Lepadins D−F:  Antiplasmodial and Antitrypanosomal Decahydroquinoline Derivatives from the Tropical Marine Tunicate Didemnum sp.

Abstract

From a new tunicate species, belonging to the genus Didemnum, three alkaloids possessing an unusual and extremely rare decahydroquinoline skeleton and showing significant and selective antiplasmodial and antitrypanosomal activity were obtained as follows: (2R*,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methylquinoline (lepadin D,1), its quaternary nitrogen derivative (2), (2R*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin E, 3), and (2S*,2"E,3S*,4aR*,5R*,8aS*)-decahydro-3-hydroxy-5-(5'-hydroxyoctyl)-2-methyl-3-quinolinyl ester 2"-octenoic acid (lepadin F, 4). These isolates may well serve as lead structures for the development of new antimalarial drugs.

Stereocontrolled construction of decahydro quinoline ring systems: the case of lepadin alkaloids (Review)

“…The structurally related but biologically different lepadins 1-8 (Fig. 1) are on the other hand marine alkaloids isolated from three distinct ascidians: Clavelina lepadiformis (found in the North Sea), Didemnum, and Aplidium tabascum (both found in the Great Barrier Reef) [2][3][4][5]. The third group consists of more complex polycyclic alkaloids that besides the DHQ ring system, can contain several other heterocyclic ring systems fused into one molecule.…”

Stereoselective synthesis of (−)-lepadins A–C

“…2 and ascidian Aplidium tabascum. 3 Structurally, all of them incorporate a methyl substituent at the C-2 position of the decahydroquinoline nucleus, a functionalized eight-carbon chain at C-5, and a free or acylated hydroxy group at C-3.…”

“…4 Lepadins D-F have low cytotoxicity but significant and selective 25 antiplasmodial and antitrypanosomal activity. 2 Further pharmacological research on these alkaloids has been hampered by the low quantities of samples available from natural sources. This has stimulated considerable synthetic effort in this area, 5 although the development of facile enantioselective routes to 30 lepadins or synthetic analogs is still required.…”

“…However, the trimethylsilylethyl (TMSE) protecting group had to be replaced by TIPS to avoid its oxidation to trimethylsilylacetyl during the ruthenium-mediated oxidation 40 step. 13 Thus, LiAlH 4 /AlCl 3 reduction of 8, followed by BF 3 ·Et 2 O-promoted deprotection and hydrogenolysis of the benzylic C-N bond in the presence of (Boc) 2 O gave cisdecahydroquinoline 9. After reprotection of the hydroxyl group as a TIPS derivative, the ruthenium oxidation step took place in 45 nearly quantitative yield to give lactam 10, which was efficiently converted to enecarbamate 11 via a triflate, and then to alcohol 12 by stereoselective hydroboration-oxidation.…”

Total Synthesis of Lepadins B, D, E, and H; Determination of the Configuration of the Latter Three Alkaloids

“…[2] These compounds have been found to possess significant in vitro cytotoxicity against several human cancer cell lines. [2] Very recently, Wright et al reported the isolation of lepadins D-F from a new Didemnum species collected from the Great Barrier Reef, [3] whereas Carroll and co-workers described their discovery of lepadins F-H in Aplidium tabascum Kott. [4] Interestingly, lepadins D-F showed low cytotoxicity but significant and selective antiplasmodinium and antitrypanosomal activity and therefore may serve as lead structures for the development of novel antimalarial drugs.…”