Regio‐ and Stereospecific Synthesis of Cholesterol Derivatives and Their Hormonal Activity in Caenorhabditis elegans

Abstract

Cholesterol is essential for the survival of the nematode Caenorhabditis elegans. Recent studies have demonstrated that cholesterol derivatives regulate two processes in the life cycle of worms: controlling molting and inducing a specialized non‐feeding larval stage. However, the chemical structure of the cholesterol‐derived signalling molecules for these or any other functions has not yet been identified. Herein, we describe the regio‐ and stereospecific synthesis of a number of cholesterol derivatives. The lithium–ammonia reduction of 4‐cholesten‐3‐one was utilized to develop a general method for the introduction of diverse functional groups at C‐4α of 5α‐cholestan‐3β‐ol. Stereoselective functionalization at C‐7 was achieved starting from 7‐ketocholesterol derivatives. 6‐Keto‐5α‐cholestan‐3β‐ol was utilized for specific functionalizations at C‐6 and C‐7. The structure–activity relationships of the different cholesterol derivatives have been investigated by feeding worms of different genetic background with these compounds. Our study is the first step in assigning the relationships of hormonal activity in C. elegans on the substitution at different positions of cholesterol. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Preliminary Structure-Activity Relationship on Theonellasterol, a New Chemotype of FXR Antagonist, from the Marine Sponge Theonella swinhoei

“…As previously reported for several natural and synthetic 4-methyl cholestane derivatives [33], in the 4α-methyl-3β-ol derivative ( 8 ), the 3α-proton resonance is consistently shifted upfield with respect to the corresponding resonances in the 4α-methyl-3α-ol ( 9 ) and 4β-methyl-3β-ol diasteroisomers ( 5 ) ( δ H 2.93 in 8 , δ H 3.55 in 9 , δ H 3.54 in 5 ), thus substantiating the stereochemical assignment reported in Scheme 2. Moreover in the 1 H NMR of 9 , H-3 was observed as a broad multiplet, allowing its assignment as equatorial and therefore establishing the orientation of the hydroxyl group at C-3 on the α-face of the molecule.…”

A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity

“…2), and with additional incubation time the larvae become adults. These observations are supported by structure-activity studies that included 6-difluorocholesterol fed nematodes showing compound specifically induced L2 dauer formation (30).…”

“…1). In contrast to C4-methyl sterol utilization in sterol prototrophs, in which the C4-methyl group(s) is necessarily removed in conversion to cholesterol for growth support (25,26), in C. elegans the inclusion of a C4-methyl group on the metabolite product is essential for larval growth or to effect dauer formation (27)(28)(29)(30). This work nevertheless leaves open questions regarding the number, properties, and evolutionary origin of sterol metabolases in nematodes, most notably the 4-SMT that controls the balance of neutral C 28 to acidic C 27 sterols in C. elegans (23); its substrate specificity and reaction mechanism remain enigmatic.…”

Total synthesis of biologically active alkaloids using transition metals

“…In cooperation with groups from biochemistry, biology, and medicine, we are investigating the potential of these compounds as novel lead structures for drugs. One of our current projects is dealing with the stereoselective synthesis of steroids [1][2][3][4][5][6][7][8][9][10][11][12][13]. These studies have led to highly efficient total syntheses of the dafachronic acids ( Fig.…”