3.1.2. Azaphilones from *Chaetomium* Genus

*Chaetomium* is a large genus presenting more than 300 species worldwide. *Chaetomium globosum* represents one of the most studied species and is known as a rich source of azaphilones. Since the last two years, this species has still been contributing with new metabolites. The arthropod-associated endophytic fungus *C. globosum* TW1–1 was investigated considering whether the presence of 1-methyl-l-tryptophan into the growth medium would activate a biosynthetic pathway to produce novel alkaloids [37]. However, instead of nitrogenated metabolites, the authors isolated and identified two chlorinated azaphilones, chaephilone C and D (**25–26**) with anti-inflammatory activity. Their stereostructures were unequivocally confirmed by X-ray analyses. Nevertheless, chaephilone C was also previously reported from the deep sea-derived fungus *Chaetomium* sp. NA-S01-R1 with the same planar structure of **25** but with different stereochemistry, suggesting that

its structure should be revised [38]. Two months after the report of chaephilone C (**25**), a new chlorinated azaphilone from *C. globosum*, endophytic of *Polygonatum sibiricum*, was reported and also called chaephilone C (**27**) [39]. However, this latter compound displayed a chemical structure similar to (**26**), but completely different from the former (**25**).

From the wild-type strain *C. globosum*, a new dimeric azaphilone called cochliodone J (**28**) was identified in the same medium which cochliodone A had been isolated before [40]. The deep-sea *C. globosum* MP4-S01–7 provided eight new structurally correlated nitrogenated azaphilones **29–36** (Figure 3 and Table 1) [41]. The azaphilone core is the same in all compounds with differences only in the lactone acyl substituents and the N-alquil groups. Seco-chaetomugilin (**37**) was isolated for the first time from the ethyl acetate extract of *Chaetomium cupreum* in a bio-guided fractionation for activities against human breast adenocarcinoma cell lines [42]. Although the authors named the compound isolated as seco-chaetomugilin, it presented the same structure of seco-chaetomugilin D, previously isolated from *C. globosum* [43]. A screening by LC-MS/MS-GNPS data base of a strain of an endophytic plant fungus *Chaetomium* sp. g1 resulted in the isolation of chaetolactam A (**38**), a unique 9-oxa-7-azabicyclo[4.2.1]octan-8-onering system with two new compounds chaetoviridins derivatives, 11-epi-chaetomugilide B (**39**), and chaetomugilide D (**40**) [44]. Another plant endophytic fungus *C. globosum* isolated from the desert Asteraceae species, *Artemisia desterorum,* yielded globosumone (**41**), a new stereoisomer of the known chaetoviridin E [45].

**Figure 3.** Chemical structures of *Chaetomium* azaphilones: **25**: Chaephilone C (1R,7S,8R,8aR,9E,11S,4 R,5 R); **26**: chaephilone D; **27**: chaephilone C\*; **28**: cochliodone J; **29**: N-(3,7-Dimethyl-2,6-octadienyl)-2 aza-2-deoxychaetoviridin A; **30**: 4 -epi-N-(3,7-Dimethyl-2,6-octadienyl)-2-aza-2-deoxychaetoviridin A; **31**: N-(3-Methyl-2-butenyl)-2-aza-2-deoxychaetoviridin A, **32**: 4 -epi-N-(3-Methyl-2-butenyl)- 2-aza-2-deoxychaetoviridin A; **33**: N-(3,7-Dimethyl-2,6-octadienyl)-2-aza-2-deoxychaetoviridin E; **34**: N-(3-Methyl-2-butenyl)-2-aza-2-deoxychaetoviridin E; **35:** 4 ,5 -dinor-5 -Deoxy-N-(3,7-dimethyl-2,6-octadienyl)-2-aza-2- deoxychaetoviridin A; **36**: 4 ,5 -dinor-5 -Deoxy-N-(3-methyl-2-butenyl)-2 aza-2-deoxy- chaetoviridin A; **37**: seco-chaetomugilin; **38**: chaetolactam A; **39**: 11-epi-chaetomugilide B; **40**: chaetomugilide D; **41**: globusumone [37–45].
