Synthesis of silodosin glucuronide and its deuterated counterpart: solving a problematic O-glycosylation of a nitrogen-containing molecule

2017 ◽  
Vol 23 (3) ◽  
pp. 187-195
Author(s):  
Jun Zhou ◽  
Yunpeng Liu ◽  
Hailiang Zhu ◽  
He Zhu ◽  
Peng George Wang
Keyword(s):  
Hydrogen Bond ◽  
Chemical Synthesis ◽  
Small Molecule ◽  
Acyl Migration ◽  
Complex Mixture ◽  
Side Reactions ◽  
Reaction Conditions ◽  
Adrenoceptor Antagonist ◽  
Small Molecule Drugs ◽  
Sequential Addition

AbstractWe report here the first chemical synthesis of silodosin glucuronide, a metabolite of the α1A-adrenoceptor antagonist silodosin, and its deuterium-labeled counterpart. As a key synthetic step, the incorporation of a glucuronosyl unit onto silodosin invariably led to either an undesired orthoester or a complex mixture under an array of standard glycosylation conditions. This problematic O-glycosylation may be attributed to the presence of multiple basic groups that could neutralize the acidic activators, decrease the nucleophilicity of a hydroxy group via hydrogen bond or even facilitate acyl migration side reactions. After elaborate tuning of reaction conditions, success was eventually achieved by using perbenzoylated d-glucuronosyl N-phenyltrifluroacetimidate (PTFA) as donor in combination with a procedure of sequential addition of TMSOTf. This protocol is potentially general for the glycosylation of other nitrogen-containing small molecule drugs.

scholarly journals Modular ketal-linked prodrugs and biomaterials enabled by organocatalytic transisopropenylation of alcohols

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Na Yu ◽  
Yang Xu ◽  
Tao Liu ◽  
Haiping Zhong ◽  
Zunkai Xu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Small Molecule ◽  
Functional Group ◽  
Building Blocks ◽  
Hydroxyl Group ◽  
Reaction Conditions ◽  
Small Molecule Drugs ◽  
Wide Range ◽  
Scalable Synthesis ◽  
Traditional Approaches

AbstractIsopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis. The development of this organocatalytic transisopropenylation approach enables access to modular preparation of various acid-sensitive ketal-linked prodrugs and functionalized ketalated biomaterials. We expect our syntheses and transformations of isopropenyl ethers will find utility in several diverse fields, including medicinal chemistry, drug delivery, and biomaterials.

A Facile, Efficient and Selective Deprotection of P - Methoxy Benzyl Ethers Using Zinc (II) Trifluoromethanesulfonate

2019 ◽  
Vol 16 (12) ◽  
pp. 955-958
Author(s):  
Reddymasu Sireesha ◽  
Reddymasu Sreenivasulu ◽  
Choragudi Chandrasekhar ◽  
Mannam Subba Rao
Keyword(s):  
Room Temperature ◽  
Protecting Groups ◽  
Side Reactions ◽  
Reaction Conditions ◽  
Acid Sensitivity ◽  
Time Period ◽  
Protective Groups ◽  
Benzyl Ethers ◽  
Last Stage ◽  
Zinc Triflate

: Deprotection is significant and conducted over mild reaction conditions, in order to restrict any more side reactions with sensitive functional groups as well as racemization or epimerization of stereo center because the protective groups are often cleaved at last stage in the synthesis. P - Methoxy benzyl (PMB) ether appears unique due to its easy introduction and removal than the other benzyl ether protecting groups. A facile, efficient and highly selective cleavage of P - methoxy benzyl ethers was reported by using 20 mole% Zinc (II) Trifluoromethanesulfonate at room temperature in acetonitrile solvent over 15-120 min. time period. To study the generality of this methodology, several PMB ethers were prepared from a variety of substrates having different protecting groups and subjected to deprotection of PMB ethers using Zn(OTf)2 in acetonitrile. In this methodology, zinc triflate cleaves only PMB ethers without affecting acid sensitivity, base sensitivity and also chiral epoxide groups.

scholarly journals Cyclodextrin-Based Supramolecular Complexes of Osteoinductive Agents for Dental Tissue Regeneration

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 136
Author(s):  
Masahiko Terauchi ◽  
Atsushi Tamura ◽  
Yoshinori Arisaka ◽  
Hiroki Masuda ◽  
Tetsuya Yoda ◽  
...  
Keyword(s):  
Growth Factors ◽  
Bone Formation ◽  
Small Molecule ◽  
Tissue Regeneration ◽  
Alveolar Bone ◽  
Inclusion Complexation ◽  
Dental Tissue ◽  
Polyelectrolyte Complexes ◽  
Small Molecule Drugs

Oral tissue regeneration has received growing attention for improving the quality of life of patients. Regeneration of oral tissues such as alveolar bone and widely defected bone has been extensively investigated, including regenerative treatment of oral tissues using therapeutic cells and growth factors. Additionally, small-molecule drugs that promote bone formation have been identified and tested as new regenerative treatment. However, treatments need to progress to realize successful regeneration of oral functions. In this review, we describe recent progress in development of regenerative treatment of oral tissues. In particular, we focus on cyclodextrin (CD)-based pharmaceutics and polyelectrolyte complexation of growth factors to enhance their solubility, stability, and bioactivity. CDs can encapsulate hydrophobic small-molecule drugs into their cavities, resulting in inclusion complexes. The inclusion complexation of osteoinductive small-molecule drugs improves solubility of the drugs in aqueous solutions and increases in vitro osteogenic differentiation efficiency. Additionally, various anionic polymers such as heparin and its mimetic polymers have been developed to improve stability and bioactivity of growth factors. These polymers protect growth factors from deactivation and degradation by complex formation through electrostatic interaction, leading to potentiation of bone formation ability. These approaches using an inclusion complex and polyelectrolyte complexes have great potential in the regeneration of oral tissues.

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