Oroidin-family

From a taxonomic perspective, the agelastatins belong to the Oroidin family of alkaloids, and two chemically distinct pathways have been suggested for their biogenesis by the groups of Pietra and Potier. In Pietra s proposal (Scheme 2), (-)-agelastatin A derives from an enzyme mediated nucleophilic addition of the C(7)-C(8) alkene in 1 onto one of the tethered imidazolinone carbonyl groups. 

D Ambrosio, M., Guerriero, A., Debitus, C., Ribes, O., Pusset, J., Leroy, S., Pietra, F., (1993). Agelastatin A, a new skeleton eytotoxic alkaloid of the oroidin family. Isolation from the axinellid sponge Agelas dendromorpha of the Coral Sea. J. Chem. Soc. Chem. Comm. 16, 1305-1306. 

This class of compounds is extensively described in Chapter 10. Oroidin (64) is considered the precursor in the elaboration of polycyclic CjjNs oroidin derivatives isolated from sponges belonging to the Axinellidae and Agelasidae families. These include the antiangiogenic compounds agelastatin A (65) and ageladine A (70). 

Phakellins (41, 42), tetracyclic derivatives in which both the pyrrole and the amidic nitrogen atoms are involved in the formation of a linkage with carbon atoms of the imidazole ring, represented the first members of the family of oroidin-related cyclic bromopyrrole alkaloids to be isolated. They were found in 1971 by Sharma et al. in the marine sponge Phakelliaflabellata their structure was confirmed by X-ray diffraction analysis of a single crystal of the monoacetyl derivative of 41 [70]. Complete spectral data were provided by the same authors a few years later [71]. 

This class includes only agelastatins A-D (60-65), a family of tetracyclic oroidin derivatives isolated from Agelas dendromorpha [92,93] and Cymbastela sp. [94]. The absolute configuration of these molecules was deduced through the application of exciton-coupling techniques [93]. 

The first examples of tetrameric pyrrole imidazole alkaloids, stylissadine A (100) and B, were isolated from the Caribbean sponge Stylissa carihica in 2006 [128]. They possess a symmetric dimeric stmcture derived from condensation of two massadine units, and differ in the configuration at the center C-2. Stylissadines represent the largest pyrrole-imidazole alkaloids isolated so far, and, with their 16 stereogenic centers, they are the most complex stmctures known within the oroidin alkaloid family. 

Bromination of the pyrrole 4-position or of the imidazole part has never been observed. A great molecular diversity is observed in this group of alkaloids extremely varied chemical architectures are reported, ranging from linear oroidin-like monomers to complex polyciclic and tetrameric molecules. In this chapter illustrative structures of this alkaloids family are reported, divided into the following groups ... 

Pyrrole 2-aminoimidazole alkaloids (PIAs) represent one of the most important groups of sponge secondary metabolites which show a large panel of biological activities [308]. Marine sponges, specifically the Agelasidae and Leucetta families, are the primary sources of structurally diverse secondary metabolites containing a 2-aminoimidazole functionality. Oroidin, isolated in 1971 by Forenza et al., was the first discovered member of this alkaloid family, and since then nearly 150 additional natural products have been isolated [309, 310]. 

In Fig. 9.7 are displayed acyclic and cyclic dimeric members of the pyrrole-imidazole family. Nagelamide D, from Okinawan marine sponges of the genus Agelas, is a dimer comprised of oroidin monomer units connected between the C-10 and C-15 positions [80]. However, the assigned structure of this substance is questionable (see below). Sceptrin, isolated in 1981 by Faulkner and Clardy from Agelas sceptrum, is the first reported symmetric dimer comprised of hymenidin subunits [81]. 

Vhh conplings together with chemical shifts have been calcnlated by Chini et al for kedarcidin chromofore and palau amine in the attempt to establish the correct configuration of these two compoimds prior to their total synthesis. Kedarcidin chromofore is a compoimd that belongs to the enediyne family of antitumor antibiotics, whereas palau amine is an oroidin dimer, belonging to the class of pyrrole-imidazole alkaloid family isolated from the sponge Stylotella aurantiwn. Populations of conformers in three cinchona alkaloid O-ethers at ambient and low temperatnres have been estimated by Bnsygin et al ... 

Although the number of studies using (radio) labeled substrates in an attempt to confirm the generation of these PIAs in nature is limited, numerous biosynthetic hypotheses occupy the chemical/synthetic literature [34, 35]. These proposals represent all levels of the complexity spectrum for this family, from simple cyclic compounds derived from an oroidin monomer to those that result from dimerization of oroidin and further cyclizations. To prevent this chapter from occupying the whole book, only two examples will be presented in this subsection to serve as a general overview. 

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