Citrinin Monomer, Trimer, and Tetracyclic Alkaloid Derivatives from the Hydrothermal Vent-Associated Fungus Penicillium citrinum TW132-59

Abstract

Five new unusual citrinin-derived alkaloids with a tetracyclic core, citrinidines A–E (1–5), two new amide alkaloids, methyl (2S,8E)-1′-(2-methyl-3-oxodec-8-enamido) butanoate (6) and (2S,8E)-2-methyl-3-oxodec-8-enamide (7), a new unusual citrinin trimer, tricitrinol C (8), a new citrinin acetal-ketal derivative, citrininol (9), together with four known citrinin monomers (10–13), and three known citrinin dimers (14–16), were isolated from the fermentation of hydrothermal vent-associated fungus Penicillium citrinum TW132-59. Their structures were unambiguously determined by nuclear magnetic resonance (NMR), mass spectrometry, Mosher′s method, 13C NMR calculation in combination with DP4+, and ECD calculations. A plausible biosynthetic pathway of all new compounds (1–9) was proposed. Citrinin trimer (8) exhibited potent cytotoxicity activity with an IC50 value of 1.34 ± 0.11 μM, and compounds 1 and 15 showed moderate cytotoxicity with IC50 values of 17.50 ± 1.43 and 9.45 ± 0.55 μM, respectively, against A549 cell line.

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“…Several unlikely natural product structures have been revised, largely as a result of 13 C NMR chemical shi calculations. 1 In 2020, isatindigoside F, from Isatis tinctoria, was proposed to be 1 with an antiaromatic azacyclobutane ring.…”

“…In 2017, balsamiside A, from Impatiens balsamina, was originally assigned as a biavonoid containing a 2,3-epoxide 3. 3 Comparison of calculated and experimental 13 C NMR chemical shi values has resulted in the revision of balsamiside A to the furanoid structure 4. 4 Diagnostic NMR shi values have been established and the structures of several other biavonoids have been changed.…”

“…7 Subsequent reisolation and crystal structure analysis have indicated that 12,16-dideoxyaegyptinone B should be revised to the o-quinone 8 which is identical to the previously known zhumerianone C. 8 Examination of the NMR shis of other abietane derivatives has indicated that several structures should be revised. Based on calculated 13 C NMR shis, the authors have revised the structure of clonorosin B, a metabolite of Clonostachys rosea, from 9 to 10. 9 The structure of myrionsumamide A 11, from Myrioneuron effusum, was conrmed by X-ray analysis.…”

“…The structure of podaxisterol A 22 was conrmed by X-ray analysis. Stable isotope labelling experiments with ( 15 N 4 , 13 C 6 )-L-arginine produced podaxisterols with two 15 N atoms and one 13 C atom in the nitrosyl cyanide unit. This implies that the guanidine moiety of arginine might be the source of nitrosyl cyanide that undergoes a Diels-Alder cycloaddition with ergostadiene precursors.…”

“…The hydrothermal vent-associated fungus Penicillium citrinum TW132-59 produces a range of citrinin-derived metabolites including citrinidines A 14 – E that have an unusual tetracyclic core. 13 Biosynthetic pathways to the citrinidines are proposed involving a hetero-Diels–Alder cycloaddition.…”