Total Structure Determination of Apratoxin A, a Potent Novel Cytotoxin from the Marine Cyanobacterium Lyngbya majuscula

Abstract

Apratoxin A (1), a potent cytotoxin with a novel skeleton, has been isolated from the marine cyanobacterium Lyngbya majuscula Harvey ex Gomont. This cyclodepsipeptide of mixed peptide-polyketide biogenesis bears a thiazoline ring flanked by polyketide portions, one of which possesses an unusual methylation pattern. Its gross structure has been elucidated by spectral analysis, including various 2D NMR techniques. The absolute configurations of the amino acid-derived units were determined by chiral HPLC analysis of hydrolysis products. The relative stereochemistry of the new dihydroxylated fatty acid unit, 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid, was elucidated by successful application of the J-based configuration analysis originally developed for acyclic organic compounds using carbon-proton spin-coupling constants ((2,3)J(C,H)) and proton-proton spin-coupling constants ((3)J(H,H)); its absolute stereochemistry was established by Mosher analysis. The conformation of 1 in solution was mimicked by molecular modeling, employing a combination of distance geometry and restrained molecular dynamics. Apratoxin A (1) possesses IC(50) values for in vitro cytotoxicity against human tumor cell lines ranging from 0.36 to 0.52 nM; however, it was only marginally active in vivo against a colon tumor and ineffective against a mammary tumor.

Synthesis of the Biologically Active Natural Product Cyclodepsipeptides Apratoxin A and Its Analogues

“…They concluded that apratoxin A exhibits potent cytotoxicity for cancer cells, with IC 50 values of 0.52 nM against KB and 0.36 nM against LoVo cancer cells 4,5) (Fig. 1).…”

Total Structure Determination of Grassypeptolide, a New Marine Cyanobacterial Cytotoxin

“…Using a previously established molecular modeling protocol suitable for cyclodepsipeptides, 19 10 randomly drawn structures of 1 were subjected to distance geometry, 20 followed by simulated annealing and finally restrained molecular dynamics simulation for 1 ns. The modeled structures could be divided into two distinct conformational families.…”

Research Progress of Apratoxin A：A Marine Cyclicdepsipeptide with Significant Anti-cancer Activity

“…通过比 对分析, apratoxin A 的构效关系(图 4)也可从中窥得一 斑 [18,19] . [3] 0.36 [3] 1.4 [20] 10 [20] /2.2 [7] /190 [9] 10 [20] 5.97 [21] /1.21 [18] 2.5 [19] 70 21.3 [22] 10.8 [22] 71 1.0 [22] 0.73 [22] 72 2.6 [23] 73 21 [20] 72 [20] 59 [20] 184 [21] 74 4.92 [21] 2 [18] 75 14 [18] 76 3.4 [19] 77 89.9 [19] 78 37.6 [22] 85.1 [22] 41 [20] 121 [20] 160 [20] 79 9.7 [7] /380 [9] 80 920 [7] 81 ＞10000 [7] 82 ＞10000 [7] 83 1.14 [21] 84 258 [21] 85 1.58 [21] 86 373 [21] 87 4.15 [21] 88 1700 [21] 89 28000 [9] 90 450 [9] 91 2100 [9] 92 1700 [9] 93 80 [9] 94 350 [9] 95 30 [9] 3...…”