Total Synthesis of the Cyclodepsipeptide Apratoxin A and Its Analogues and Assessment of Their Biological Activities

Abstract

A novel total synthesis of apratoxin A is described, with key steps including the assembly of its ketide segment through a D-proline-catalyzed direct aldol reaction and Oppolzer's anti aldol reaction and the preparation of its thiazoline unit in a biomimetic synthesis. An oxazoline analogue of apratoxin A has also been elaborated by a similar approach. This compound has a potency against HeLa cell proliferation only slightly lower than that of apratoxin A, whilst a C(40)-demethylated oxazoline analogue of apratoxin A displays a much lower cytotoxicity and the C(37)-epimer and C(37) demethylation product of this new analogue are inactive. These results suggest that the two methyl groups at C(37) and C(40) and the stereochemistry at C(37) are essential for the potent cellular activity of the oxazoline analogue of apratoxin A. Further biological analysis revealed that both synthetic apratoxin A and its oxazoline analogue inhibited cell proliferation by causing cell cycle arrest in the G1 phase.

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

“…Wipf and Uto elegantly demonstrated that the oxazoline moiety was ringopened to the corresponding thioamide on a cyclic peptide by treatment with H 2 S, and then dehydrative cyclization using N,N-dimethylaminosulfur trifluoride (DAST) led to the total synthesis of the thiazoline-containing cyclic peptide trunkamide A. 13) We initially synthesized the oxazoline analogue of apratoxin A (16) 7,14,15) and attempted to convert the oxazoline moiety to a thiazoline ring. triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIEA)), gave undesired azlactone 10 in 49% yield, along with the desired tetrapeptide 9 in only 21% yield.…”

“…The oxazoline analogue of apratoxin A (16) was also so potent that the thiazoline ring could be replaced by an oxazoline ring, as also reported by Ma's group. 15) Protection of the hydroxy group with a TES group, or removal of all substituents from the hydroxy acid moiety, led to a loss of cytotoxicity. Azido-containing analogues 41-45 exhibited potent cytotoxicity.…”

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...…”

Synthesis of Macrocyclic Lactams and Lactones Containing Sulfur and Nitrogen

“…[78] и обладающие цитотоксичностью in vitro против различных опухолевых клеток человека и животных. [79] В литературе [30,[80][81][82] представлены синтезы только апратоксина А (152), один из которых [81] основан на макролактамизации ациклического предшественника 153, доступного при сочетании двух блок-синтонов 154 и 155 (Cхема 39).…”

“…Соединение 154 представляет из себя тетрапептид, полученный инициируемым с помощью гексафторфосфата (7-азабензотриазол-1-илокси)трипир-ролидинфосфония (PyAOP) сочетанием производных изолейцина (156), аланина (157), тирозина (158) и цистеина (159) [82] (Cхема 40). Синтон 155 получен из оптически активного непредельного спирта 160 -продукта асимметрической конденсации изокамфеилаллилборана с трет-амиловым альдегидом по Брауну.…”