The Active Centres of Agelastatin A, a Strongly Cytotoxic Alkaloid of the Coral Sea Axinellid Sponge Agelas dendromorpha, as Determined by Comparative Bioassays with Semisynthetic Derivatives

✍ Scribed by Michele D'Ambrosio; Antonio Guerriero; Francesco Pietra; Marina Ripamonti; Cécile Debitus; Jean Waikedre

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: German
• Weight: 650 KB
• Volume: 79
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.19960790315

✦ Synopsis

Dedicated to Professor Mario Piattelli on the occasion of his 70th birthday (2.11.96)

Agelastatin A (l), an unusual alkaloid ofthe axinellid sponge Agelas dendromorpha from the Coral Sea, can be selectively acetylated (+ 7) or methylated at OH-C(8a) (-+ 4), peracetylated (+ 8) or permethylated at OH-C(8a), NH(5), and NH(6) (+5), or, finally, subjected to C(9)-C(8a) (+ 14) or C(Sb)-C(Sa)B-elirnination (+ 11-13), in a regiospecific manner or not, depending on the reaction conditions. Under acidic conditions, compound 12 adds H,O or MeOH, regioselectively though not endolexo stereoselectively, giving transoidlcisoid mixtures 1/18 or 4/19, respectively. Similarly 11 or 13 add MeOH to give mixtures (-)-2/20 or 15/16, respectively. Compound 13 also adds AcOH giving mixture 8/17. The intermediate cisoid form obtained on treatment of 21 with H30+ undergoes N(5)-N(6) bridging affording pentacyclic 22 which constitutes a proof for the cisoid configuration. From conformational studies, rules are devised that allow assigning the configuration of these compounds from NMR data. In vitro comparative cytotoxicity assays of these compounds show that for high cytotoxic activity, such as of 1 in vivo, unsubstituted OH-C(8a), H-N(S), H-N(6) moieties are needed in the natural B/D transoid configuration.