Synthesis of Novel C/D Ring Modified Bile Acids

Abstract

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro–furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.

The discovery of 12β-methyl-17-epi-18-nor-bile acids as potent and selective TGR5 agonists

“…[α] 20 D = +64.5 (c 0.67, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) δ 4.70 (dd, J = 5.9, 1.7 Hz, 1H), 3.65 (s,3H),3.50 (tt,J = 10.9,4.5 Hz,1H),2H),1H),6H),11H),1H),3H), 0.94 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.80-0.70 (overlapping signals: 0.79, s, 3H and m, 2H), 0.15 (s, 9H), 0.09 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ) δ 174.18, 151. 58, 108.39, 71.56, 55.15, 51.33, 51.22, 47.72, 47.12, 42.79, 40.83, 39.27, 38.79, 35.50, 35.22, 34.63, 34.44, 33.02, 32.33, 30.67, 29.03, 24.83, 23.53, 22.43, 21.47, 19.76, 0.35 (3C) Methyl 6-ethyliden-3α-hydroxy-12β-methyl-7-oxo-25-homo-18nor-5β-cholan-25-oate (49). According to the same procedure as for the preparation of compound 31, a solution of compound 48 (1.14 g, 2.03 mmol) in dry dichloromethane (10 mL) and acetaldehyde (0.23 mL, 4.10 mmol) was treated with a solution of boron trifluoride diethyl etherate (1.00 mL, 8.10 mmol) in dry dichloromethane (2 mL) at -60 • C by dropwise addition via cannula and the resulting reaction mixture was stirred at -60 • C for 2 h before being allowed to warm to room temperature.…”

“…Our approach is to explore 12β-methyl-18-nor-BA scaffolds for the development of new BA-based drugs (Fig. 3) [47][48][49]. Following our initial work on the synthesis of 12β-methyl-18-nor-BAs, we also recently published results from an investigation into the applicability of 12β-methyl-18-nor-avicholic acids as potential TGR5 agonists [47,48].…”

3α,7-Dihydroxy-14(13→12)abeo-5β,12α(H),13β(H)-cholan-24-oic Acids Display Neuroprotective Properties in Common Forms of Parkinson’s Disease

“…[α] 20 D = +32.4 (c 0.565, MeOH), [29]: [α] 20 D = +30.5 (EtOH); 1 H NMR (500 MHz, CD 3 OD) δ 3.83-3.79 (m, 1H), 3.41-3.33 (m, 2H), 2.34 (ddd, J = 15.4, 10.2, 5.3 Hz, 1H), 2.29-2.17 (m, 2H), 2.03-1.87 (m, 4H), 1.84 (dt, J = 14.3, 3.0 Hz, 1H), 1.81-1.72 (m, 2H), 1.68-1.59 (m, 3H), 1.59-1.47 (m, 3H), 1.46-1.20 (m, 7H), 1.06-0.96 (overlapping signals: m, 1H and 1.03, d, J = 6.9 Hz, 3H), 0.94 (s, 3H), 0.72 (s, 3H); 13 Mixture of methyl 3α,7α-dihydroxy-14(13→12)abeo-5β,12α(H)-chol-13(18)-en-24-oate (22) and methyl 3α,7α-dihydroxy-14(13→12)abeo-5β-chol-12(13)-en-24-oate (23).…”

“…In this paper, we describe the synthesis of 3, its taurine conjugate (24) as well as the 7β-configured analogue 4. These compounds were part of a wider library of 12β-methyl-18-nor-bile acids that were screened for activity in various bile acid-relevant assays [15,23,24]. Screening of these compounds in fibroblasts from patients with Parkinson's Disease revealed compound 4 and the taurine conjugate of 3 as potential candidates for further assessment.…”