Total synthesis and biological evaluation of halipeptins A and D and analogues.
The marine-derived halipeptins A (1a) and D (1d) and their analogues 3a, 3d and 4a, 4d were synthesized starting from building blocks 10, 13, 14a or 14d, 15, and 16. The first strategy for assembling the building blocks, involving a macrolactamization reaction to form the 16-membered ring hydroxy thioamide 52d as a precursor, furnished the epi-isoleucine analogue (4d) of halipeptin D, whereas a second approach involving thiazoline formation prior to macrolactamization led to a mixture of halipeptins A (1a) and D (1d) and their analogues 3a, 3d (epimers at the indicated site) and 4a, 4d (epimers at the indicated site). The same route starting with D-Ala resulted in the exclusive formation of the epimeric halipeptin D analogue 3d. The synthesized halipeptins, together with the previously constructed oxazoline analogues 5d and 6d, were subjected to biological evaluation revealing anti-inflammatory properties for 1a, 1d, and 6d while being noncytotoxic against human colon cancer cells (HCT-116).
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA. kcn@scripps.edu
K C
KC
Nicolaou
Dimitrios E
DE
Lizos
David W
DW
Kim
Daniel
D
Schlawe
Rita G
RG
de Noronha
Deborah A
DA
Longbottom
Manuela
M
Rodriquez
Mariarosaria
M
Bucci
Giuseppe
G
Cirino
D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D047630:Depsipeptides; C444504:halipeptin A; C444503:halipeptin B