Total Synthesis of the Aristolochic Acids, Their Major Metabolites, and Related Compounds

Abstract

Plants from the Aristolochia genus have been recommended for the treatment of a variety of human ailments since the time of Hippocrates. However, many species produce the highly toxic aristolochic acids (AAs), which are both nephrotoxic and carcinogenic. For the purposes of extensive biological studies, a versatile approach to the synthesis of the AAs and their major metabolites was devised based primarily on a Suzuki–Miyaura coupling reaction. The key to success lies in the preparation of a common ring-A precursor, namely, the tetrahydropyranyl ether of 2-nitromethyl-3-iodo-4,5-methylendioxybenzyl alcohol (27), which was generated in excellent yield by oxidation of the aldoxime precursor 26. Suzuki–Miyaura coupling of 27 with a variety of benzaldehyde 2-boronates was accompanied by an aldol condensation/elimination reaction to give the desired phenanthrene intermediate directly. Deprotection of the benzyl alcohol followed by two sequential oxidation steps gave the desired phenanthrene nitrocarboxylic acids. This approach was used to synthesize AAs I–IV and several other related compounds, including AA I and AA II bearing an aminopropyloxy group at position-6, which were required for further conversion to fluorescent biological probes. Further successful application of the Suzuki–Miyaura coupling reaction to the synthesis of the N-hydroxyaristolactams of AA I and AA II then allowed the synthesis of the putative, but until now elusive, N-acetoxy- and N-sulfonyloxy-aristolactam metabolites.

Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

“…AL-I-NOSO 3 and AL-I-NOH were synthesized as described previously (42). Probenecid (water soluble) was purchased from ThermoFisher Scientific (catalog P36400).…”

Bioactivation mechanisms of N‐hydroxyaristolactams: Nitroreduction metabolites of aristolochic acids

“…AL‐I‐OH and AL‐II‐NOH were synthesized in our laboratory as described (Attaluri et al ), and AA‐I was purified from A. indica by high‐performance liquid chromatography. AA‐related compounds were dissolved in dimethyl sulfoxide (DMSO) at 30–40 mM and stored at −20°C.…”

“…Nevertheless, the controversy regarding the enzymes involved in the bioactivation of AA remains, because it was reported that following AA‐I exposure, transgenic mice carrying the functional human SULT1A1‐SULT1A2 gene cluster accumulate comparable levels of AL‐DNA to that detected in the parental strain deficient in the murine sult1a1 and sult1a2 (Arlt et al ). Therefore, it is important to assess fully the mechanisms and enzymes involved in the activation of N ‐hydroxyaristolactams, which latter we are capable of synthesizing on demand (Attaluri et al ).…”

Y-family DNA polymerase-independent gap-filling translesion synthesis across aristolochic acid-derived adenine adducts in mouse cells

“…1A) were synthesized as described previously (35, 36). The oligonucleotide, 5’CCATCATCTCCAGAC A GATCCTCACAC (Fig.…”