Desmethoxymajusculamide C, a cyanobacterial depsipeptide with potent cytotoxicity in both cyclic and ring-opened forms.
Cytotoxicity-guided fractionation of the organic extract from a Fijian Lyngbya majuscula led to the discovery of desmethoxymajusculamide C (DMMC) as the active metabolite. Spectroscopic analysis including 1D and 2D NMR, MS/MS, and chemical degradation and derivatization protocols were used to assign the planar structure and stereoconfiguration of this new cyclic depsipeptide. DMMC demonstrated potent and selective anti-solid tumor activity with an IC(50) = 20 nM against the HCT-116 human colon carcinoma cell line via disruption of cellular microfilament networks. A linear form of DMMC was generated by base hydrolysis, and the amino acid sequence was confirmed by mass spectrometry. Linearized DMMC was also evaluated in the biological assays and found to maintain potent actin depolymerization characteristics while displaying solid tumor selectivity equivalent to DMMC in the disk diffusion assay. A clonogenic assay assessing cytotoxicity to HCT-116 cells as a function of exposure duration showed that greater than 24 h of constant drug treatment was required to yield significant cell killing. Therapeutic studies with HCT-116 bearing SCID mice demonstrated efficacy at the highest dose used (%T/C = 60% at 0.62 mg/kg daily for 5 days).
Simmons
T Luke
TL
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92037, USA.
Nogle
Lisa M
LM
Media
Joseph
J
Valeriote
Frederick A
FA
Mooberry
Susan L
SL
Gerwick
William H
WH
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000458:Cyanobacteria / Q000737:chemistry*; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005367:Fiji; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047630:Depsipeptides; C542046:desmethoxymajusculamide C