Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

Santosh R. Kotturi; Brinda Somanadhan; Jun Hong Ch'Ng; Kevin S.W. Tan; Mark S. Butler; Martin J. Lear

doi:10.1016/j.tetlet.2014.02.008

Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

Santosh R. Kotturi, Brinda Somanadhan, Jun Hong Ch'Ng, Kevin S.W. Tan, Mark S. Butler, Martin J. Lear

SCI - Chemistry

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH₂). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF₃) analogue displaying sub-micromolar IC₅₀ activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.

Original language	English
Pages (from-to)	1949-1951
Number of pages	3
Journal	Tetrahedron Letters
Volume	55
Issue number	11
DOIs	https://doi.org/10.1016/j.tetlet.2014.02.008
Publication status	Published - 2014 Mar 12

Keywords

Antimalarial agents
Falcitidin
Natural products
Tetrapeptide
Trifluoromethyl

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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title = "Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads",

abstract = "We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH2). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF3) analogue displaying sub-micromolar IC50 activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.",

keywords = "Antimalarial agents, Falcitidin, Natural products, Tetrapeptide, Trifluoromethyl",

author = "Kotturi, {Santosh R.} and Brinda Somanadhan and Ch'Ng, {Jun Hong} and Tan, {Kevin S.W.} and Butler, {Mark S.} and Lear, {Martin J.}",

note = "Funding Information: We thank the Ministry of Education of Singapore for initial funding (AcRF Tier-2 Grant T206B1112 ) and a Ph.D. graduate scholarship (to S.R.K.). We appreciate the help of Alvin Choong for initial antimalarial tests. Latterly, this work was supported by the National Medical Research Council (NMRC/1310/2011) of Singapore (to K.S.W.T., J.H.C. and M.J.L.). ",

year = "2014",

month = mar,

day = "12",

doi = "10.1016/j.tetlet.2014.02.008",

language = "English",

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T1 - Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

AU - Kotturi, Santosh R.

AU - Somanadhan, Brinda

AU - Ch'Ng, Jun Hong

AU - Tan, Kevin S.W.

AU - Butler, Mark S.

AU - Lear, Martin J.

N1 - Funding Information: We thank the Ministry of Education of Singapore for initial funding (AcRF Tier-2 Grant T206B1112 ) and a Ph.D. graduate scholarship (to S.R.K.). We appreciate the help of Alvin Choong for initial antimalarial tests. Latterly, this work was supported by the National Medical Research Council (NMRC/1310/2011) of Singapore (to K.S.W.T., J.H.C. and M.J.L.).

PY - 2014/3/12

Y1 - 2014/3/12

N2 - We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH2). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF3) analogue displaying sub-micromolar IC50 activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.

AB - We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH2). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF3) analogue displaying sub-micromolar IC50 activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.

KW - Antimalarial agents

KW - Falcitidin

KW - Natural products

KW - Tetrapeptide

KW - Trifluoromethyl

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DO - 10.1016/j.tetlet.2014.02.008

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AN - SCOPUS:84896726227

VL - 55

SP - 1949

EP - 1951

JO - Tetrahedron Letters

JF - Tetrahedron Letters

SN - 0040-4039

IS - 11

ER -

Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

Abstract

Keywords

ASJC Scopus subject areas

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