Verruculogens

Total synthesis of fumitremorgins and verruculogens, tremorgenic my cotoxins— pentacyclic systems with (3-carboline fragments 97H(46)673. 

Streptoverticillium album K-25l/ the antitumoral bis-indole alkaloids vinblastine and vincristine/ verruculogen, a very potent mycotoxin produced by several Penicillium species and melatonin, a hormone found in all living creatures from algae to humans, just to mention the most important ones. 

The structural and biological diversity of naturally occurring endoperoxides is further illustrated by the antimalarial cardamom peroxide (7) containing a 7-membered ring cyclic peroxide moiety , and by the tremorgenic verruculogen (8) containing an 8-membered endoperoxide system (Chart 1) . 

The indolyl diketopieprazine family of natural products includes the fu-mitremorgins, verruculogens, and cyclotryprostatins 68. A solid-phase syn-... 

A further common source of fumitremorgin B and verruculogen has been found in Penicillium piscarium, isolated from ryegrass.30... 

Fumitremorgen B, cyclopiamine B, and a compound designated TR 2 (25) have been shown to occur in Aspergillus caespitosus Raper et Thom. 25 of these, cyclopiamine B has not previously been isolated from an Aspergillus species, and TR 2 was known only as a hydrogenation product of verruculogen. 

Convulsive compounds, verruculogen and penitrems, were produced by the isolates P. simplicissimum MF-24 and P. simplicissimum ATCC 90288, respectively, indicating that our convenient bioassay system with silkworms could be used to search for convulsive compounds. Novel convulsive compounds, brasiliamides A, B, C, D, and E, were found in the cultural media of Penicillium brasilianum JV-379. 

Verruculogen-related compounds are summarized in Fig. (14). In 1982, Uramoto and coworkers reported the isolation and structural elucidation of acetoxyverruculogen (84) from P. verruculosum as a tremorgenic metabolite [58]. 

As mentioned earlier, P. simplicissimum ATCC 90288 produced insecticidal okaramines. Moreover, this strain induced the same effect on the silkworms as verruculogen (83). The acetone extract obtained from the mycelia and media of this strain was concentrated and the aqueous residue was extracted with dichloromethane. The dichloromethane extract was partitioned between hexane and methanol, containing 10% water. The activity was found only in the lower layer. The active ethyl acetate extract obtained from the lower layer was chromatographed on silica gel with a hexane-ethyl acetate mixture. The 40-60% ethyl acetate eluates were rechromatographed on silica gel with a hexane-chloroform mixture. HPLC of the active 90-100% chloroform eluates on a Capcell pack Ci8 column, using 65.7% aqueous methanol with a flow rate of 1.0 ml/min, yielded two active compounds, AC 1 and AC 2. 

The convulsive effect induced by penitrem A (96), 6-bromopenitrem E (98), or verruculogen (83) in silkworms suggested that this bioassay using silkworms may be valuable as an initial screening in the search for compounds that act on the nervous system. Further random screening using this bioassay resulted in the finding that the isolate Penicilium... 

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