ABSTRACT
Lagunamide C (1) is a cytotoxic cyclodepsipeptide isolated from the marine cyanobacterium, Lyngbya majuscula, from the western lagoon of Pulau Hantu Besar, Singapore. The complete structural characterization of the molecule was achieved by extensive NMR spectroscopic analysis as well as chemical manipulations. Several methods, including the advanced Marfey's method, a modified method based on derivatization with Mosher's reagents and analysis using LC-MS, and the use of (3)J(H-H) coupling constant values, were utilized for the determination of its absolute configuration. Compound 1 is related to the aurilide-class of molecules and it differs mainly in the macrocyclic structure by having a 27 membered ring system due to additional methylene carbon in the polyketide moiety. Lagunamide C displayed potent cytotoxic activity against a panel of cancer cell lines, such as P388, A549, PC3, HCT8, and SK-OV3 cell lines, with IC(50) values ranging from 2.1 nM to 24.4 nM. Compound 1 also displayed significant antimalarial activity with IC(50) value of 0.29 µM when tested against Plasmodium falciparum. In addition, lagunamide C exhibited weak anti-swarming activity when tested at 100 ppm against the Gram-negative bacterial strain, Pseudomonas aeruginosa PA01.
Subject(s)
Cyanobacteria/chemistry , Depsipeptides/chemistry , Lyngbya Toxins/chemistry , Cell Line, Tumor , Depsipeptides/isolation & purification , Depsipeptides/pharmacology , Humans , Lyngbya Toxins/isolation & purification , Lyngbya Toxins/pharmacology , Microbial Sensitivity Tests , Plasmodium falciparum/drug effects , Pseudomonas aeruginosa/drug effectsABSTRACT
Synthetic efforts culminating the construction of several highly advanced intermediates, and completed syntheses of the recently disclosed cortistatin family of anti-proliferative agents are described in this perspective.
Subject(s)
Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Neuropeptides/chemistry , Neuropeptides/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Humans , Neuropeptides/chemical synthesisABSTRACT
The spirocyclic core of the siphonarins was constructed by a directed cyclization of a linear triketone, prepared using a Sn(II)-mediated aldol coupling and Swern oxidation at C9 and C13. To circumvent a facile retro-Claisen pathway generating a baconipyrone-type ester, a Ni(II)/ Cr(II)-mediated coupling reaction with vinyl iodide was used to complete the first synthesis of siphonarin B and dihydrosiphonarin B. A stable isomeric spiroacetal was also prepared which could not be equilibrated to the siphonarin skeleton.
