Resorcylic Acid Lactones
The resorcylic acid lactones (RALs) are a family of benzannulated macrolides, which are produced by a variety of fungi and show versatile biological activities (6). According to their name, they consist structurally of a partially substituted β-resorcylic
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The resorcylic acid lactones (RALs) are a family of benzannulated macrolides, which are produced by a variety of fungi and show versatile biological activities (6). According to their name, they consist structurally of a partially substituted b-resorcylic acid scaffold, which is linked to a 12- or 14-membered macrolactone moiety. Selected members of this group are shown in Fig. 9.1. OH
O
O
OH O
OH O
O
HO
O
HO Cl
O
HO
O
O
R1 O
O
O
OH O HO
O
OH
OH
HO Cl
O
O
R
R1=OH, R2=H: 480a (a-zearalenol) R1=H, R2=OH: 480b (b-zearalenol)
O
HO
OH OH
2
479 (zearalenone)
478 (radicicol)
OH
O
OH
O
481 (hypothemycin)
O
O
Cl
O O
O HO
HO O
OH 482 (aigialomycin D)
483 (pochonin C)
484 ((Z )-resorcylide)
485 (lasiodiplodin)
Fig. 9.1 Selected resorcylic acid lactones
Radicicol (478) (335), formerly called monorden (336), was first isolated from Monosporium bonorden in 1953 (337). The most well-known member of the RAL family, zearalenone (F-2) (479), was found in 1962 in spoiled grain infected with Gibberella zeae, which was fed to swine. This contamination led among other symptoms to vulvar hypertrophy, vaginal eversion, and the growth of mammary glands among the affected animals (338, 339). Figure 9.2 shows the fungus Gibberella zeae on corn (340).
S. Bra¨se et al., The Chemistry of Mycotoxins, Progress in the Chemistry of Organic Natural Products, Vol. 97, DOI 10.1007/978-3-7091-1312-7_9, # Springer-Verlag Wien 2013
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9 Resorcylic Acid Lactones
Fig. 9.2 Corn infected with Gibberella zeae
The reduced form of zearalenone (479), a-zearalenol (480a) (341), and hypothemycin (481) (342) are further examples of the first known RALs. It should be noted that the initial structure proposed for hypothemycin (343) was erroneous. During the last decade, two new subgroups of 14-membered resorcylic macrolides, the aigialomycins (344) and the pochonins (345) have been isolated and characterized, leading to a renewed interest in this class of natural products. While aigialomycins A–F were isolated together with hypothemycin from the marine mangrove fungus Aigialus parvus, pochonins A–F were found in cultures of Pochonia chlamydosporia var. catenulata. Recently, two further subgroups, paecilomycins A–F and cochliomycins A–C, have been isolated from a Paecilomyces fungus and Cochliobolus lunatus (346, 347). (Z)-Resorcylide (484), called in the literature mostly (cis)-resorcylide, and lasiodiplodin (485), are examples of bioactive RALs containing a 12-membered macrolactone system (348, 349).
9.1
Biological Properties
According to their structural diversity, the RALs exhibit a variety of biological activities. Although it is classed as a mycotoxin, zearalenone (479) is barely toxic (9). Its anabolic and uterotrophic traits (338) are the result of its interaction with estrogenic receptors. Zearalenone (479) is able to bind to these receptors and thus mimic the ability of 17b-estradiol to stimulate transcriptional activity. Therefore, it
9.2 Total Syntheses
93
is also called a non-steroidal estrog
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