during the 4 h study period, suggests carbamates as alternative scaffolds for mitigating dose to nontarget tissues

Metabolic disorders across hepatocellular carcinoma in Italy

Background: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology. Methods: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features. Results: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P\ua0=.021), larger tumours (P\ua0=.038), better liver function (higher percentage of Child-Pugh class A [P\ua0=.007] and MELD\ua0<\ua010 [P\ua0=.003]), higher percentage of metastasis (P\ua0=.024) and lower percentage of portal vein thrombosis (P\ua0=.010). The BCLC stage and treatment options were similar among the 3 groups, with the exception of a less frequent access to loco-regional therapies for BCLC stage B patients with 3-5 features (P\ua0=.012). Overall survival and survival according to BCLC stage and/or treatment did not significantly differ among the 3 groups. Only using a probabilistic sensitivity analysis, diabetic patients showed a lower survival (P\ua0=.046). MELD score, HCC morphology, nodule size, BCLC stage, portal vein thrombosis and metastasis were independent predictors of lead-time adjusted survival. Conclusions: Our \u201creal world\u201d study suggests that metabolic disorders shape the clinical presentation of HCC but do not seem to play a major role in setting patient survival