Chemical Synthesis of Rare Natural Bile Acids: 11α‐Hydroxy Derivatives of Lithocholic and Chenodeoxycholic Acids

A method for the preparation of 11α‐hydroxy derivatives of lithocholic and chenodeoxycholic acids, recently discovered to be natural bile acids, is described. The principal reactions involved were (1) elimination of the 12α‐mesyloxy group of the methyl esters of 3α‐acetate‐12α‐mesylate and 3α,7α‐diacetate‐12α‐mesylate derivatives of deoxycholic acid and cholic acid with potassium acetate/hexamethylphosphoramide; (2) simultaneous reduction/hydrolysis of the resulting △¹¹‐3α‐acetoxy and △¹¹‐3α,7α‐diacetoxy methyl esters with lithium aluminum hydride; (3) stereoselective 11α‐hydroxylation of the △¹¹‐3α,24‐diol and △¹¹‐3α,7α,24‐triol intermediates with B₂H₆/tetrahydrofuran (THF); and (4) selective oxidation at C‐24 of the resulting 3α,11α,24‐triol and 3α,7α,11α,24‐tetrol to the corresponding C‐24 carboxylic acids with NaClO₂ catalyzed by 2,2,6,6‐tetramethylpiperidine 1‐oxyl free radical (TEMPO) and NaClO. In summary, 3α,11α‐dihydroxy‐5β‐cholan‐24‐oic acid and 3α,7α,11α‐trihydroxy‐5β‐cholan‐24‐oic acid have been synthesized and their nuclear magnetic resonance (NMR) spectra characterized. These compounds are now available as reference standards to be used in biliary bile acid analysis.     

Stabilization of α‐amylase by chemical modification with carboxymethylcellulose

Carboxymethylcellulose activated by periodate oxidation was covalently linked to porcine pancreatic α‐amylase (EC 3.2.1.1). The specific activity of the conjugate prepared was 54% of the native enzyme. The carbohydrate content was estimated to be 62% by weight as a result of the modification of 67% of the amino groups from the protein. In comparison with the native enzyme, the thermostability and pH stability were improved for α‐amylase by this modification. The conjugate was also more resistant to the action of denaturant agents such as urea and sodium dodecylsulfate. We conclude that modification of enzymes by the anionic polysaccharide carboxymethylcellulose might be a useful method for improving enzyme stability under various denaturing conditions. © 1999 Society of Chemical Industry     

Cationic copolymers of α,β‐poly‐(N‐2‐hydroxyethyl)‐DL‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy): synthesis and characterization

In the present study the derivatization of two water‐soluble synthetic polymers, α,β‐poly(N‐2‐hydroxyethyl)‐DL ‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introduce positive groups in their chains and it permits the preparation of interpolyelectrolyte complexes with DNA. © 2000 Society of Chemical Industry     

The Tunable Functionality of α,β‐Unsaturated Carbonyl Compounds Enables Their Differential Application in Biological Systems

α,β‐Unsaturated carbonyl compounds as potential drug candidates is a controversial topic since their potential Michael acceptor activity can lead to cell damage and cytotoxicity. Nevertheless, the α,β‐unsaturated carbonyl functionality can be employed as a tool to fine tune biological activity by directly manipulating this entity. Depending on their electronic properties, α,β‐unsaturated carbonyl functionalities display different reactivities, namely Michael addition, radical scavenging, oxidation or double bond isomerization. Modifying the α‐position of the α,β‐unsaturated carbonyl system, a concept that has not been widely explored, could produce new, very interesting derivatives. Currently in drug development, irreversible binding in active sites has proven to be one answer to drug resistance in cancer treatment. Overall, natural products containing the α,β‐unsaturated carbonyl unit possess multiple biological activities that could be transferred into novel pharmaceutical agents.     

N‐Heterocyclic Carbene‐Mediated Organocatalytic Transfer of Tin onto Aldehydes: New Access to α‐Silyloxyalkylstannanes and γ‐Silyloxyallylstannanes

A new, highly efficient and mild N‐heterocyclic carbene (NHC)‐mediated organocatalytic procedure for the transfer of tin from tributyl(trimethylsilyl)stannane (Bu₃SnSiMe₃) onto aldehydes for the preparation of α‐silyloxyalkylstannanes and γ‐silyloxyallylstannanes has been developed.