Chemical and Biological Study of Novel Aplysiatoxin Derivatives from the Marine Cyanobacterium Lyngbya sp.

Abstract

Since 1970s, aplysiatoxins (ATXs), a class of biologically active dermatoxins, were identified from the marine mollusk Stylocheilus longicauda, whilst further research indicated that ATXs were originally metabolized by cyanobacteria. So far, there have been 45 aplysiatoxin derivatives discovered from marine cyanobacteria with various geographies. Recently, we isolated two neo-debromoaplysiatoxins, neo-debromoaplysiatoxin G (1) and neo-debromoaplysiatoxin H (2) from the cyanobacterium Lyngbya sp. collected from the South China Sea. The freeze-dried cyanobacterium was extracted with liquid–liquid extraction of organic solvents, and then was subjected to multiple chromatographies to yield neo-debromoaplysiatoxin G (1) (3.6 mg) and neo-debromoaplysiatoxin H (2) (4.3 mg). They were elucidated with spectroscopic methods. Moreover, the brine shrimp toxicity of the aplysiatoxin derivatives representing differential structural classifications indicated that the debromoaplysiatoxin was the most toxic compound (half inhibitory concentration (IC50) value = 0.34 ± 0.036 µM). While neo-aplysiatoxins (neo-ATXs) did not exhibit apparent brine shrimp toxicity, but showed potent blocking action against potassium channel Kv1.5, likewise, compounds 1 and 2 with IC50 values of 1.79 ± 0.22 µM and 1.46 ± 0.14 µM, respectively. Therefore, much of the current knowledge suggests the ATXs with different structure modifications may modulate multiple cellular signaling processes in animal systems leading to the harmful effects on public health.

Marine natural products

“…115 A total of 45 aplysiatoxin derivatives had been reported from marine cyanobacteria prior to 2020. 116 Recent additions to this polyketide structure class include neo-debromoaplysiatoxins G 290 and H 291 from a Lyngbya species, that block the Kv1.5 channel, with IC 50 values of 1.8 and 1.5 mM respectively, 116 and neo-aplysiatoxin A 292 from Moorea producens. 117 In addition, neo-debromoaplysiatoxin C 293 from Lyngbya sp.…”

Structure Elucidation of Two Intriguing Neo-Debromoaplysiatoxin Derivatives from Marine Cyanobacterium Lyngbya sp. Showing Strong Inhibition of Kv1.5 Potassium Channel and Differential Cytotoxicity

“…Aplysiatoxins (ATXs) are polyketides existing in cyanobacteria with anti-proliferative, antiviral, pro-inflammatory and Kv1.5 K + channel inhibition properties [ 7 , 8 , 9 , 10 ]. Up to now, there have been about 55 aplysiatoxins isolated from cyanobacteria [ 11 , 12 , 13 , 14 ]. Based on structural skeletons, we classified them into four categories: 6/12/6 fused ring system featuring a macrolactone ring; spirobicyclic system; linear structure; and some neo-ATXs displaying uncommon carbon skeletons.…”

“…Several ATXs were found to be activators of protein kinase C (PKC) [ 15 , 16 ], a vital therapeutic target for cancers [ 17 ], such as debromoaplysiatoxin (DAT) and 3-deoxy-DAT, probably owing to the dihydroxyvaleryl moiety in their structures, namely a recognition domain interacting with the PKC δ C1B domain in the form of hydrogen bonds [ 18 ]. In our previous studies, the inhibitory activity on the shaker-related subfamily of voltage-gated channels (Kv1.1–Kv1.5) was investigated, and potential drug targets for the treatment of diverse disease processes, ranging from cancer to autoimmune diseases to metabolic, neurological and cardiovascular disorders [ 19 ], of ATXs were tested, and it turned out several ATXs had selective and strong blocking inhibitory effects on the Kv1.5 K + channel [ 10 , 11 , 12 , 20 , 21 , 22 ]. Among them, neo-debromoaplysiatoxin B (Neo-B) and oscillatoxin E displayed the strongest Kv1.5 inhibition activities with IC 50 values of 0.3 μM and 0.79 μM respectively.…”

Collective Synthesis of Aplysiatoxin/Oscillatoxin Analogues by a Bioinspired Strategy

“…Recently, many new analogues of ATX/OTX incorporating ring structures different from those in ATX and OTX-D were isolated from cyanobacteria by Nagai and Han (Figure ). Intriguing preliminary biological activities have been reported for these analogues, including toxicity toward brine shrimp and cancer cells, and inhibition of the potassium channel Kv1.5 . However, the minute quantities in which they are available from the cyanobacteria preclude their detailed biological evaluation.…”