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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
As can be seen from this figure, acetal 198 (obtained in two steps from acrolein and diethylnitromalonate in 98% overall yield) was further hydrolyzed to furnish the nitroester aldehyde 199 (quantitative from TLC), which, without any isolation, was treated with rabbit muscle aldolase (RAMA) and DHAP at pH 7.5. After the DHAP was consumed (followed by enzymatic assay), the pH was adjusted to 3.9 and phytase was used just to hydrolyze the phosphate group. In this way, nitrocyclitol 201 was then isolated in 60% yield, and finally reduced to yield (1S,2S,3R,6R)-6-amino-1-(hydroxymethyl)cyclohexane-1,2,3-triol 202 in 80%. To confirm the mechanism of the conversion from 200 to 201, authors also designed an alternative and easier methodology starting from nitroaldehyde 203.
Pharmacokinetic-Pharmacodynamic Correlations of Corticosteroids
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Helmut Möllmann, Stefan Baibach, Günther Hochhaus, Jürgen Barth, Hartmut Derendorf
The optimal therapeutic corticoid should have maximal glucocorticoid and minimal mineralcorticoid effects. Structural modification of HC can approach this ideal.13,138 Introducing a second double bond (Δ) in ring A increases the glucocorticoid potency fourfold and decreases the mineralocorticoid (sodium-retaining) effect by 30%. It also decreases the rate of metabolism. Methyl (CH3) and fluorine (F) substitution in the 6α-position (ring B) results in a significant enhancement of the antiphlogistic efficacy. Fluorination in 9α improves the glucocorticoid and the mineralocorticoid potency. The 11-hydroxy group (ring C) is required for glucocorticoid activity. Ring D offers various possibilities for modification. Methylation of 16α and as well as β hydroxylation in 16a reduces the sodium-retaining effect significantly. An important factor to maintain the glucocorticoid activity is the 17α-hydroxy group, even though modifications may increase the receptor affinity. Increased lipophilicity, due to esterification in position 21, is primarily used to sterically protect readily metabolized partial structures as well as to improve pharmacokinetic properties of the compound (prodrug principle). Derivatives with 16α, 17α acetal or ketone groups were originally designed as prodrugs, but their high receptor binding supports drug action of the unmetabolized moieties. Figure 4 illustrates the possibilities of structure modification in corticosteroids.
Dendrimers as Drug and Gene Delivery Systems
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Frechet and coworkers synthesized novel dendritic unimolecular micelles with a hydrophobic polyether dendrimer core surrounded by hydrophilic PEGs.21 For the G-3 micelle, the loading of indomethacin was found to be of 11%, a value corresponding to approximately nine to ten drug molecules per micelle, and preliminary in vitro release tests showed that sustained release characteristics were achieved. Recently, linear dendritic block copolymers comprising PEG and either a polylysine or polyester dendrons were designed, and highly acid-sensitive cyclic acetals were attached to the dendrimer periphery for pH-responsive micelle systems.22 At pH 7.4, the fluorescence of micelle-encapsulated Nile Red was constant, indicating it was retained in the micelle, whereas at pH 5, the fluorescence decreased, consistent with its release into aqueous solution. The rate of release was strongly correlated with the rate of acetal hydrolysis. These results suggest that the loading and controlled-release of drugs are dependent on the chemical structure of the dendrimer.
Dietary n-3 polyunsaturated fatty acid deficiency alters olfactory mucosa sensitivity in young mice but has no impact on olfactory behavior
Published in Nutritional Neuroscience, 2023
Vanessa Soubeyre, Laetitia Merle, David Jarriault, Stéphane Grégoire, Lionel Bretillon, Niyazi Acar, Xavier Grosmaitre, Anne Marie Le Bon
Compared to the CON group, the level of total dimethyl acetals (DMAs) in offspring OM was significantly lower (- 6%) in the HIGH group (Table 2). The levels of total saturated FAs (SFAs), monounsaturated FAs (MUFAs) and PUFAs were not affected by the LOW and HIGH diets. Nevertheless, both diets significantly modified the proportions of n-6 and n-3 PUFAs in offspring OM. Compared to the CON group, the n-6:n-3 ratio was significantly enhanced (x 3.8) in the LOW group. This effect was due to a substantial increase in n-6 PUFAs (+ 50%) and an important reduction in n-3 PUFAs (- 60%) compared to the CON group (Table 2). The OM of the LOW group contained significantly higher levels of AA (+ 35%), 22:4n-6 (+ 94%) and DPA n-6 (x 11) than the OM of the CON group. Conversely, the levels of eicosapentaenoic acid (EPA; 20:5n-3), DPA n-3 and DHA were strongly reduced (−82%, −73% and −57%, respectively). Opposite effects were noticed in OM of the HIGH group. Compared to the CON group, the level of total n-3 PUFAs was increased by approximately +10%, whereas the level of total n-6 PUFAs was decreased by −20%, which led to a significant reduction in the n-6:n-3 ratio (- 30%; Table 2). OM from the HIGH offspring had significantly higher EPA and DPA n-3 levels than the CON group (x2.6 and x1.7, respectively). In contrast, the levels of AA, 22:4n-6 and DPA n-6 were greatly reduced (−27%, −44% and −72%, respectively).
Fluorinated scaffolds for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Charu Upadhyay, Monika Chaudhary, Ronaldo N. De Oliveira, Aniko Borbas, Prakasha Kempaiah, Poonam S, Brijesh Rathi
In view of these intriguing observations, O’Neill et al. [77] also prepared a library of C-10 acetal derivatives 53a-53f (Figure 10). These derivatives were synthesized by the C-10 phenoxylation of DHA 50a with trimethylsilyl trifluoromethanesulfonate (TMSOTf), silver perchlorate (AgClO4), and substituted phenols to give C-10 acetal derivatives 53a-53f with optimum yields and magnificent stereoselectivity. In vitro results showed that analogue 53a (IC50 = 3.66 nM) and 53b (IC50 = 3.92 nM) were the most active against the PfK1 CQ-resistant strain. Derivatives 53d and 53e showed equal potency against PfK1 strain. Based on these promising results and high stereoselectivity of C-10, acetal derivatives 53a and 53c with an IC50 values of 3.66 and 5.29 nM, respectively, were subjected to animal testing. Notably, analogue 53c was found to be extremely effective against CQ-sensitive P. berghei-infected mice (ED50 = 2.1 mg/kg) [77].
Sustained release of a model water-soluble compound via dry powder aerosolizable acetalated dextran microparticles
Published in Pharmaceutical Development and Technology, 2019
Nishan K. Shah, Zimeng Wang, Sweta K. Gupta, Andrew Le Campion, Samantha A. Meenach
The drug release patterns of Ac-Dex MP at acidic and physiological pH values are similar to previous studies (Meenach et al. 2012; Chen et al. 2016; Wang et al. 2017). By controlling the reaction time of Ac-Dex, alterations in the acetalation of dextran altered the release kinetics. However, regardless of Ac-Dex synthesis time, hydrolysis of acetal groups accelerated in acidic conditions, resulting in fast drug release from the NP. The Corrigan model was developed to evaluate initial burst release that occurs in drug delivery systems (Gallagher and Corrigan 2000). When exposed to acidic pH conditions, Ac-Dex degrades quickly, which allows for burst release, resulting in a release pattern similar to those described in a previous report which studied 152 drug release experiments to evaluate burst release (Gallagher and Corrigan 2000; Corrigan and Li 2009; Rodrigues de Azevedo et al. 2017). The variation in KC values is likely related to differences in the diffusion coefficient and solubility of the drug, as well as the differences in surface area of the systems (Corrigan and Li 2009). Since all of the systems encapsulated the same compound and were similar in diameter, the effect of surface area is the likely caused by the different morphologies of the particles (Weers and Miller 2015).