Prenylated indole alkaloids containing the bicyclo-[2.2.2]diazaoctane ring system as a core structure, now number more than 38 family members. These natural substances, produced by various genera of fungi, in particular Aspergillus and Penicillium spp. (among others), exhibit a range of interesting structural and stereochemical features. Significantly, a myriad of biological activities, including insecticidal, antitumor, anthelmintic, calmodulin inhibitory, and antibacterial properties, are displayed by members of this family. Structurally, these substances arise from the oxidative condensation of one or two isoprene units, tryptophan, and another cyclic amino acid residue such as proline, b-methylproline, or pipecolic acid. With respect to the relative stereochemistry within the core bicyclo[2.2.2]diazaoctane ring system, all of the known members of the paraherquamide family, for example, paraherquamides (1 and 2), stephacidins (3 and 4), and notoamides (5 and 6) possess a syn configuration, while only the brevianamides (9 and 10) possess the anti relative configuration (Scheme 1). The syn/anti relationship refers to the relative configuration between the C19ÀC22 bond (sclerotiamide numbering) and the C17ÀN13 bond of the cyclic amino acid residue (proline, b-methylproline, or pipecolic acid; Scheme 2). This relationship reveals that to construct the core ring system biosynthetically in the oxidative cyclization process(es) both faces of the isoprene-derived dienophile participate in the ring-forming process. However, Scheme 1. Structures of several members of the paraherquamide/ stephacidin/brevianamide family of prenylated indole alkaloids.

Bioactivities of 42 didemnin congeners, either isolated from the marine tunicates Trididemnun solidum and Aplidium albicans or prepared synthetically and semisynthetically, have been compared. The growth inhibition of various murine and human tumor cells and plaque reduction of HSV-1 and VSV grown on cultured mammalian cells were used to assess cytotoxicity and antiviral activity. Biochemical assays for macromolecular synthesis (protein, DNA, and RNA) and enzyme inhibition (dihydrofolate reductase, thymidylate synthase, DNA polymerase, RNA polymerase, and topoisomerases I and II) were also performed to specify the mechanisms of action of each analogue. Immunosuppressive activity of the didemnins was determined using a mixed lymphocyte reaction (MLR) assay. These assays revealed that the native cyclic depsipeptide core is an essential structural requirement for most of the bioactivites of the didemnins, especially for cytotoxicities and antiviral activities. The linear side-chain portion of the peptide can be altered with a gain, in some cases, of bioactivities. In particular, dehydrodidemnin B, tested against several types of tumor cells and in in vivo studies in mice, as well as didemnin M, tested for the mixed lymphocyte reaction and graft vs host reaction in murine systems, showed remarkable gains in their in vitro and in vivo activities compared to didemnin B.

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