Water-Soluble Glutamic Acid Derivatives Produced in Culture by Penicillium solitum IS1-A from King George Island, Maritime Antarctica

Abstract

A new method of screening was developed to generate 770 organic and water-soluble fractions from extracts of nine species of marine sponges, from the growth media of 18 species of marine-derived fungi, and from the growth media of 13 species of endophytic fungi. The screening results indicated that water-soluble fractions displayed significant bioactivity in cytotoxic, antibiotic, anti-Leishmania, anti-Trypanosoma cruzi, and inhibition of proteasome assays. Purification of water-soluble fractions from the growth medium of Penicillium solitum IS1-A provided the new glutamic acid derivatives solitumine A (1), solitumine B (2), and solitumidines A−D (3−6). The structures of compounds 1−6 have been established by analysis of spectroscopic data, chemical derivatizations, and vibrational circular dichroism calculations. Although no biological activity could be observed for compounds 1−6, the new structures reported for 1−6 indicate that the investigation of water-soluble natural products represents a relevant strategy in finding new secondary metabolites.

Chemical Constituents of the Deep-Sea-Derived Penicillium solitum

“…The 1 H and 13 C NMR spectroscopic data, by the aide of the HSQC and 1 H– 1 H COSY spectra, showed characteristics of a 1,2-disubsituted benzoic unit [ δ H 7.19 (t, J = 7.8 Hz, H-5), 7.60 (t, J = 7.8 Hz, H-6), 8.04 (t, J = 7.8 Hz, H-4), 8.54 (t, J = 7.8 Hz, H-7); δ C 120.1 (d, C-7), 122.6 (s, C-7a), 122.8 (d, C-5), 131.4 (d, C-4), 134.5 (d, C-6), 139.9 (s, C-3a)], an isoprene [ δ H 1.32 (s × 2, C-11, 12), 5.25 (d, J = 17.4 Hz, H-10a), 5.29 (d, J = 10.6 Hz, H-10b),6.08 (d, J = 17.4, 10.6 Hz); δ C 24.5 (q × 2, C-11, 12), 46.2 (s, C-8), 114.6 (t, C-10), 142.4 (d, C-9)], glutamic acid [ δ H 1.77−1.95 (m, H 2 -18), 2.23 (m, H 2 -17), 3.19 (m, H-19); δ C 27.0 (t, C-18), 31.8 (t, C-17), 53.7 (d, C-19), 169.6 (s, C-20), 172.1 (s, C-16)], β -aminopropanone [ δ H 3.22 (t, J = 6.6 Hz, H 2 -13), 3.37 (m, H 2 -14), 8.16 (t, J = 4.9 Hz, H-15); δ C 34.6 (t, C-14), 39.3 (t, C-13), 203.2 (s, C-3)], and one acylamide [ δ H 11.5 (s, H-1); δ C 174.8 (s, C-2)]. These five fragments could be connected by the HMBC correlations of H 3 -11/H 3 -12 to C-2, H-1 to C-2/C-3a/C-7/C-7a, H 2 -4 to C-3, and H-14 to C-16 to construct the planar structure of 2 ( Figure 4 ), the same as solitumidine D [ 10 ], namely 4 , which was simultaneously obtained along with 2 by HPLC using the A4-5 chiral column. Since the specific optical rotation of 2 was +6, opposite to that of 4 (−7) in the same concentration of MeOH ( c 0.10), 2 was then deduced to be the enantiomer of 4 .…”

“…Compound 3 presented its molecular formula asC 21 H 28 N 2 O 4 by the positive HRESIMS at m/z 395.1947 [M + Na] + . The 1 H and 13 C NMR spectra consisted of signals almost the same as those of solitumidine B [ 10 ] except for an additional methoxyl unit. This was confirmed by the HMBC correlation of 20-OMe ( δ H 3.73, s) to C-20 ( δ C 176.0, s).…”

“…Chemical investigation of this fungus provided a broad spectrum of secondary metabolites, including compactin (known as mevastatin or ML-236B, which is utilized for the production of an important cholesterol-lowering drug, pravastatin) [ 7 ] and its analogues [ 8 , 9 ], in addition to sesquiterpenoids [ 5 ], alkaloids [ 10 ], and polyketides etc. [ 11 ].…”

“…As a result, three new ( 1 – 3 ) and 22 known ( 4 – 25 ) compounds ( Figure 1 ) were obtained. By comparison of the NMR and MS data with those published in the literature, the known compounds were determined to be (−)-solitumidines D ( 4 ) [ 10 ], ML-236A ( 5 ) [ 13 ], solitumidine A ( 6 ) [ 10 ], methyl-2-([2-(1H-indol-3-yl)-ethyl]carbamoyl)acetate ( 7 ) [ 14 ], solitumine A ( 8 ) [ 10 ], indole-3-acetic acid methyl ester ( 9 ) [ 15 ], penicopeptide A ( 10 ) [ 16 ], (2′ S )-7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone ( 11 ) [ 17 ], hydroxypropan-2′,3′-diol orsellinate ( 12 ) [ 18 ], viridicatol ( 13 ) [ 19 ], viridicatin ( 14 ) [ 19 ], (−)-cyclopenol ( 15 ) [ 20 ], cyclopenin ( 16 ) [ 21 ], 3-benzylidene-3,4-dihydro-4-methyl-1 H -1,4-benzodiazepine-2,5-dione ( 17 ) [ 16 ], β -sitosterol-3- O - β - d -glucopyranoside ( 18 ) [ 22 ], cerebrosides C ( 19 ) [ 23 ], methyl-2,4-dihydroxy-3,5,6-trimethylbenzoate ( 20 ) [ 24 ], felinone A ( 21 ) [ 25 ], xylariphilone ( 22 ) [ 26 ], 5,6-dihydroxy-2,3,6-trimethylcyclohex-2-enone ( 23 ) [ 27 ], ( R )-mevalonolactone ( 24 ) [ 28 ], and 3-methyl-2-penten-5-olide ( 25 ) [ 29 ]. Here, we report the isolation, structure, and bioactivities of these 25 compounds.…”

Vibrational Circular Dichroism for the Assignment of Absolute Configuration of Natural Products in Brazil

“…In this section, we will present a list of natural products and related compounds studied by Brazilian researchers (Table S1), which had their absolute configuration assigned using VCD spectroscopy and DFT calculations, associated or not with other techniques (Batista Jr et al 2011b;2013;2015b;Batista et al 2019;Caldas et al 2020;Caleffi et al 2019;Canzi et al 2018;Covington et al 2016;Demarque and Merten 2017;Felippe et al 2012;Gimenes et al 2019;Joseph-Nathan et al 2010;Lianza et al 2020;Londero et al 2021;Medina et al 2019;Morais et al 2020;Ortega et al 2017;Ortega et al 2018;Ortega et al 2019;Queiroz et al 2019;Rodriguez et al 2020;Santos Jr et al 2014;Scatena et al 2017;Socolsky et al 2012;Souza et al 2019;Teodoro et al, 2018a;2018b). Some selected examples will be discussed in detail below.…”