The antiplasmodial activity of norcantharidin analogs

被引：23

作者：

Bajsa, Joanna ^{[1
]}

McCluskey, Adam ^{[2
]}

Gordon, Christopher P. ^{[2
]}

Stewart, Scott G. ^{[2
]}

Hill, Timothy A. ^{[2
]}

Sahu, Rajnish ^{[3
]}

Duke, Stephen O. ^{[1
]}

Tekwani, Babu L. ^{[3
]}

机构：

[1] ARS, USDA, Nat Prod Utilizat Res Unit, University, MS 38677 USA

[2] Univ Newcastle, Sch Environm & Life Sci, Callaghan, NSW 2308, Australia

[3] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 22期

关键词：

Plasmodium falciparum; Antimalarial drugs; Cantharidin; Protein phosphatase inhibitors; PROTEIN PHOSPHATASE 2A; ANTICANCER ACTIVITY; CANTHARIDIN ANALOGS; INHIBITION; CELL; MALARIA; PP2A; REGULATOR; APOPTOSIS; FAMILY;

D O I：

10.1016/j.bmcl.2010.09.004

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The antiplasmodial activities of sixty norcantharidin analogs were tested in vitro against a chloroquine sensitive (D6, Sierra Leone) and chloroquine resistant (W2) strains of Plasmodium falciparum. Forty analogs returned IC(50) values <500 mu M against at least one of the P. falciparum strains examined. The ring open compound 24 ((1S,4R)-3-(allylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid) is the most active aliphatic analog (D6 IC(50) = 3.0 +/- 0.0 and W2 IC(50) = 3.0 +/- 0.8 mu M) with a 20-fold enhancement relative to norcantharidin. Surprisingly, seven norcantharimides also displayed good antiplasmodial activity with the most potent, 5 returning D6 = 8.9 +/- 0.9 and W2 IC(50) = 12.5 +/- 2.2 mu M, representing a fivefold enhancement over norcantharidin. (C) 2010 Published by Elsevier Ltd.

引用

页码：6688 / 6695

页数：8

共 29 条

[1] Inhibition of serine/threonine-specific protein phosphatases causes premature activation of cdc2MsF kinase at G2/M transition and early mitotic microtubule organisation in alfalfa [J].

Ayaydin, F ;

Vissi, E ;

Mészáros, T ;

Miskolczi, P ;

Kovács, I ;

Fehér, A ;

Dombrádi, V ;

Erdödi, F ;

Gergely, P ;

Dudits, D .

PLANT JOURNAL, 2000, 23 (01) :85-96

[2] A survey of synthetic and natural phytotoxic compounds and phytoalexins as potential antimalarial compounds [J].

Bajsa, Joanna ;

Singh, Kshipra ;

Nanayakkara, Dharnmika ;

Duke, Stephen Oscar ;

Rimando, Agnes Marnaril ;

Evidente, Antonio ;

Tekwani, Babu Lal .

BIOLOGICAL & PHARMACEUTICAL BULLETIN, 2007, 30 (09) :1740-1744

[3] Plasmodium falciparum Serine/Threonine Phoshoprotein Phosphatases (PPP): From Housekeeper to the 'Holy Grail' [J].

Bajsa, Joanna ;

Duke, Stephen O. ;

Tekwani, Babu L. .

CURRENT DRUG TARGETS, 2008, 9 (11) :997-1012

[4] Structural Basis of Serine/Threonine Phosphatase Inhibition by the Archetypal Small Molecules Cantharidin and Norcantharidin [J].

Bertini, I. ;

Calderone, V. ;

Fragai, M. ;

Luchinat, C. ;

Talluri, E. .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (15) :4838-4843

[5] Protein phosphatase 1, a Plasmodium falciparum essential enzyme, is exported to the host cell and implicated in the release of infectious merozoites [J].

Blisnick, T ;

Vincensini, L ;

Fall, G ;

Braun-Breton, C .

CELLULAR MICROBIOLOGY, 2006, 8 (04) :591-601

[6] A Maurer's cleft-associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells [J].

Cooke, BM ;

Buckingham, DW ;

Glenister, FK ;

Fernandez, KM ;

Bannister, LH ;

Marti, M ;

Mohandas, N ;

Coppel, RL .

JOURNAL OF CELL BIOLOGY, 2006, 172 (06) :899-908

[7] Antimalarial drug discovery: Efficacy models for compound screening [J].

Fidock, DA ;

Rosenthal, PJ ;

Croft, SL ;

Brun, R ;

Nwaka, S .

NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (06) :509-520

[8] A molecular modeling analysis of the binding interactions between the okadaic acid class of natural product inhibitors and the Ser-Thr phosphatases, PP1 and PP2A [J].

Gauss, CM ;

Sheppeck, JE ;

Nairn, AC ;

Chamberlin, R .

BIOORGANIC & MEDICINAL CHEMISTRY, 1997, 5 (09) :1751-1773

[9] Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Cα [J].

Gotz, J ;

Probst, A ;

Ehler, E ;

Hemmings, B ;

Kues, W .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12370-12375

[10] Modified norcantharidins: synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity [J].

Hart, ME ;

Chamberlin, AR ;

Walkom, C ;

Sakoff, JA ;

McCluskey, A .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (08) :1969-1973

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