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Design and Synthesis of New Conjugates of Bile Acids with Salicylic, Acetylsalicylic and Nicotinic Acids

[ Vol. 13 , Issue. 4 ]

Author(s):

Tomasz Pospieszny and Bogumił Brycki   Pages 302 - 309 ( 8 )

Abstract:


Backgroung: A new bile acids conjugates have been obtained from 3α-bromoacetoxy derivatives of lithocholic, deoxycholic and cholic acids with salicylic, acetylsalicylic or nicotinic acids. These new conjugates were confirmed by spectroscopic (<sup>1</sup>H-, <sup>13</sup>C NMR, FT-IR) analysis, mass spectrometry (ESI-MS) and semiempirical methods (PM5) as well as in silico (PASS) studies. </p> <p> Methods: This work reports an original synthesis and physicochemical properties of new conjugates of bile acid derivatives with salicylic (SA), acetylasalicylic (ASA) or nicotinic (NA) acids. The 3α- bromoacetates of bile acids were prepared with good yield according to the literature procedures. The structures of all synthesized compounds were determined from their <sup>1</sup>H- and <sup>13</sup>C-NMR, FT-IR as well as ESI-MS spectra. Moreover, PM5 calculations were performed on all the products. Additionally, in silico studies PASS (Prediction of Activity Spectra for Substances) were performed for all compounds. </p> <p> Results: The direct alkylation reaction of the carboxylate ions from SA, ASA or NA with methyl litocholate 3α- bromoacetate, methyl deoxycholate 3α-bromoacetate and methyl cholate 3α-bromoacetate with a catalytic amount of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) in dry toluene is reliable and simple. This esterification method enables to obtain stable esters with very good yields and without any decomposition, e.g. decarboxylation or other degradation processes. The most frequently predicted types of biological activity (than 90%) are: cholesterol antagonist, antihypercholesterolemic, alkenylglycerophosphocholine hydrolase inhibitor and hypolipemic. The synthesised steroidal conjugates were characterised by <sup>1</sup>H and <sup>13</sup>C NMR as well as FT-IR spectroscopy. The lowest HOF values were observed for cholic acid derivatives. The number of hydroxyl groups in the bile acid skeleton lowers the value of the determinant of HOF. In addition HOF lowest values observed for conjugates with aspirin. This can be explained by reducing the reactivity of the phenol group of salicylic acid. Hydrogen bonding between hydroxyl group of cholic acid and carbonyl group of aspirin also reduces HOF. This fact can be explained by reduction of electrostatic and steric interactions between the steroid skeletons. </p> <p> Conclusion: In conclusion, nine new conjugates of bile acids were prepared from methyl litocholate 3α-bromoacetate, methyl deoxycholate 3α-bromoacetate and methyl cholate 3α-bromoacetate with a salicylic acid (SA), acetylsalicylic acid (ASA), as well as nicotinic acid (NA) with catalytic amount DBU in dry toluene at 95°C for 24 hours. All new compounds were characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, FT-IR as well as ESI-MS. Molecular structure of all conjugates was performed by PM5 semiempirical method. Additionally, analyses of the biological prediction activity spectra for conjugates of bile acids with SA, ASA and NA prepared herein are examples of in silico studies of chemical compounds. Estimation of the pharmacotherapeutic potential has been accomplished for the synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS). Given the a combination of two types of biologically active compounds these conjugates may find applications in medicinal chemistry, biology, and in pharmacology.

Keywords:

Acetylsalicylic acid, bile acids, conjugates, nicotinic acid, PM5 calculations, salicylic acid, spectral analysis.

Affiliation:

Laboratory of Microbiocides Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland.

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