Synthesis of Phidianidine B, a highly cytotoxic 1,2,4-oxadiazole marine metabolite

Abstract

Phidianidine B (1), a natural 1,2,4-oxadiazole linking both an indole system and an aminoalkyl guanidine group that has been recently reported from a marine mollusk, has been synthesized in seven steps (14% total yield). The synthetic procedure, which is based on the coupling of 3-indolacetic acid methyl ester and the amino-alkyl hydroxy guanidine intermediate 2, opportunely prepared, is of general application and allows the synthesis of analogues with either different alkyl chain length or substitution on the indole ring.

Bioactive Compounds from Marine Heterobranchs

“…Phidianidines A ( 257 ) and B are bromoindole alkaloids from the Chinese slug Phidiana militaris [ 361 , 592 ]. Phidianidines ( 257 ) are the only known marine source of the 1,2,4-oxadiazole system, and their interesting structure promoted their synthesis, as well as that of several analogues [ 593 , 594 , 595 , 596 , 597 , 598 , 599 , 600 , 601 , 602 , 603 , 604 , 605 ]. Phidianidines ( 257 ) show cytotoxicity against several cell lines, such as C6 and HeLa tumor cells at nanomolar concentrations [ 592 ].…”

Marine natural products

“…915 Also conrmed by synthesis are the structures of the 1,2,4oxadiazole ring-containing alkaloids phidianidine A and B (Phidiana militaris). [916][917][918] In addition to a number of known PUFAs, heneicosa-5,8,11,14-tetraenoic acid (21;4 n-7) was reported as a new natural product from the opistobranch mollusc Scaphander lignarius (Arctic). 919 Mild, non-specic cytotoxicity was observed.…”

Natural Products with Heteroatom-Rich Ring Systems

“…Coupling of indole-3-acetic acid precursors ( 20a and b ) with alkyl bisguanidine 21 followed by oxidation would afford intermediate hydroxyguanidines 22 , which upon cyclodehydration forms phidianidines A ( 18 ) and B ( 19 ) . This biosynthesis was validated through three biomimetic syntheses of 18 and 19 . − …”