Predictive preventive personalized medicine Liver cancer is the fifth most common form of cancer worldwide [1], with an incidence rate almost equals the mortality rate and ranks 3 rd among causes of cancer related death [2]. The coexistence of two life threatening conditions, cancer and liver cirrhosis makes the staging challenging. However, there are some staging systems, e.g. the Barcelona staging system for Hepatocellular carcinoma (HCC) [3], that suggest treatment options and management. Whereas diagnosis in early stages gives hope for a curative outcome, the treatment regime for around 80 % [2] of the patients classified as severe stages only gears towards palliation [4]. An intra-arterial radiation approach, radioembolisation (RE) is ubiquitously applied as one of palliative approaches. Although, in general RE shows promising results in intermediate and advanced stage HCC [5], individual treatment outcomes are currently unpredictable. Corresponding stratification criteria are still unclear. We hypothesised that individual radioresistance/radiosensitivity may play a crucial role in treatment response towards RE strongly influencing individual outcomes. Further, HCC represents a highly heterogeneous group of patients which requires patient stratification according to clear criteria for treatment algorithms to be applied individually. Multilevel diagnostic approach (MLDA) is considered helpful to set-up optimal predictive and prognostic biomarker panel for individualised application of radioembolisation. Besides comprehensive medical imaging, our MLDA includes non-invasive multi-omics and sub-cellular imaging. Individual patient profiles are expected to give a clue to targeting shifted molecular pathways, individual RE susceptibility, treatment response. Hence, a dysregulation of the detoxification pathway (SOD2/Catalase) might indicate possible adverse effects of RE, and highly increased systemic activities of matrix metalloproteinases indicate an enhanced tumour aggressiveness and provide insights into molecular mechanisms/targets. Consequently, an optimal set-up of predictive and prognostic biomarker panels may lead to the changed treatment paradigm from untargeted "treat and wait" to the cost-effective predictive, preventive and personalised approach, improving the life quality and life expectancy of HCC patients. Keywords: Market access, Value, Strategy, Companion diagnostics, Cost-effectiveness, Reimbursement, Health technology assessment, Economic models, Predictive preventive personalized medicine Achieving and sustaining seamless "drug -companion diagnostic" market access requires a sound strategy throughout a product life cycle, which enables timely creation, substantiation and communication of value to key stakeholders [1, 2]. The study aims at understanding the root-cause of market access inefficiencies of companies by gazing at the "Rx-CDx" co-development process through the prism of "value", and developing a perfect co-development scenario based on the literature review and discussions with the ...
1,3-Dipolar cycloadditions between the D-erythrose and D-threose derived nitrones and methyl acrylate proceed in a regiospecific manner to afford the corresponding 3,5-disubstituted diastereomeric isoxazolidines in good yields. The stereoselectivity was dependent on the steric hindrance of the nitrone. The major products were found to have the C-3/C-4´ erythro and C-3/C-5 cis relative configuration. Its formation can be rationalized by less hindered endo attack of the Z-nitrone in an antiperiplanar manner with respect to the largest group of the cyclic acetal.The nitrone-olefin 1,3-dipolar cycloaddition is a powerful reaction in that it can create as many as three new contiguous stereogenic centres in a single step. 1 Based on an evaluation of the nitrone cycloaddition, it was felt that the stereochemistry of these new centers could be controlled if the reaction system were properly designed. 2,3 Regioand stereoselective nitrone cycloaddition, followed by reduction of the N-O bond to produce both an amino and a hydroxy function, allows the synthesis of many products of potential interest. 4 With our continuing efforts to utilize chiral 1,3-dipolar cycloadditions, 5 and with the goal of developing a simple route to the synthesis of polyhydroxylated derivatives of pyrrolizidines, 6 which have been shown to display antiviral activity, 7 via an asymmetric 1,3-dipolar cycloaddition we have recently published the preparation of new D-erythrose-1a and D-threose-6a derived nitrones and the stereoselectivity of their cycloadditions to styrene. 8 We now report the stereoselectivity of the cycloaddition of chiral sugar-derived nitrones 1a-c, 6a and 6b with methyl acrylate.The results are presented in the Table. In all cases the reactions were highly regiospecific, leading to the formation of diastereomeric isoxazolidines 2-5 (Scheme 1) and 7-10 (Scheme 2) as a mixture of three or four diastereoisomers in a good overall yield. 9 Purification by flash chromatography allowed the isolation of the pure major diastereoisomers 2a-c, 7a and 7b, while the isolation and/ or characterization of minor isomers was possible only for some of them. 10 When, methyl acrylate was used instead of styrene, 8 selectivity decreased. Only 48% of major diastereomer 2a for nitrone 1a (Table, entry 1) versus 81% in the case of styrene as dipolarophile 8 was deemed unacceptable. The usefulness of the chiral 1,3-dipolar cycloaddition depends on the diastereoselectivity achieved, since the major diastereoisomers 2a will be used subsequently for the synthesis of pyrrolizidines 11. 11 In light of these differences; we undertook a systematic study of the possibility to influence the selectivity of the cycloaddition. Our objective was the study of diastereoselectivity of cycloadditions stemming from the nitrone part. In the case of the cycloadditions with styrene we have found, that the stereoselectivity of the cycloaddition was influenced by the steric hindrance of both the N-and C-substituent of the nitrone, i.e. the selectivity increases as the nitrogen ...
S y n t h e s i s o f T r i h y d r o x y l a t e d P y r r o l i z i d i n e b y C y c l o a d d i t i o n o f D -E r y t h r o s e D e r i v e d N i t r o n eAbstract: A route has been developed for the synthesis of enantiomerically and diastereomerically pure trihydroxylated pyrrolizidines. A chiral sugar derived nitrone undergoes diastereoselective dipolar cycloaddition with methyl acrylate to afford erythro-cis isoxazolidine; a suitable cycloadduct undergoes N-O cleavage and recyclization to (1S,2R,6R,7aS)-trihydroxylated pyrrolizidine.Many naturally occurring polyhydroxylated pyrrolizidine alkaloids are endowed with a wide spectrum of biological activities and therapeutic applications in diabetes, obesity and AIDS due to their action of glycosidase inhibitors because of a structural resemblance to the sugar moiety of the natural substrate. 1 The high potential of pyrrolizidine alkaloids in a range of biological applications makes them inviting targets for synthesis. In particular the preparation of other structural analogs of alexine (1) and australine (2), that are specific inhibitors of amylglycosidase, has created much interest since the biological activity of these molecules varies substantially with the number, position, and stereochemistry of the hydroxy groups in the pyrrolizidine skeleton ( Figure 1). 2 Figure 1Pyrrolizidine syntheses involving 1,3-dipolar cycloadditions have been recently reviewed. 3 Most of these approaches make use of carbohydrates as chiral auxiliaries or chiral building blocks. In connection with our interest concerning the utilization of chiral nitrones in asymmetric cycloadditions, 4 we have designed sugar-derived nitrones 5 as templates for synthesis of polyhydroxylated derivatives of pyrrolizidines. Nitrones are 1,3-dipoles known to undergo cycloadditions to form isoxazolidines and cleavage of the N-O bond to enable recyclization to carbon-nitrogen heterocycles is a recognized synthetic strategy. 6As part of our program devoted to developing of a simple route to polyhydroxylated derivatives of pyrrolizidines, we describe herein a stereoselective synthesis of enantiopure (1S,2R,6R,7aS)-trihydroxylated pyrrolizidine 3. The synthesis of diastereoisomers (±)-4, (+)-5 and (-)-5 using the cycloadditions of 3,4-disubstituted pyrroline-Noxides with O-silyl-protected allyl alcohol has been described by Wightman 7 but, to the best of our knowledge, 3 has not been described previously.In the foregoing paper we have shown that sugar derived nitrones react with methyl acrylate with useful stereoselectivity, particularly if hydroxy group in the nitrone is protected with the bulky tert-butyldimethylsilyl group. 8 We decided to exploit this knowledge of the stereochemical course of these cycloadditions in the development of a synthetic method to (1S,2R,6R,7aS)-pyrrolizidine-1,2,6-triol (3) from carbohydrate precursors. Our retrosynthetic strategy is outlined in Figure 2 in which we proposed to build the pyrrolizidine skeleton of general formula 3 via nitrone cycloaddition. Reaction of nitr...
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