Salfredins, New Aldose Reductase Inhibitors Produced by Crucibulum sp. RF-3817. I. Fermentation, Isolation and Structures of Salfredins.

Abstract

New inhibitors of aldose reductase, designated salfredins A3, A4, A7, Cl5 C2, C3 and Bll5 were isolated from the fermentation broth of Crucibulum sp. RF-3817 by successive purification procedures of solvent extraction, silica gel column chromatographies and reverse-phase HPLC.Their structures were established by spectroscopic methods, including UV, SI-MS and NMR. The structures of salfredins A4 and B1 ]L were confirmed by X-ray crystallographic analysis.Aldose reductase (Alditol:NADP+ oxidoreductase, EC1.1.1.21) plays a key role in the "polyol pathway", and inhibition of this enzyme represents a new pharmacological approach towards the treatment of certain chronic complications of diabetes mellitus1~3).In a screening program for unique microbial products with pharmacological activity, new aldose reductase inhibitors4' 5), designated as salfredins A3 (la), A4 (2a), A7 (3a), Ci (4a), C2 (5a), C3 (6a) and B1X (7a), were isolated from the fermentation broth of Crucibulum sp. RF-3817. The taxonomy, fermentation, isolation, physico-chemical properties and structures of salfredin congeners are described in this paper. Their biological properties will be reported in a following paper (in preparation). TaxonomyThe strain RF-3817 was isolated as follows. First, peridioles within the peridium formed on a rotten wood block were immersed in a solution of sodium hypochlorite for one minute to sterilize the surface of the peridioles. Next, the peridioles were washed with sterile water and the basidiospores formed within the peridioles were placed on an appropriate mediumto isolate the strain. On the hyphae of the strain grown on the medium,clamp connections were observed, the width of each hypha being 1 to 5/mi. The peridium of the strain formed on the rotten wood block is pyriform, 5 to 8mm in height, 4 to 6mm in diameter, and has an ocher color. In the upper portion of the peridium, there is an epiphragm having a pale yellowish-white color, which will dehisce when matured.Within the peridium are lenticular peridioles. The peridioles, 1 to 1.5mm in size, are attached by funiculi to the inner wall of the peridium. Within the peridioles, basidiospores, 3 to 5 by 7 to 10fim, are formed. These properties were compared with the characteristics of other genera belonging to the order Nidulariales,

Polyketide Skeletons from the Marine Alga‐Derived Fungus Coniothyrium cereale

“…[11] However, these compounds have a significantly different substitution pattern in comparison to conioimide, revealing a divergent biosynthetic background. The aromatic ring in 1 is substituted with a methyl group at C-11 and a hydroxy group at C-9, whereas reported isoindoles like marilines, [12] salfredins C1-C3, [13] spirodihydrobenzofuranlactam V, [11] zinnimide, [14] and aspernidine A [15] have a methyl group or a terpene substituent at the respective carbon atom C-10 and oxygen-containing functional groups at C-9 and C-11 (see Figure S12). In the latter cases, the compounds are clearly derived from an orsellinic acid or 3methylorsellinic acid precursor (see Figure S13, Supporting Information), all having the same substitution pattern, which upon further modification yields phthalides and phthalimidines.…”

“…The resonances for 1-H 2 also showed correlations to carbonyl carbon atom C-14, thus, clarifying the C-14 to C-19 part of the molecule. Unfortunately, no correlation was observed from 1-H 2 to any carbon atom of the aromatic ring, even after optimizing the delay time, for example, for a heteronuclear coupling constant of 4 Hz, in the 1 H- 13 fore, the dimethylpentenoyl moiety may either be attached to C-13 with the imide ring at C-4 and C-8 (as in Figure 1) or at C-8 and C-9 (candidate structure 1b in Figure 3). These correlations indicate the position of methyl group CH 3 -12, but do not firmly establish the positions of the dimethylpentenoyl side chain and the imide ring.…”

“…Four further resonance signals arose from two aryl CH groups (δ H = 6.99 ppm and δ C = 108.6 ppm for CH-8 and δ H = 6.97 ppm and δ C = 124.6 ppm for CH-10) and two aliphatic CH groups (δ H = 3.55 ppm and δ C = 60.7 ppm for CH-1 and δ H = 4.24 ppm and δ C = 87.5 ppm for CH-15). Labeling experiments with 1-13 C enriched acetate showed 13 C enrichment at C-2, C-4, C-9, C-11, C-14, C-16, and C-17 of (-)-trypethelone (3). The 13 C NMR spectrum (see Table 2) showed a resonance for one oxygenated aromatic sp 2hybridized methine carbon atom at δ C = 160.9 ppm (C-9) whose position was confirmed by the HMBC correlations with 8-H and 10-H. An interesting 13 C NMR resonance was detected at δ C = 113.3 ppm and accounted for the quaternary sp 3 -hybridized carbon atom C-14.…”

“…[20,21] The suggested precursor (-)-trypetholone (3), which we recently described from this fungus, [9] is the enantiomer of the trypethelone reported by Steglich. [22] Labeling experiments with 1-13 C enriched acetate in our laboratory yielded this major metabolite and showed 13 C enrichment at C-2, C-4, C-9, C-11, C-14, C-16, and C-17 (see Figure S14, Supporting Information). From these results it is clear that compound 3 is a hexaketide with the final C 2 building block being truncated, leaving only one carbon atom, that is, C-3 of 3, in the molecule (see Figures 1 and 5).…”

Atom-Economical Synthesis of Cyclic Imides

“…Through extensive screening with several Ru catalytic systems developed for the direct amide synthesis, 25 an in situ catalyst from readily available RuH 2 (PPh 3 ) 4 , an NHC precursor, NaH, and acetonitrile was identified as an active catalyst for the cyclic imide synthesis from diols (Scheme 9). 26 A mechanism involving the formation of an amide intermediate and further cyclization to the imide product by an intramolecular reaction of the amide intermediate was proposed, based on the previous mechanistic investigation for the direct amide synthesis using the ruthenium hydride based catalytic system (Scheme 10).…”