Homophymines B–E and A1–E1, a family of bioactive cyclodepsipeptides from the sponge Homophymia sp.

Zampella, Angela; Sepe, Valentina; Bellotta, Filomena; Luciano, Paolo; D’Auria, Maria Valeria; Cresteil, Thierry; Debitus, Cécile; Petek, Sylvain; Poupat, C.; Ahond, A.

doi:10.1039/b910015f

Cited by 53 publications

(54 citation statements)

References 33 publications

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“…This b-branched framework, which characterizes all the members of this new class of non-ribosomal cyclodepsipeptides 5 , comprises the following: a 22-or a 25-membered macrolactone; the presence of complex and rare amino acids; a branching position occupied by a D-allo-b-hydroxy-a-amino acid acylated by the unique (2S,3S,4R)-3,4-dimethylglutamine (diMeGln) residue; and an N-terminus coupled to a saturated or unsaturated b-hydroxy acid. Examples of members of this family include callipeltin A 6 , papuamides 7,8 , neamphamides [9][10][11] , theopapuamides 12,13 , mirabamides 14,15 and homophymines 16,17 . Of note, all of them show relevant therapeutic profiles, mostly including potent cytotoxic and anti-HIV activities.…”

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confidence: 99%

The first total synthesis of the cyclodepsipeptide pipecolidepsin A

et al. 2013

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Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered g-branched b-hydroxy-a-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid. Here we describe the first total synthesis of a D-allo-AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner.

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The first total synthesis of the cyclodepsipeptide pipecolidepsin A

et al. 2013

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“…Two new saponins from Parthenium hysterophorus were found to be potent TNF-inhibitors (Shah et al, 2009). The successful isolation and structure determination of new cyclodepsipeptides has been reported (Zampella et al, 2009). These compounds, named homophymine B-E and A1-E1, were shown to exhibit potent anti-proliferative effects against several human cancer cell lines.…”

Section: Natural Products -Isolation Synthesis and Biosynthesismentioning

confidence: 99%

Chemical Biology: What is Its Role in Drug Discovery?

Pirrie¹,

Westwood²

2011

Drug Discovery and Development - Present and Future

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“…Chart 4. Synthesis of (2R,3R,4R)-2-Amino-3-hydroxy-4,5-dimethylhexanoic Acid (2) prepared from [RuCl 2 (C 6 H 6 )] 2 (48 mg, 0.096 mmol) and (R)-BINAP (121 mg, 0.195 mmol) according to the literature procedure.…”

Section: (R)-45-dimethyl-3-oxo-hexanoic Acid Methyl Ester (9)mentioning

confidence: 99%

“…Homophymine A (1) is known to exhibit cytoprotective activity against human immunodeficiency virus-1 (HIV-1) infection and moderate cytotoxicity. As part of the study on synthesizing bioactive cyclodepsipeptides of marine origin, [4][5][6][7][8] we focused on homophymine A, which contains (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid 9) and novel amino acid residues: (2S,3S,4R)-3,4-dimethylglutamine, 10,11) (2R,3R,4S)-4-amino-2,3-dihydroxy-1,7-heptandioic acid, and (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (2). In earlier studies, we demonstrated that the asymmetric hydrogenation of α-amino-β-keto esters using chiral catalysts anti-selectively proceeds to afford anti β-hydroxy-α-amino acids in a high diastereo-and enantioselective manner.…”

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Efficient Diastereoselective Synthesis of (2R,3R,4R)-2-Amino-3-hydroxy-4,5-dimethylhexanoic Acid, the Lactone Linkage Unit of Homophymine A

Ohtaka

Hamajima

Nemoto

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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For the total synthesis of novel cyclodepsipeptide homophymine A, (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid was successfully synthesized by Evans' asymmetric alkylation and the anti-selective asymmetric hydrogenation of a chiral α-amino-β-keto ester as the key steps.Key words homophymine A; β-hydroxy-α-amino acid; anti-selective asymmetric hydrogenation; Evans' asymmetric alkylation Homophymines (A-E and A1-E1), isolated from the New Caledonian sponge Homophymia species, are a new family of novel dimethylglutamine-containing cyclodepsipeptides with interesting biological activities 1-3) ( Fig. 1). Homophymine A (1) is known to exhibit cytoprotective activity against human immunodeficiency virus-1 (HIV-1) infection and moderate cytotoxicity. As part of the study on synthesizing bioactive cyclodepsipeptides of marine origin, 4-8) we focused on homophymine A, which contains (2R,3R,4R,6R)-3-hydroxy-2,4,6-trimethyloctanoic acid 9) and novel amino acid residues: (2S,3S,4R)-3,4-dimethylglutamine, 10,11) (2R,3R,4S)-4-amino-2,3-dihydroxy-1,7-heptandioic acid, and (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (2). In earlier studies, we demonstrated that the asymmetric hydrogenation of α-amino-β-keto esters using chiral catalysts anti-selectively proceeds to afford anti β-hydroxy-α-amino acids in a high diastereo-and enantioselective manner. [12][13][14][15][16][17][18][19][20] Following is an example of an efficient diastereoselective hydrogenation of a chiral substrate under the conditions of our developed antiselective asymmetric hydrogenation, which provides an efficient synthesis of (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA, 2). Our synthesis is outlined by a retrosynthetic analysis in Chart 1.Our synthesis commenced with the straightforward synthesis of (R)-2,3-dimethylbutanoic acid (4) (Chart 2). According to Evans' procedure, the oxazolidinones (6a, 6b) were treated with n-butyl lithium at −78°C and the resulting lithium salts were acylated with isovaleryl chloride to give imides 7a and 7b in 98% and 75% yield, respectively. The imides 7a and 7b were treated with lithium diisopropylamide in tetrahydrofuran (THF) at −78°C followed by methylation of the resulting enolates with iodomethane to afford the methylated products 8a and 8b in 80% and 45% yield, respectively. In this asymmetric methylation, 7b was inferior to 7a in the diastereoselectivity. Although crude 8a was a 93 : 7 mixture of diastereomers, the recrystallization of the crude material from n-hexane provided pure 8a in diastereomeric purity and in 80% yield. The cleavage of the chiral auxiliary was accomplished by the treatment with alkaline hydrogen peroxide in aqueous THF.In the next β-keto ester formation, it was found that the acid chloride derived from 4 was volatile. To prevent the loss of valuable 4, we first attempted the modified procedure through the corresponding imidazolide of 4 ( Table 1). The reaction of methyl tert-butoxycarbonylaminomalonate half ester (11) 21) with the imidazolide failed to give...

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Homophymines B–E and A1–E1, a family of bioactive cyclodepsipeptides from the sponge Homophymia sp.

Cited by 53 publications

References 33 publications

The first total synthesis of the cyclodepsipeptide pipecolidepsin A

The first total synthesis of the cyclodepsipeptide pipecolidepsin A

Chemical Biology: What is Its Role in Drug Discovery?

Efficient Diastereoselective Synthesis of (2<i>R</i>,3<i>R</i>,4<i>R</i>)-2-Amino-3-hydroxy-4,5-dimethylhexanoic Acid, the Lactone Linkage Unit of Homophymine A

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