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

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

7 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
Externally published	Yes

Keywords

Antimalarial agents
Falcitidin
Natural products
Tetrapeptide
Trifluoromethyl

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1016/j.tetlet.2014.02.008

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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",

volume = "55",

pages = "1949--1951",

journal = "Tetrahedron Letters",

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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

M3 - Article

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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