Structure Determinants of Lagunamide A for Anticancer Activity and Its Molecular Mechanism of Mitochondrial Apoptosis

Abstract

Marine natural products are served as attractive source of anticancer therapeutics, with the great success of "first-in-class" drugs, such as Yondelis, Halaven, and Brentuximab vendotin. Lagunamides A-C from marine cyanobacterium, Lyngbya majuscula, exhibit exquisite growth inhibitory activities against cancer cells. In this study, we have systematically investigated the structure-activity relationships (SARs) of a concise collection of lagunamide A and its analogues constructed by total chemical synthesis against a broad panel of cancer cells derived from various tissues or organs, including A549, HeLa, U2OS, HepG2, BEL-7404, BGC-823, HCT116, MCF-7, HL-60, and A375. The R configuration of lagunamide A at C-39 position was found to be the structure determinant for anticancer activity. Further molecular mechanism study in A549 cells revealed that lagunamide A induced caspase-mediated mitochondrial apoptosis. Accompanied with the dissipation of mitochondrial membrane potential (Δφm) and overproduction of reactive oxygen species (ROS), lagunamide A led to mitochondrial dysfunction and finally caused cell death. Moreover, both anti- and pro-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins participated in lagunamide A-induced mitochondrial apoptosis, especially myeloid cell leukemia-1 (Mcl-1). Overexpression of Mcl-1 partly rescued A549 cells from lagunamide A-induced apoptosis. This study suggests that lagunamide A may exert anticancer property through mitochondrial apoptosis. Together, our findings would provide insightful information for the design of new anticancer drugs derived from lagunamides.

Isolation, Structure Elucidation and Biological Evaluation of Lagunamide D: A New Cytotoxic Macrocyclic Depsipeptide from Marine Cyanobacteria

“…Similar to other analogues in this compound family (data was reported for aurilide [18], aurilide B [24], and lagunamide A [25,26]), lagunamide D and D’ were also demonstrated to trigger the apoptosis pathway (Figure 6). Both compounds possess the ability to rapidly induce apoptosis, evidenced by the activation of caspase 3/7 after only 6 h of treatment.…”

Synthesis and structure revision of symplocin A

“…Inversion of the carbinol center in 14 was straight-forward through Swern oxidation 20 followed by reduction (NaBH 4 , MeOH) to afford (2 S , 3 S )- 14 (67%, two steps). 8c Hydrolysis of (2 S , 3 S )- 14 (LiOH•H 2 O, H 2 O 2 ) gave ring-opened (3 S , 4 S )- 7 in quantitative yield. Following the synthetic sequences described above, diastereomeric (26S, 50 S , 51 S )-symplocin A ( 3c ) {[α] D 21.1 +27.6 ( c 1.00, MeOH)} was obtained in 7% overall yield from (3 S ,4 S )- 7 .…”

“…As a continuation of our interest in developing divergent syntheses of natural products 8 isolated from cyanobacteria and investigating their structure-activity relationships, together with unusual features of the structure, we decided to develop an asymmetric synthesis of symplocin A. Herein, we present the synthesis of symplocin A, along with those of two non-natural diastereomers, and a stereochemical revision of the natural product.…”

Natural Cyclopeptides as Anticancer Agents in the Last 20 Years

“…Lagunamides A-C (152-154) were cyclic depsipeptides isolated from L. majuscula with anti-proliferative effects against several cancer cell lines [228]. Tripathi et al assessed the inhibitory activities of lagunamides A against the cancer cell lines P388, A549, PC3, HCT8 (human colorectal adenocarcinoma) as well as the SK-OV3 cells.…”