Sorbicillinoids from Fungi and Their Bioactivities

Sorbicillinoids are important hexaketide metabolites derived from fungi. They have a variety of biological activities including cytotoxic, antioxidant, antiviral and antimicrobial activity. The unique structural features of the sorbicillinoids make them attractive candidates for developing new pharmaceutical and agrochemical agents. About 90 sorbicillinoids have been reported in the past few decades. This mini-review aims to briefly summarize their occurrence, structures, and biological activities.


Introduction
Sorbicillinoids (also called vertinoids) belong to hexaketide metabolites in which the cyclization has taken place on the carboxylate terminus [1]. They have highly diverse bioactivities and have been isolated from either marine [2][3][4] or terrestrial fungi [5][6][7]. Many of them possess elaborate bicyclic or tricyclic systems that appear to arise from the oxidative dearomatizaton and subsequent dimerization/trimerization of sorbicillin (5). The presence of the C1'-C6' sorbyl sidechain is another structural feature of these compounds. The term "sorbicillinoid" has come to encompass the family as a whole and generally refers to any compound that contains the carbon skeleton of sorbicillin.
Since first reported in 1948 by Cram et al., sorbicillinoids have been extensively studied [8,9]. In 2011, Harned and Volp reviewed the structures of 62 sorbicillinoids [1]. Since then, many new members of this family were isolated and great progress has been made [4,[10][11][12][13]. According to the structural features, sorbicillinoids can be divided into four groups: monomeric sorbicillinoids, bisorbicillinoids, trisorbicillinoids, and hybrid sorbicillinoids. Biosynthesis and chemical synthesis have been extensively studied and reviewed [1,11,[14][15][16][17]. In this mini-review, we focus on the occurrence and biological activities of sorbicillinoids, and 28 additional sorbicillinoids were added on the basis of the previous review [1].
Sorbicillinol (1) was found to be highly reactive and it was the biosynthetic precursor of the other sorbicillinoid family members [11].
Sorbicillinol (1) was found to be highly reactive and it was the biosynthetic precursor of the other sorbicillinoid family members [11].

Hybrid Sorbicillinoids
Hybrid sorbicillinoids are proposed to be derived from either a Diels-Alder or a Michael reaction of a monomeric sorbicillinoid diene and a second non-sorbicillinoid dienophile. About 25 hybrid sorbicillinoids have been isolated from fungi so far.
The structure of sorbicillamine A (78) was a tentative assignment for the C-2/C-7 unit, which might exist as either enol or keto tautomers, and they were interconverting on the NMR timescale in solution [10].
Compound 73 from an intertidal marine fungus Paecilomyces marquandii was an unnamed sorbicillinoid urea [57]. Chloctanspirones A (74) and B (75) containing chlorine were isolated from Penicillium terrestre derived from a marine sediment. The differences between them were their absolute configuration at C-19 [58]. Similarly, both sorbicatechols A (76) and B (77) were isolated from the marine sediment-derived fungus Penicillium chrysogenum PJX-17, and their differences were the absolute configuration at C-7 [59].

Hybrid Sorbicillinoids
Hybrid sorbicillinoids are proposed to be derived from either a Diels-Alder or a Michael reaction of a monomeric sorbicillinoid diene and a second non-sorbicillinoid dienophile. About 25 hybrid sorbicillinoids have been isolated from fungi so far.
The structure of sorbicillamine A (78) was a tentative assignment for the C-2/C-7 unit, which might exist as either enol or keto tautomers, and they were interconverting on the NMR timescale in solution [10].
Compound 73 from an intertidal marine fungus Paecilomyces marquandii was an unnamed sorbicillinoid urea [57]. Chloctanspirones A (74) and B (75) containing chlorine were isolated from Penicillium terrestre derived from a marine sediment. The differences between them were their absolute configuration at C-19 [58]. Similarly, both sorbicatechols A (76) and B (77) were isolated from the marine sediment-derived fungus Penicillium chrysogenum PJX-17, and their differences were the absolute configuration at C-7 [59].

Cytotoxic Activity
Many sorbicillinoids were screened to have cytotoxic activities, which are summarized in Table 5.
Sorbicillactone A (85) from a sponge-derived fungus Penicillium chrysogenum displayed anti-HIV activity. It protected human T lymphocytes (H9 cells) against the cytopathic effect of HIV-1 in the concentration range of 0.3 and 3.0 µg/mL [21]. This hybrid sorbicillinoid was considered to be a potential inhibitor to VP40 matrix protein of the Ebola virus [63].

Antioxidant Activity
Active oxygen species cause many diseases such as atherosclerosis, inflammation, ischemia-reperfusion injury, rheumatioid arthritis and central nervous diseases. Furthermore, senility, cancer initiation and progression are also believed to involve active oxygen species [64,65]. Thus, it is expected that the effective antioxidant agents may prevent the onset and development of these diseases. Some sorbicillinoids exhibited obviously antioxidant activity. The DPPH radical scavenging activity of the sorbicillinoids isolated before 2011 was well summarized [1]. After 2011, only one sorbicillinoid JBIR-124 (81) from Penicillium citrinum Sp1080624G1f01 was screened to have DPPH radical scavenging activity with IC 50 value of 30 µM [62].

Conclusions
About 90 sorbicillinoids have been isolated from terrestrial and marine ascomycetous fungi in the past few decades. Some of them exhibited promising bioactivities, especially cytotoxic, antioxidant, antimicrobial, and antiviral activities. In recent years, more and more new members of sorbicillinoids have been isolated. All these sorbicillinoids could be the rich resources of biologically active substances with significant medicinal and agricultural potential.
In most cases, biological activities, structure-activity relations, and mode of action of sorbicillinoids have been investigated based on in vitro studies or animal models. Few studies have been performed at the level of clinical trials in patients. Future studies should be emphasized on the improvement in methodological quality and warrant further clinical research on the effects of these compounds. The applications of sorbicillinoids as antitumor agents, antimicrobials, antivirus agents and antioxidants, as well as their underlying bioactivities, have led to considerable interest within the pharmaceutical community and health-care industry. With a good understanding of the biosynthetic pathways of some sorbicillinoids, we can not only increase outputs of the bioactive sorbicillinoids but also block biosynthesis of some harmful sorbicillinoids by specific interferences.