Cholic acid derivatives, structures

Figure 19 Basic structure of cholic acid derivatives.

Cholanic acid C24H40O2, a monobasic saturated acid containing four hydroaromatic rings, is the parent substance of the two natural acids, which are its trihydroxy- and dihydroxy-derivatives. It is very highly probable that the following structural formula for cholic acid is correct ... 

As noted earlier, bile acids were among the first steroids to be obtained in pure crystalline form. These compounds played an important role in the effort devoted to divining the structure of steroids. Bile acids as a result acquired a sizeable number of trivial names, most of which gave little information as to their chemical structure. One approach to systematic names is based on the hypothetical cholanoic acid 8-1 (Scheme 8). Bile acids are then named as derivatives of this structure using the mles used for other classes of steroids. Note the cis A-B ring fusion in this series. The systematic name for 8-2, lithocholic acid, is then simply 3a-hydroxy-5/3-cholanic acid. Chenodeoxycholic acid, 8-3, becomes 3a,7a-dihydroxy-5/3-cholanic acid. The predominant acid in bile, 8-3, is cholic acid itself, or, 3a,7a,12a-trihydroxy-5 )8-cholanic acid. 

With this information in hand, it seemed reasonable to attempt to use force field methods to model the transition states of more complex, chiral systems. To that end, transition state.s for the delivery of hydrogen atom from stannanes 69 71 derived from cholic acid to the 2.2,.3-trimethy 1-3-pentyl radical 72 (which was chosen as the prototypical prochiral alkyl radical) were modeled in a similar manner to that published for intramolecular free-radical addition reactions (Beckwith-Schicsscr model) and that for intramolecular homolytic substitution at selenium [32]. The array of reacting centers in each transition state 73 75 was fixed at the geometry of the transition state determined by ah initio (MP2/DZP) molecular orbital calculations for the attack of methyl radical at trimethyltin hydride (viz. rsn-n = 1 Si A rc-H = i -69 A 6 sn-H-C = 180°) [33]. The remainder of each structure 73-75 was optimized using molecular mechanics (MM2) in the usual way. In all, three transition state conformations were considered for each mode of attack (re or ) in structures 73-75 (Scheme 14). In general, the force field method described overestimates experimentally determined enantioseleclivities (Scheme 15), and the development of a flexible model is now being considered [33]. 

F. 5.23. Cholesterol and its derivatives. The steroid nucleus is shown in blue. The bile salt, cholic acid, and the steroid hormone 17p-estradiol are derived from cholesterol and contain the steroid ring structure. 

A macrocyclic resorcin[4]arene with four hydrophobic substituents in the axial position provides an ion-conducting molecular pore by tail-to-tail dimerization.Because the pore size and characteristics of the entry way are defined explicitly by the molecule, only one conductance level is observed. The relatively simple structure is amenable to systematic structural modifications and is, therefore, appropriate in establishing the structure-function relationships. When a methyl ether derivative of cholic acid was employed as the axial substituent,the conductance was increased by 50% to 9.9 pS, compared with the value 6.1 pS observed for 1 with simple alkyl substituents. The cation and anion selectivity ratio Pk/Pc was 20 for 2. showing a significantly larger selectivity factor compared to 8 for 1. A hydrophilic molecular plane of methoxy substituents certainly contributes to the increase of conductance and a higher cation and anion selectivity by the arrangement of a more hydrophilic environment at the central pore. Both ion channels exhibited moderate preferences compared to Na by a facior of ca. 3. The aromatic moiety provides a weak electric field... 

Sada. K. Kondo, T. Yasuda. Y. Miyata. M. Miki, K. Interpretation of variable inclusion abilities of cholic acid and its derivatives on the basis of the crystal structure of sp-petromyzonol. Cheni. Lett. 1994. 727. 

Steroid-based anion receptors show exceptional binding constants, encouraging enantioselectivities and a range of membrane-related activities. Much structural space remains unexplored, especially in the series derived from cholic acid 2. and further advances can be expected. In particular, the podand architecture of 6-15, 17. and 18 is amenable to variation through combinatorial chemis-t. and this technietue may expand the scope and effectiveness of steroid-based anion recognition in years to come. 

However, more active and selective eatalysts are adamantyl-L-prolinamide 36, and camphor-lO-sulfonamide-based prolinamides 37, which contain additional stereocentres. Prolinamides derived from bile acids such as epiandrosterone 38, or cholic acid 39 ° exert good enantiocontrol, probably because the cholestanic structure that forms a functionalised chiral cavity with the appended prolinamide groups that were able to exert a good stereocontrol on the orientation of the substrate. 

The four isomeric acids can be derived by a series of chemical reactions from cholic acid, which is commercially available (Sigma Chemical). Some of the reactions have already been discussed with regard to structures. This section is intended to provide practical methods by which the four acids can be prepared. Some of the intermediates are by themselves interesting derivatives with regard to the stereochemistry of bile acids. The procedures described here are taken from published works with certain modifications and have been tested in the author s laboratory. 

Figure 5 (a and b) Chemical structure of the sodium salt of several bile acids 1 cholic acid, 2 chenodeoxycholate, 3 deoxychoUc acid, 4 glycocholic acid, 5 taurochoUc acid, and 6 tauro deoxychoUc acid, (c) Structures of micelles from choUc acid derivatives, proposed by Small and coworkers. Two or four molecules assemble because of hydrophobic interactions between the cholesterol groups. The hydroxyl groups (black dots on cholesterol) and the carboxylic acids side group shield the hydrophobic domain from water. (Refs. 22-24 for cmcs and Ref. 16 for aggregation numbers.) (Reproduced with permission from Ref. 21. Indian Academy of Sciences, 2004.)... 

The physical chemistry of micellar structure and formation has been reviewed extensively elsewhere[40,45-47], and is only briefly summarized. The concentration at which micellar aggregation of bile salts molecules occurs (critical micellar concentration, CMC) is affected by bile salt structure, pH, temperature and a variety of other factors. Conjugated bile salts have a higher CMC than the unconjugates, and the CMC for trihydroxycholanates (cholic acid) is higher than for the dihydroxy derivatives. Among the latter, deoxy-cholate forms micelles at a lower CMC than does chenodeoxycholate. 

The most prominent BA present in human are cholic acid (C), chenodeoxy-cholic acid (CDC), deoxycholic acid (DC), lithocholic acid (LC), and ursodeoxycholic acid (UDC), as derivatives of 5p-cholan-24-oic acid. Primarily they are present as glycine and taurine conjugates, with the conjugation occurring at carbon 24 of the structure. In addition to the above major BA, a wide array of minor components has been identified. 

The chemical structures of monomers derived from chohc acid, the most frequently used bUe acid in this respect, are shown in Fig. 9. The methacrylate derivatives of bile acids, containing one (lithochohc acid), two (deoxychohc acid), or three (cholic acid) OH groups (see Scheme 1 la), have been prepared. The COOH is protected by an ester group, and the OH at C3 position can be selectively functionalized with methacryloyl and a spacer in between [211, 212]. The (co)polymerization is initiated by AIBN at elevated temperature with or without comonomers (i.e., styrene and MM A). High MWs are acquired at low monomer conversion. 

Mrozek et al. synthesized fourteen acyloxy derivatives of 5(S-cholic acid as novel potential transdermal penetration enhancers and intestinal drug absorption modifiers (Figure 49.6). Nontoxic bile acid/salt derivatives (as amphiphilic compounds) are used widely in drug formulations as excipients and can influence gastrointestinal solubility, absorption, and chemical/enzymatic stability of drugs. Transdermal penetration enhancers are special pharmaceutical excipients that interact with skin components to increase the penetration of drugs into blood circulation after topical application. Structure confirmation of all generated compounds was accomplished by H NMR, NMR, IR, and mass spectrometer (MS) spectroscopy. 

---